gastrins and Stomach-Neoplasms

Studies on the regulation of gastric acid secretion started more than 100 years ago at an early phase of experimental physiology. In nearly the whole last century there were disputes about the interpretation of the findings: the interaction between the three principle gastric acid secretagogues acetylcholine, gastrin and histamine, the cell producing the relevant histamine which turned out to be the ECL cell, the ability of the ECL cell to divide and thus develop into tumours, the classification of gastric carcinomas and the mechanism for Helicobacter pylori carcinogenesis. The elucidation of the central role of the ECL cell and thus its main regulator, gastrin, solve all these controversies, and gives a solid base for handling upper gastrointestinal diseases.

Topics: Animals; Carcinogenesis; Enterochromaffin-like Cells; Gastric Acid; Gastric Mucosa; Gastrins; Helicobacter pylori; Humans; Stomach Neoplasms

Gastric cancer, a disease with a reduced frequency for decades, now appears to be on the rise again in young Americans. The epidemiology of gastric cancer differs between tumors in the cardia and those of the more distal parts of the stomach. The tumors are divided into the intestinal type showing glandular growth pattern and the diffuse type with a different pattern. The latter often expresses neuroendocrine and more specifically ECL-cell markers suggesting that they originate from the ECL cell, the target cell for the antral hormone, gastrin. Helicobacter pylori gastritis is accepted as the major cause of gastric cancer, but only after having induced oxyntic atrophy which reduces gastric acid secretion and thus induces hypoacidity leading to hypergastrinemia. Long-term hypergastrinemia is known to induce malignant neoplasia in the stomach of animals as well as man. Recently treatment with proton pump inhibitor after Helicobacter pylori eradication in patients with gastroesophageal reflux disease, has been reported to predispose to gastric cancer. Since profound acid inhibition is a well-known cause of gastric neoplasia, it is to be expected that Helicobacter pylori infection and profound acid inhibition has an additive or possibly potentiating effect on the development of gastric cancer.

Topics: Animals; Enterochromaffin-like Cells; Gastrins; Gastritis; Gastroesophageal Reflux; Helicobacter Infections; Helicobacter pylori; Humans; Proton Pump Inhibitors; Stomach Neoplasms

Proton pump inhibitors (PPIs) are recommended as a first-line treatment for gastroesophageal reflux disease (GERD) and other acid related disorders. In recent years, concerns have been raised about the increasing prevalence of patients on long-term PPI therapy and inappropriate PPI use. It is well known that short-term PPI therapy is generally well tolerated and safe; however, their extensive long-term use is a major global issue. One of these long-standing concerns is PPI-induced gastrin elevation secondary to hypoacidity. Hypergastrinemia is believed to play a role in rebound hyperacidity when PPIs are discontinued resulting in induced dyspeptic symptoms that might result in the reinstitution of therapy. Gastrin exerts tropic effects in the stomach, especially on enterochromaffin-like (ECL) cells, and concerns have also been raised regarding the potential progression to dysplasia or tumor formation following long-term therapy. It is well known that a substantial number of patients on long-term PPI therapy can discontinue PPIs without recurrence of symptoms in deprescribing trials. What is unknown is how sustainable deprescribing should be undertaken in practice and how effective it is in terms of reducing long-term outcomes like adverse drug events, morbidity and mortality. Moreover, there is no clear consensus on when and how deprescribing strategies should be attempted in practice. This review sought to summarize the harms and benefits of long-term PPI therapy with special focus on gastrin elevation and its relation to deprescribing studies and future interventions that may improve PPI use.

Topics: Deprescriptions; Enterochromaffin Cells; Gastrins; Gastroesophageal Reflux; Humans; Proton Pump Inhibitors; Risk Factors; Stomach; Stomach Neoplasms; Withholding Treatment

The diagnosis of gastric neuroendocrine tumors (NETs) is being made with increased frequency likely as a result of more upper endoscopies being done for unrelated reasons. It is therefore vital that gastroenterologists become familiar with the basic work-up and management of patients found to have these tumors. This review describes the classification, pathophysiology, clinical characteristics, and treatment options of the different gastric NETs.. In addition to the three traditional subtypes of gastric NETs, additional cases associated with achlorhydria and appropriate hypergastrinemia may exist. The management of gastric NETs between 1 and 2 cm in size remains controversial and needs to be individualized. Gastric NETs are uncommon but are now diagnosed more frequently. This review highlights the role of hypergastrinemia in their development and the controversies around their management.

Topics: Gastrins; Gastroscopy; Humans; Neuroendocrine Tumors; Prognosis; Stomach Neoplasms

Gastrin acts physiologically as a gut hormone to stimulate acid secretion after meal and as a cell-growth factor of oxyntic mucosa. Increase in serum gastrin level happens under various conditions including Zollinger-Ellison syndrome, antral G cell hyperplasia, autoimmune gastritis, atrophic gastritis, renal failure, vagotomy, Helicobacter pylori infection and acid suppressive therapy. As acid suppressive therapy causes hypergastrinemia, the association between acid suppressive therapy and gastric neuroendocrine cell tumor (NET) has been discussed during the past 30 years. In this review article, the definition of hypergastrinemia and the related disorders including acid suppressive therapy and gastric NET are discussed.

Topics: Carcinogenesis; Gastric Acid; Gastric Mucosa; Gastrins; Gastritis; Helicobacter Infections; Helicobacter pylori; Humans; Neuroendocrine Tumors; Proton Pump Inhibitors; Stomach Neoplasms

Gastric cancer has reduced prevalence, but poor prognoses. To improve treatment, better knowledge of carcinogenesis and cells of origin should be sought. Stomach cancers are typically localized to one of the three mucosae; cardial, oxyntic and antral. Moreover, not only the stem cell, but the ECL cell may proliferate and give rise to tumours. According to Laurén, the classification of gastric carcinomas seems to reflect biological important differences and possible different cell of origin since the two subtypes, intestinal and diffuse, do not transform into the other and show different epidemiology. The stem cell probably gives rise to the intestinal type, whereas the ECL cell may be important in the diffuse type. Elevation of gastrin may be the carcinogenic factor for

Topics: Carcinogenesis; Carcinoma; Cell Proliferation; Gastric Mucosa; Gastrins; Helicobacter Infections; Helicobacter pylori; Humans; Stomach Neoplasms

Neuroendocrine tumors (NETs) were initially identified as a separate entity in the early 1900s as a unique malignancy that secretes bioactive amines. GI-NETs are the most frequent type and represent a unique subset of NETs, because at least 75% of these tumors represent gastrin stimulation of the enterochromaffin-like cell located in the body of the stomach. The purpose of this review is to understand the specific role of gastrin in the generation of Gastric NETs (G-NETs).. We review here the origin of enterochromaffin cells gut and the role of hypergastrinemia in gastric enteroendocrine tumorigenesis. We describe generation of the first genetically engineered mouse model of gastrin-driven G-NETs that mimics the human phenotype. The common mechanism observed in both the hypergastrinemic mouse model and human carcinoids is translocation of the cyclin-dependent inhibitor p27

Topics: Animals; Carcinoid Tumor; Cyclin-Dependent Kinase Inhibitor p27; Cytoplasm; Disease Models, Animal; Enterochromaffin-like Cells; Gastrins; Humans; Mice; Neuroendocrine Tumors; Phenotype; Receptor, Cholecystokinin B; Stomach Neoplasms

The combination of pepsinogen, gastrin-17 and anti-H. pylori antibodies serological assays (panel test) is a non-invasive tool for the diagnosis of atrophic gastritis. However, the diagnostic reliability of this test is still uncertain.. To assess the diagnostic performance of the serum panel test for the diagnosis of atrophic gastritis.. Medline via PubMed, Embase, Scopus, Cochrane Library databases and abstracts of international conferences proceedings were searched from January 1995 to December 2016 using the primary keywords "pepsinogens," "gastrin," "atrophic gastritis," "gastric precancerous lesions." Studies were included if they assessed the accuracy of the serum panel test for the diagnosis of atrophic gastritis using histology according to the updated Sydney System as reference standard.. Twenty studies with a total of 4241 subjects assessed the performance of serum panel test for the diagnosis of atrophic gastritis regardless of the site in the stomach. The summary sensitivity was 74.7% (95% confidence interval (CI), 62.0-84.3) and the specificity was 95.6% (95%CI, 92.6-97.4). With a prevalence of atrophic gastritis of 27% (median prevalence across the studies), the negative predictive value was 91%. Few studies with small sample size assessed the performance of the test in detecting the site of atrophic gastritis.. The combination of pepsinogen, gastrin-17 and anti-H. pylori antibodies serological assays appears to be a reliable tool for the diagnosis of atrophic gastritis. This test may be used for screening subjects or populations at high risk of gastric cancer for atrophic gastritis; however, a cost-effectiveness analysis is needed.

Topics: Cost-Benefit Analysis; Gastrins; Gastritis, Atrophic; Helicobacter Infections; Helicobacter pylori; Hematologic Tests; Humans; Pepsinogen A; Prevalence; Reproducibility of Results; Sensitivity and Specificity; Stomach Neoplasms

Despite being an overall safe drug, several long-term adverse effects are associated with proton pump inhibitors (PPIs). The link between PPI use and gastric neuroendocrine tumors (NETs), gastric adenocarcinomas and Barrett's esophagus progression gastric cancers has been investigated due to PPI-induced hypergastrinemia.. The pathophysiological mechanisms underlying PPI exposure and gastric NETs, gastric adenocarcinomas and Barrett's esophagus progression are discussed. The quality of randomized control studies, cohort studies and case reports investigating the link between gastric cancers and PPIs are examined. Recommendations for clinicians are provided.. PPIs cause a hypergastrinemic state, increasing enterochromaffin-like cell dysplasia and risk of gastric NET development, increasing gastritis severity in the context of Helicobacter pylori infection, and progression of carcinogenesis in a certain predisposed subset of Barrett's esophagus patients. There are case reports of PPI-induced gastric NETs and adenocarcinomas as consequences of these effects. In pernicious anemia and chronic gastritis, clinicians should be aware of potential increased risk of gastric NET development with chronic PPI use in these patients. Eradication status of H. pylori prior to commencing long-term PPI therapy should be established to reduce the risk of severe atrophic gastritis and development of gastric dysplasia.

Topics: Adenocarcinoma; Animals; Barrett Esophagus; Disease Progression; Gastrins; Helicobacter Infections; Helicobacter pylori; Humans; Neuroendocrine Tumors; Proton Pump Inhibitors; Stomach Neoplasms

Gastric cancer is the third leading cause of cancer-related mortality worldwide. This is in part due to the asymptomatic nature of the disease, which often results in late-stage diagnosis, at which point there are limited treatment options. Even when treated successfully, gastric cancer patients have a high risk of tumor recurrence and acquired drug resistance. It is vital to gain a better understanding of the molecular mechanisms underlying gastric cancer pathogenesis to facilitate the design of new-targeted therapies that may improve patient survival. A number of chemically and genetically engineered mouse models of gastric cancer have provided significant insight into the contribution of genetic and environmental factors to disease onset and progression. This review outlines the strengths and limitations of current mouse models of gastric cancer and their relevance to the pre-clinical development of new therapeutics.

Topics: Animals; Disease Models, Animal; Gastrins; Helicobacter felis; Helicobacter Infections; Helicobacter pylori; Methylnitrosourea; Mice, Inbred Strains; Mice, Transgenic; Molecular Targeted Therapy; Stomach Neoplasms

Gastrin was initially identified as the hormone primarily responsible for gastric acid secretion, but was subsequently shown to be a growth factor for the proximal stomach, acting through the gastrin receptor CCK2R. Studies in the past several decades have explored the role of gastrin, along with its incompletely processed precursors, in cancer development. The growth in long-term PPI use has frequently led to elevations in serum gastrin levels in patients with upper GI disease, including GERD, peptic ulcers, and chronic gastritis. However, while accumulated evidence has shown that gastrin likely does not promote-and may even suppress-distal antral gastric cancer, questions have now arisen regarding possible effects of gastrin on the development of gastric cardia cancer or esophageal adenocarcinoma at gastroesophageal junction. Here, we provide an overview of the possible roles of these gastrin peptides in upper GI cancer.

Topics: Adenocarcinoma; Animals; Esophageal Neoplasms; Esophagogastric Junction; Gastrins; Gastrointestinal Diseases; Humans; Proton Pump Inhibitors; Stomach Neoplasms

Gastrin controls gastric acid secretion and mucosal cell growth, especially of enterochromaffin-like cells, via gastrin/cholecystokinin-2 receptor (CCK

Topics: Animals; Antineoplastic Agents; Benzodiazepinones; Disease Models, Animal; Drug Design; Gastric Acid; Gastrins; Humans; Neuroendocrine Tumors; Pancreatic Neoplasms; Phenylurea Compounds; Receptor, Cholecystokinin B; Stomach Neoplasms

Gastric cancer occurs almost exclusively in patients with gastritis. Since Helicobacter pylori (Hp) was proved to cause gastritis, Hp was also expected to play a role in gastric carcinogenesis. Despite extensive studies, the mechanisms by which Hp cause gastric cancer are still poorly understood. However, there is evidence that the anatomical site of Hp infection is of major importance. Infection confined to the antral mucosa protects against gastric cancer but predisposes to duodenal ulcer, whereas Hp infection of the oxyntic mucosa increases the risk of gastric cancer. Hp infection does not predispose to cancers in the gastric cardia. In patients with atrophic gastritis of the oxyntic mucosa, the intragastric pH is elevated and the concentration of microorganisms in the stomach is increased. This does not lead to increased risk of gastric cancer at all anatomical sites. The site specificity of Hp infection in relation to cancer risk indicates that neither Hp nor the changes in gastric microflora due to gastric hypoacidity are carcinogenic per se. However, reduced gastric acidity also leads to hypergastrinemia, which stimulates the function and proliferation of enterochromaffin-like (ECL) cells located in the oxyntic mucosa. The ECL cell may be more important in human gastric carcinogenesis than previously realized, as every condition causing long-term hypergastrinemia in animals results in the development of neoplasia in the oxyntic mucosa. Patients with hypergastrinemia will far more often develop carcinomas in the gastric corpus. In conclusion, hypergastrinemia may explain the carcinogenic effect of Hp.

Topics: Animals; Gastric Mucosa; Gastrins; Gastritis; Helicobacter Infections; Helicobacter pylori; Humans; Hydrogen-Ion Concentration; Risk; Stomach Neoplasms

Helicobacter pylori (H. pylori) have long been associated with a spectrum of disease outcomes in the gastro-duodenal system. Heterogeneity in bacterial virulence factors or strains is not enough to explain the divergent disease phenotypes manifested by the infection. This review focuses on host genetic factors that are involved during infection and eventually are thought to influence the disease phenotype. We have summarized the different host genes that have been investigated for association studies in H. pylori mediated duodenal ulcer or gastric cancer. We discuss that as the bacteria co-evolved with the host; these host gene also show much variation across different ethnic population. We illustrate the allelic distribution of interleukin-1B, across different population which is one of the most popular candidate gene studied with respect to H. pylori infections. Further, we highlight that several polymorphisms in the pathway gene can by itself or collectively affect the acid secretion pathway axis (gastrin: somatostatin) thereby resulting in a spectrum of disease phenotype.

Topics: Animals; Cell Transformation, Neoplastic; Duodenal Ulcer; Gastric Acid; Gastric Mucosa; Gastrins; Genetic Predisposition to Disease; Helicobacter Infections; Helicobacter pylori; Host-Pathogen Interactions; Humans; Interleukin-1beta; Molecular Mimicry; Phenotype; Polymorphism, Genetic; Risk Factors; Signal Transduction; Somatostatin; Stomach Neoplasms; Virulence

Gastrin is the main hormone stimulating gastric acid secretion, but it exerts proliferative and anti-apoptotic actions on various cancer cell types, in addition to its well-known trophic effect on enterochromaffin-like cells. As treatment with proton pump inhibitors (PPIs) increases the biosynthesis and secretion of gastrin, it has been postulated that treatment with PPIs could increase the risk of cancer, especially in Barrett's esophagus, gastric carcinoids, and colorectal cancer (CRC). Some tumors produce gastrin of their own, which can act in an autocrine manner to promote tumor growth. In addition, gastrin is known to foster the tumor microenvironment. However, in spite of these potentially increased cancer risks due to PPI-induced hypergastrinemia, prospective, large-scale cohort studies did not show an increase in CRC prevalence. The question as to why the long-term use of PPIs was not associated with an increased cancer risk of CRC might be answered by the fact that the PPIs antagonized the trophic effects of hypergastrinemia. Furthermore, the blockade of proton pumps or potassium channels in cancer cells could limit the abnormal glycolytic energy metabolism of cancer cells. Apart from their suppressive effect on gastric acids, PPIs exert an anti-tumor effect through the selective induction of apoptosis as well as an anti-inflammatory effect, and they protect cells from developing chemo- or radiotherapeutic resistance. Moreover, the anti-carcinogenic actions of PPIs were augmented with PPI-induced hypergastrinemia. Together with their potential targeted killing of cancer stem cells, these effects demonstrate their potential anti-cancer actions.

Topics: Animals; Antineoplastic Agents; Carcinogenesis; Gastrins; Humans; Proton Pump Inhibitors; Proton Pumps; Stomach Neoplasms

Proton pump inhibitors (PPIs) have a well-established safety profile. However, concerns have been raised about a potential relationship between PPI-induced hypergastrinaemia and the development of enterochromaffin-like (ECL) cell hyperplasia, neuroendocrine tumours and gastric cancer during long-term therapy.. To review the effects of long-term PPI use on serum gastrin levels and gastric histopathology.. A systematic literature search was conducted in PubMed on 21 April 2015 to identify studies reporting the effects of long-term (defined as >3 years) PPI use on gastrin levels and gastric histopathology.. A total of 16 studies (1920 patients) met the inclusion criteria. During long-term PPI therapy, mean gastrin levels rose to one to three times the upper limit of the normal range (~100 pg/mL), and an increased prevalence of ECL cell hyperplasia was observed (+7.8-52.0%). Helicobacter pylori-positive patients had a significantly increased risk of developing ECL linear/micronodular hyperplasia compared with H. pylori-negative patients [OR: 2.45 (95% CI: 1.47-4.10), P = 0.0006]; however, no evidence of neoplastic changes was found. The risk of corpus atrophy was markedly higher in H. pylori-positive patients than in H. pylori-negative patients [OR: 11.45 (95% CI: 6.25-20.99), P < 0.00001]. Not a single case of gastric adenocarcinoma was found.. Long-term PPI therapy induced moderate hypergastrinaemia in most patients and an increased prevalence of ECL cell hyperplasia. H. pylori-positive patients receiving long-term PPI therapy were exposed to a higher risk of corpus atrophy than H. pylori-negative patients. No neuroendocrine tumours or gastric cancers were found.

Topics: Drug Administration Schedule; Enterochromaffin-like Cells; Gastrins; Helicobacter Infections; Helicobacter pylori; Humans; Hyperplasia; Neuroendocrine Tumors; Proton Pump Inhibitors; Risk Factors; Stomach Neoplasms

The purpose of this review, based upon 40 years of research, is to clear old controversies. The gastric juice is a strong acid with active enzymes (pepsin and lipase); ideal for killing swallowed microorganisms. Totally isolated rat stomach and histamine determination. Human gastric carcinomas were examined for ECL cell differentiation because tumours found in rodents after dosing with inhibitors of acid secretion were reclassified to be of ECL cell origin. The gastrin receptor is localized to the ECL cell only, where gastrin stimulates the function and growth. Drug-induced hypo-acidity induces hypergastrinaemia and ECL cell hyperplasia responsible for rebound acid hypersecretion. Every condition with long-term hypergastrinaemia disposes to ECL cell neoplasia. In man, both atrophic gastritis and gastrinoma lead to ECL cell carcinoids. Proton pump inhibitors induce hypergastrinaemia with ECL cell hyperplasia and ECL cell carcinoids that disappear when stopping treatment. The gastrin antagonist netazepide induces regression of ECL cell carcinoids due to atrophic gastritis. Human gastric carcinomas of diffuse type, particularly the signet-ring subtype, show ECL cell differentiation, suggesting involvement of gastrin in the carcinogenesis. Helicobacter pylori (Hp) causes gastritis and peptic ulcer, and when infecting the antrum only gives a slight hypergastrinaemia with acid hypersecretion predisposing to duodenal ulcer, but protecting from gastric cancer. When Hp infection spreads to oxyntic mucosa, it induces atrophy, reduced acid secretion and marked hypergastrinaemia and cancer.It is remarkable that the interaction between Hp and gastrin may explain the pathogenesis of most diseases in the upper gastrointestinal tract.

Topics: Animals; Gastric Acid; Gastrins; Humans; Stomach Neoplasms

Gastrin has been identified as the principal effector of gastric secretion, but several studies have demonstrated its role as a biomarker of cancer risk and as a growth factor for colorectal, stomach, liver, and pancreatic cancer. Hypergastrinemia characterizes autoimmune gastritis, with body and fundic gland atrophy and increased risk for both gastric adenocarcinoma and neuroendocrine tumors. Gastric type I carcinoids develop in the context of autoimmune gastritis because of the stimulus exerted by gastrin on enterochromaffin-like cells and remain gastrin-sensitive for long durations because the removal of hypergastrinemia leads to tumor regression. The treatment of gastric carcinoid is still open to debate, but when the disease frequently relapses, or is multicentric or infiltrating, surgery is advocated or, in the alternative, a costly and long-lasting treatment with long-acting somatostatin analogues is prescribed. A technology allowing the preparation of an immunogen eliciting an immune system response with generation of antibodies against G17 has been developed. This vaccine has been tested in patients with colorectal, pancreatic or advanced gastric cancer. The vaccine has also been used in the treatment of gastric type I carcinoids, and the administration of G17DT in patients harboring these lesions leads to carcinoid regression. Antigastrin vaccination in the treatment of gastrointestinal cancer obviously needs validation, but this immunotherapy may well represent a simple, inexpensive, and active 'adjuvant' treatment.

Topics: Adenocarcinoma; Autoimmune Diseases; Cancer Vaccines; Carcinoid Tumor; Colorectal Neoplasms; Gastrins; Gastritis; Humans; Liver Neoplasms; Pancreatic Neoplasms; Stomach Neoplasms

Gastric carcinoids (GCs) or neuroendocrine tumours (NETs) are increasingly identified at endoscopy, and account for 0.6-2% of all gastric polyps identified. The SEER database in the US has demonstrated a rising incidence of gastric NETs amongst all NETs; from 2.2% between 1950 and 1969 to 6.0% between 2000 and 2007.. To review the literature and assist clinicians in managing patients with GCs.. A literature search was conducted through MEDLINE using search terms: gastric, carcinoid, neuroendocrine tumour, therapy, endoscopy, mucosal resection, submucosal dissection. Relevant articles were identified through manual review. The reference lists of these articles were reviewed to include further appropriate articles.. There are three types of GCs with important epidemiological, pathophysiological, histological and endoscopic differences that affect prognosis and management. Type 1 and 2 GCs develop in the context of hypergastrinaemia that originates from achlorhydria in atrophic gastritis and a gastrinoma, respectively. Type 3 GCs occur sporadically and independent of gastrin. The histological type, grade and Ki67 index are used to determine prognosis and direct clinical management. Type 1 GCs >1 cm in size and type 2 GCs should be assessed for invasion beyond the submucosa with EUS prior to endoscopic resection with EMR or ESD. Type 3 GCs should be managed as per recommendations for gastric adenocarcinoma. The treatment of advanced disease is multimodal.. Patients with gastric carcinoids should be discussed in a specialist neuroendocrine tumour multidisciplinary meeting to ensure all treatment options are explored in localised and advanced disease. Areas of controversy exist that need further research.

Topics: Dissection; Endoscopy; Gastrins; Gastritis, Atrophic; Humans; Neuroendocrine Tumors; Polyps; Prognosis; Stomach Neoplasms

The existence of the hormone gastrin in the distal stomach (antrum) has been known for almost 110 years, and the physiological function of this amidated peptide in regulating gastric acid secretion via the CCK2 receptor is now well established. In this brief review we consider important additional roles of gastrin, including regulation of genes encoding proteins such as plasminogen activator inhibitors and matrix metalloproteinases that have important actions on extracellular matrix remodelling. These actions are, at least in part, effected by paracrine signalling pathways and make important contributions to maintaining functional integrity of the gastric epithelium. Recent studies also provide support for the idea that gastrin, in concert with other hormones, could potentially contribute a post-prandial incretin effect. We also review recent developments in the biology of other gastrin gene products, including the precursor progastrin, which causes proliferation of the colonic epithelium and in certain circumstances may induce cancer formation. Glycine-extended biosynthetic processing intermediates also have proliferative effects in colonic mucosa and in some oesophageal cancer cell lines. Whether these additional gene products exert their effects through the CCK2 receptor or a separate entity is currently a matter of debate.

Topics: Animals; Gastric Mucosa; Gastrins; Humans; Incretins; Receptor, Cholecystokinin B; Stomach Neoplasms

Gastric cancer is one of the most frequent neoplasms and a main cause of death worldwide, especially in China and Japan. Numerous epidemiological, animal and experimental studies support a positive association between chronic Helicobacter pylori (H. pylori) infection and the development of gastric cancer. However, the exact mechanism whereby H. pylori causes gastric carcinogenesis remains unclear. It has been demonstrated that expression of cyclooxygenase-2 (COX-2) is elevated in gastric carcinomas and in their precursor lesions. In this review, we present the latest clinical and experimental evidence showing the role of gastrin and COX-2 in H. pylori-infected patients and their possible association with gastric cancer risk.

Topics: Animals; Anti-Bacterial Agents; Anticarcinogenic Agents; Cell Transformation, Neoplastic; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; DNA Methylation; Epigenesis, Genetic; Gastrins; Gene Expression Regulation, Neoplastic; Helicobacter Infections; Helicobacter pylori; Humans; Risk Factors; Signal Transduction; Stomach; Stomach Neoplasms

Gastric neuroendocrine neoplasms of the stomach can be divided into the usually well-differentiated, hypergastrinemia-dependent type I and II lesions and the more aggressively behaving gastrin-independent type III lesions. Studying menin and its complex interrelationship with gastrin may provide insight into tumor biology at the clinical level and in terms of basic cell biology (eg, the role of the epigenome in neuroendocrine cell proliferation), and lead to potential consideration of other targets that are known candidates for molecular-based therapies in other adenocarcinomas.

Topics: Animals; Carcinoid Tumor; Disease Models, Animal; Gastrins; Humans; Stomach Neoplasms

Topics: Carcinoid Tumor; Female; Gastrectomy; Gastrins; Humans; Laparoscopy; Middle Aged; Pyloric Antrum; Stomach Neoplasms; Treatment Outcome

Atrophic gastritis (AG) results most often from Helicobacter pylori (H. pylori) infection. AG is the most important single risk condition for gastric cancer that often leads to an acid-free or hypochlorhydric stomach. In the present paper, we suggest a rationale for noninvasive screening of AG with stomach-specific biomarkers.. The paper summarizes a set of data on application of the biomarkers and describes how the test results could be interpreted in practice.. In AG of the gastric corpus and fundus, the plasma levels of pepsinogen I and/or the pepsinogen I/pepsinogen II ratio are always low. The fasting level of gastrin-17 is high in AG limited to the corpus and fundus, but low or non-elevated if the AG occurs in both antrum and corpus. A low fasting level of G-17 is a sign of antral AG or indicates high intragastric acidity. Differentiation between antral AG and high intragastric acidity can be done by assaying the plasma G-17 before and after protein stimulation, or before and after administration of the proton pump inhibitors (PPI). Amidated G-17 will rise if the antral mucosa is normal in structure. H. pylori antibodies are a reliable indicator of helicobacter infection, even in patients with AG and hypochlorhydria.. Stomach-specific biomarkers provide information about the stomach health and about the function of stomach mucosa and are a noninvasive tool for diagnosis and screening of AG and acid-free stomach.

Topics: Achlorhydria; Antibodies, Bacterial; Biomarkers; Gastric Mucosa; Gastrins; Gastritis, Atrophic; Helicobacter Infections; Helicobacter pylori; Humans; Mass Screening; Pepsinogen A; Pepsinogen C; Stomach Neoplasms; Vitamin B 12

Chronic atrophic gastritis, a precancerous change for gastric cancer, shows a loss of appropriate glands, Helicobacter pylori infection and autoimmune gastritis being the two main etiologic factors. While H. pylori eradication is the mandatory treatment for the former, no etiologic treatment is available for the latter, in which a Th1-type response, modulated by Tregs and Th17 cells, is involved. H. pylori-related atrophic gastritis is a risk factor for gastric adenocarcinoma, while autoimmune atrophic gastritis is also linked to a substantial risk of gastric type I carcinoid, related to the chronic stimulus exerted by hypergastrinemia on enterochromaffin-like cells. Several studies have been published on gastric cancer treatment through an active specific immunotherapy, aimed at improving the immunoregulatory response and increasing the circulating tumor-specific T cells. No study on immunotherapy of carcinoids is available but, in our experience, the administration of an antigastrin 17 vaccine induced carcinoid regression in two out of three patients treated.

Topics: Adenocarcinoma; Animals; Antineoplastic Combined Chemotherapy Protocols; Cancer Vaccines; Enterochromaffin-like Cells; Gastrins; Gastritis, Atrophic; Humans; Immunotherapy; Precancerous Conditions; Risk; Stomach Neoplasms

Patients with chronic hypergastrinemia due to chronic atrophic gastritis or gastrinomas have an increased risk of developing gastric malignancy, and it has been questioned whether also patients with hypergastrinemia caused by long-term use of acid inhibiting drugs are at risk. Gastric carcinogenesis in humans is affected by numerous factors and progresses slowly over years. When using animal models with the possibility of intervention, a complex process can be dissected by studying the role of hypergastrinemia in carcinogenesis within a relatively short period of time. We have reviewed findings from relevant models where gastric changes in animal models of long-term hypergastrinemia have been investigated. In all species where long-term hypergastrinemia has been induced, there is an increased risk of gastric malignancy. There is evidence that hypergastrinemia is a common causative factor in carcinogenesis in the oxyntic mucosa, while other cofactors may vary in the different models.

Topics: Animals; Disease Models, Animal; Gastrins; Mice; Rats; Stomach Neoplasms

Gastric carcinoid tumors comprise 7% of all gastrointestinal carcinoids and have significantly increased in incidence over the past few decades. Seventy to 80% of gastric carcinoids are type I, which usually are clinically asymptomatic and found incidentally at endoscopic evaluation for abdominal pain or anemia. In this review, advances in understanding the pathophysiology of type I gastric carcinoid are highlighted. In addition, various current diagnostic and treatment options are discussed. Although type I carcinoids generally hold a benign course, rigorous investigation is needed to ensure accurate diagnosis and optimal treatment. This includes appropriate diagnostic procedures and imaging and accurate staging of tumor. Tumor size, depth of invasion, presence of metastasis, and the tumor's gastrin dependency dictate treatment options. Appropriate treatments can consist of endoscopic resection, antrectomy, medical management, or frequent follow-up. This article provides a systematic method of evaluating and treating type I gastric carcinoid.

Topics: Carcinoid Tumor; Enterochromaffin Cells; Gastrectomy; Gastric Acidity Determination; Gastric Fundus; Gastric Mucosa; Gastrins; Gastritis, Atrophic; Gastroscopy; Humans; Neoplasm Staging; Polyps; Prognosis; Pyloric Antrum; Radionuclide Imaging; Risk Factors; Stomach Neoplasms

Topics: Anti-Ulcer Agents; Biomarkers, Tumor; Chromogranin A; Disease Progression; Enterochromaffin-like Cells; Female; Gastric Mucosa; Gastrins; Gastritis, Atrophic; Histamine Release; Humans; Hyperplasia; Metaplasia; Middle Aged; Neuroendocrine Tumors; Parietal Cells, Gastric; Stomach Neoplasms; Synaptophysin; Vesicular Transport Proteins

In addition to regulating acid secretion, the gastric antral hormone gastrin regulates several important cellular processes in the gastric epithelium including proliferation, apoptosis, migration, invasion, tissue remodelling and angiogenesis. Elevated serum concentrations of this hormone are caused by many conditions, particularly hypochlorhydria (as a result of autoimmune or Helicobacter pylori (H pylori)-induced chronic atrophic gastritis or acid suppressing drugs) and gastrin producing tumors (gastrinomas). There is now accumulating evidence that altered local and plasma concentrations of gastrin may play a role during the development of various gastric tumors. In the absence of H pylori infection, marked hypergastrinemia frequently results in the development of gastric enterochromaffin cell-like neuroendocrine tumors and surgery to remove the cause of hypergastrinemia may lead to tumor resolution in this condition. In animal models such as transgenic INS-GAS mice, hypergastrinemia has also been shown to act as a cofactor with Helicobacter infection during gastric adenocarcinoma development. However, it is currently unclear as to what extent gastrin also modulates human gastric adenocarcinoma development. Therapeutic approaches targeting hypergastrinemia, such as immunization with G17DT, have been evaluated for the treatment of gastric adenocarcinoma, with some promising results. Although the mild hypergastrinemia associated with proton pump inhibitor drug use has been shown to cause ECL-cell hyperplasia and to increase H pylori-induced gastric atrophy, there is currently no convincing evidence that this class of agents contributes towards the development of gastric neuroendocrine tumors or gastric adenocarcinomas in human subjects.

Topics: Adenocarcinoma; Animals; Cell Movement; Cell Proliferation; Gastric Mucosa; Gastrins; Gastritis, Atrophic; Helicobacter Infections; Humans; Mice; Mice, Transgenic; Models, Biological; Neoplasm Invasiveness; Neovascularization, Pathologic; Neuroendocrine Tumors; Stomach Neoplasms; Zollinger-Ellison Syndrome

Gastric cancer (GS) remains one of the most common cancers worldwide. It is considered as the second most frequent cause of cancer death worldwide, although much geographical variation in incidence exists. Many studies before linked Helicobacter pylori (Hp) which is now considered as an important pathogen, to the risk of developing noncardia GS. This overview attempts to summarize the recent basic and clinical evidence on the link between H. pylori and gastric cancer, after the award of the Nobel Prize for Physiology or Medicine to Drs. J.R. Warren and B.J. Marshall for the first culture and isolation of Hp and the investigation of their relevance to peptic ulcer disease. It become evident that Hp eradication by antibiotic treatment combined with proton pump inhibitor (PPI) serves as the primary chemoprevention strategy to reduce gastric cancer incidence. Moreover, the eradication therapy reduces gastric cancer incidence in patients without any precancerous lesions at the baseline and is most effective before the development of atrophic gastritis. Due to understanding the molecular nature of GC which has been nowadays under intense investigation, our review attempts to highlight recent progress in the field of research on Hp-induced GS. We discuss the geographical diversity in Hp infection and cancer incidence and the mechanistic role of gastrin, cyclooxygenase-2 (COX-2), growth factor, nitric oxide (NO)/NO synthase and E-cadherin/beta-cathenin systems, apoptosis and angiogenesis in Hp-induced gastric carcinogenesis. In addition host-related genetic susceptibility and the role of overexpression of a proinflammatory cytokines and their polymorphism is discussed in the relation to the cascade of events such as gastric atrophy, intestinal metaplasia and dysplasia that finally lead to adenocarcinoma.

Topics: Animals; Gastric Mucosa; Gastrins; Helicobacter Infections; Helicobacter pylori; Humans; Prevalence; Stomach Neoplasms; Virulence

Gastric cancer is the second most common cause of death from cancer in Asia. Although surgery is the standard treatment for this disease, early detection and treatment is the only way to reduce mortality. This Review summarises the epidemiology of gastric cancer, and the evidence for, and current practices of, screening in Asia. Few Asian countries have implemented a national screening programme for gastric cancer; most have adopted opportunistic screening of high-risk individuals only. Although screening by endoscopy seems to be the most accurate method for detection of gastric cancer, the availability of endoscopic instruments and expertise for mass screening remains questionable--even in developed countries such as Japan. Therefore, barium studies or serum-pepsinogen testing are sometimes used as the initial screening tool in some countries, and patients with abnormal results are screened by endoscopy. Despite the strong link between infection with Helicobacter pylori and gastric cancer, more data are needed to define the role of its eradication in the prevention of gastric cancer in Asia. At present, there is a paucity of quality data from Asia to lend support for screening for gastric cancer.

Topics: Adult; Aged; Asia; Female; Gastrins; Humans; Incidence; Male; Mass Screening; Middle Aged; Risk Factors; Stomach Neoplasms

Gastric hypoacidity and hypergastrinaemia are seen in several conditions associated with an increased risk of gastric malignancy. Hypoacidity and hypergastrinaemia are closely related and their long-term effects are difficult to study separately in patients. Studies using animal models can provide valuable information about risk factors and mechanisms in gastric cancer development as the models allow a high degree of intervention when introducing or eliminating factors possibly affecting carcinogenesis. In this report, we briefly review findings from relevant animal studies on this topic. Animal models of gastric hypoacidity and hypergastrinaemia provide evidence hypergastrinaemia is a common causative factor in many otherwise diverse settings. In all species where sufficient hypoacidity and hypergastrinaemia have been induced, a proportion of the animals develop malignant lesions in the gastric oxyntic mucosa.

Topics: Achlorhydria; Animals; Cell Proliferation; Cell Transformation, Neoplastic; Disease Models, Animal; Enterochromaffin-like Cells; Gastric Acid; Gastric Mucosa; Gastrins; Humans; Receptor, Cholecystokinin B; Risk Assessment; Risk Factors; Stomach; Stomach Neoplasms

Although the gastric cancer incidence is decreasing, this neoplasia remains one of the major causes of oncological mortality. Because of an insidious development, gastric cancer is often diagnosed in an advanced stage and consequently with a poor prognosis. Accurate non-invasive tests should be extremely useful in order to detect gastric neoplasm in an early phase. In clinical practice, there is no reliable bio-marker for detecting this malignant disease. However, intestinal as well as diffuse types of gastric cancer are preceded by gastric mucosa inflammation. Furthermore, the intestinal type of the neoplasia is, generally, related to chronic atrophic gastritis, especially if associated with intestinal metaplasia. In particular, the risk of the neoplasm is linked to both extension and severity of gastric atrophy. Serological parameters such as serum pepsinogens I (PGI) and II (PGII), gastrin-17 (G-17) cytokines (e.g. IL-8), antiparietal cells, IgG anti-Hp and CagA antibodies and lastly ghrelin supply information about either atrophic or inflammatory conditions characterising gastric mucosa. Low PGI and PGI/PGII ratio levels, especially if combined with high G-17 levels, are recognised bio-markers of corpus atrophic gastritis. Low G-17 levels could be, also, suggestive of antral atrophic gastritis. Furthermore, plasmatic ghrelin levels seem to be also a bio-marker of corpus atrophy. Anti-Hp IgG and CagA antibodies as well as PGII levels are able to detect gastric inflammation. Serological parameters could select subjects at risk for gastric mucosa alterations such as inflammation or atrophy, rather than gastric cancer itself. This review analyses the information derived from serological bio-markers as well as the involved clinical studies.

Topics: Biomarkers; Cytokines; Diagnosis, Differential; Evidence-Based Medicine; Gastric Mucosa; Gastrins; Gastritis, Atrophic; Ghrelin; Humans; Interleukin-8; Pepsinogens; Stomach Diseases; Stomach Neoplasms

Topics: Biomarkers; Gastrins; Gastritis, Atrophic; Helicobacter Infections; Helicobacter pylori; Humans; Pepsinogens; Risk Factors; Stomach Neoplasms

Gastric acid plays an important role in digesting food (especially protein), iron absorption, and destroying swallowed micro-organisms. H+ is secreted by the oxyntic parietal cells and its secretion is regulated by endocrine, neurocrine and paracrine mechanisms. Gastrin released from the antral G cell is the principal physiological stimulus of gastric acid secretion. Activation of the enterochromaffin-like (ECL) cell is accepted as the main source of histamine participating in the regulation of acid secretion and is functionally and trophically controlled by gastrin, which is mediated by gastrin/CCK-2 receptors expressed on the ECL cell. However, long-term hypergastrinemia will induce ECL cell hyperplasia and probably carcinoids. Clinically, potent inhibitors of acid secretion have been prescribed widely to patients with acid-related disorders. Long-term potent acid inhibition evokes a marked increase in plasma gastrin levels, leading to enlargement of oxyntic mucosa with ECL cell hyperplasia. Accordingly, the induction of ECL cell hyperplasia and carcinoids remains a topic of considerable concern, especially in long-term use. In addition, the activation of ECL cells also induces another clinical concern, i.e., rebound acid hypersecretion after acid inhibition. Recent experimental and clinical findings indicate that the activation of ECL cells plays a critical role both physiologically and clinically in the regulation of gastric acid secretion.

Topics: Animals; Anti-Ulcer Agents; Enterochromaffin-like Cells; Gastric Acid; Gastrins; Humans; Stomach Neoplasms

The most frequent conditions of hypergastrinemia in man are the Zollinger-Ellison syndrome with autonomous gastrin hypersecretion by the tumour cell and reactive hypergastrinemia in type A autoimmune chronic atrophic gastritis with achlorhydria causing unrestrained gastrin release from the gastrin-producing antral G-cells. Both entities differ with respect to the pH in the gastric fluid, which is < 2 in patients with Zollinger-Ellison syndrome and neutral in type A gastritis. Other conditions with moderate hypergastrinemia as treatment with proton pump inhibitors, gastric outlet obstruction, previous vagotomy, chronic renal failure or short bowel syndrome are of minor clinical importance.

Topics: Autoimmune Diseases; Carcinoid Tumor; Diagnosis, Differential; Duodenal Neoplasms; Enterochromaffin-like Cells; Gastric Mucosa; Gastrinoma; Gastrins; Gastritis, Atrophic; Humans; Hyperplasia; Pancreatic Neoplasms; Stomach Neoplasms; Zollinger-Ellison Syndrome

Gastric neuroendocrine tumours (NET) are rare. Clinically they are classified in tumours type 1 to 3. The histological classification is according to the WHO 2000 classification for endocrine tumours. NET type 1 occur in coincidence with chronic atrophic gastritis, as single or multiple small tumours. The prognosis of type 1 tumours is excellent, with no tumour related death reported during follow-up. NET type 2 are part of the MEN-1 syndrome. These tumours may be more aggressive and even develop metastasis. However, in most patients with MEN-1 the prognosis is due to other manifestations of the disease as duodenal or pancreatic neuroendocrine tumours. Gastric neuroendocrine tumours type 3 are sporadic tumours without relationship to other gastric pathology. They tend to occur earlier, without sex preference. These tumours may develop an aggressive course, with metastatic disease and an overall poor prognosis. Thus, aggressive surgical therapy is recommended.

Topics: Biopsy; Chronic Disease; Diagnosis, Differential; Duodenal Neoplasms; Enterochromaffin-like Cells; Gastric Mucosa; Gastrinoma; Gastrins; Gastritis, Atrophic; Humans; Multiple Endocrine Neoplasia Type 1; Neuroendocrine Tumors; Pancreatic Neoplasms; Prognosis; Stomach Neoplasms

Proton pump inhibitors are being increasingly used and for longer periods of time, especially in patients with gastroesophageal reflux disease. Each of these trends has led to numerous studies and reviews of the potential risk-benefit ratio of the long-term use of proton pump inhibitors. Both long-term effects of hypergastrinaemia due to the profound acid suppression caused by proton pump inhibitors as well as the effects of hypo-/achlorhydria per se have been raised and studied. Potential areas of concern that have been raised in the long-term use of proton pump inhibitors, which could alter this risk-benefit ratio include: gastric carcinoid formation; the development of rebound acid hypersecretion when proton pump inhibitor treatment is stopped; the development of tolerance; increased oxyntic gastritis in H. pylori patients and the possibility of increasing the risk of gastric cancer; the possible stimulation of growth of non-gastric tumours due to hypergastrinaemia; and the possible effect of the hypo/achlorhydria on nutrient absorption, particularly iron and vitamin B12. Because few patients with idiopathic gastro-oesophageal reflux disease/peptic ulcer disease have been treated long-term (i.e., >10 years), there is little known to address the above areas of potential concern. Most patients with gastrinomas with Zollinger-Ellison syndrome have life-long hypergastrinaemia, require continuous proton pump inhibitors treatment and a number of studies report results of >5-10 years of tratment and follow-up. Therefore, an analysis of Zollinger-Ellison syndrome patients can provide important insights into some of the safety concerns raised above. In this paper, results from studies of Zollinger-Ellison syndrome patients and other recent studies dealing with the safety concerns above, are briefly reviewed.

Topics: Animals; Carcinoid Tumor; Cell Transformation, Neoplastic; Drug Tolerance; Enterochromaffin-like Cells; Gastric Acid; Gastric Mucosa; Gastrinoma; Gastrins; Gastritis; Gastroesophageal Reflux; Gastrointestinal Agents; Helicobacter pylori; Humans; Malabsorption Syndromes; Peptic Ulcer; Proton Pump Inhibitors; Stomach Neoplasms; Time Factors; Zollinger-Ellison Syndrome

Gastrin and gastrin receptor-deficient mice have been used for genetic dissection of the role of gastrins in maintaining gastric homeostasis and control of acid secretion. The gastrin knockout mice are achlorhydric due to inactivation of the ECL and parietal cells. Moreover, this achlorhydria is associated with intestinal metaplasia and bacterial overgrowth, which ultimately leads to the development of gastric tumours. The association between progastrin, progastrin-derived processing intermediates and colorectal carcinogenesis has also been examined through genetic or chemical cancer induction in several mouse models, although the clinical relevance of these studies remains unproven. While others have focused on models of increased gastrin production, the present review describes the lessons learned from gastrin-deficient mice. Study of these mice helps our understanding of how dysregulation of gastrin secretion may be implicated in human disease.

Topics: Achlorhydria; Animals; Gastric Acid; Gastric Mucosa; Gastrins; Gene Expression Regulation; Intestinal Diseases; Metaplasia; Mice; Mice, Knockout; Models, Biological; Receptor, Cholecystokinin B; Stomach Neoplasms

Gastrin is a pro-proliferative, anti-apoptotic hormone with a central role in acid secretion in the gastric mucosa and a long-standing association with malignant progression in transgenic mouse models. However, its exact role in human gastric malignancy requires further validation. Gastrin expression is tightly regulated by two closely associated hormones, somatostatin and gastrin-releasing peptide, and aspects of their interaction may be deregulated during progression to gastric adenocarcinoma. Furthermore, agonists and antagonists of the receptors for all three hormones have shown modest clinical efficacy against gastric adenocarcinoma, which might provide useful information on the future combined use of these agents.

Topics: Animals; Antineoplastic Agents, Hormonal; Apoptosis; Cancer Vaccines; Cell Differentiation; Cell Movement; Cell Transformation, Neoplastic; Gastrin-Releasing Peptide; Gastrins; Gene Expression Regulation, Neoplastic; Helicobacter Infections; Humans; Mice; Neoplasm Invasiveness; Neoplasms, Experimental; Neovascularization, Pathologic; Precancerous Conditions; Risk Factors; Somatostatin; Stomach Neoplasms

Classifications of chronic gastritis and neoplastic gastric diseases, developed in recent years (1996 Houston update of 1990 Sidney classification system, 2002 New Orlean classification of atrophic gastritis according to recommendations of International Group for Atrophy Studies; 1998 Padova classification of gastric displasia, and 1998 Vienna classification of gastrointestinal neoplasia) allow to statandardize international research and perform more objective diagnostics of pathological changes in the gastric mucosa. Studies carried out in recent years have established that morphological manifestations of chronic gastritis caused by Helicobacter pylori infection can be reduced after its eradication. Longterm treatment with proton pump inhibitors have been demonstrated not to cause atrophic changes in the gastric mucosa when undertaken after successful eradicational therapy. It has been established that corporal gastritis intensifies in patients treated with proton pump inhibitors. The studies show that measurement of serum levels of Helicobacter pylori antibodies, gastrine, pepsinogen I and II can be used in non-invasive serologic diagnostics of atrophic gastritis. Achievements in diagnostics and treatment of chronic gastritis create the necessary prerequisites for the development of gastric cancer preventing measures.

Topics: Antibodies, Bacterial; Biopsy; Chronic Disease; Dyspepsia; Gastric Mucosa; Gastrins; Gastritis; Gastritis, Atrophic; Gastrointestinal Neoplasms; Helicobacter Infections; Helicobacter pylori; Humans; Pepsinogen A; Pepsinogen C; Proton Pump Inhibitors; Stomach; Stomach Neoplasms; Time Factors

Gastric carcinoid tumours are classified in 3 types depending on whether they are sporadic (type III), or they are associated with a chronic atrophic gastritis (type I) or a multiple endocrine neoplasia type I-associated Zollinger-Ellison syndrome (type II). For type I tumours, the role of antrectomy, which aims to suppress the causative hypergastrinemia, has not been determined.. To determine, from literature review the role of antrectomy in the management of type I gastric carcinoid tumours.. Bibliographic study searching for published observations of antrectomy for type I gastric carcinoid tumours. Data regarding postoperative evolution of gastrinemia and carcinoid tumours were collected.. Thirty-eight published cases were identified. Preoperative gastrinemia was elevated in the 32 patients in whom it was measured. It came to normal ranges in the 19 patients in whom it was postoperatively assessed. With a mean follow-up of 34 months (1 to 120), disappearance of carcinoid tumours was observed in 27 of 38 patients (71%), the 11 others having tumour recurrence or persistence. When postoperatively assessed, hyperplasia of fundic enterochromaffine-like cells persisted in 7 patients, regressed in 4 and disappeared in the 6 others. No antrectomy-related complication was reported.. Antrectomy can be considered as a worthwhile alternative for the treatment of gastric carcinoid tumours related to chronic atrophic gastritis and hypergastrinemia.

Topics: Carcinoid Tumor; Gastrins; Humans; Postoperative Period; Preoperative Care; Pyloric Antrum; Stomach Neoplasms

Gastrointestinal (GI) hormones are chemical messengers that have been recognized for over a century as regulatory factors for normal physiologic functions in the GI tract and pancreas, including absorption, secretion, motility, and digestion. These hormones traditionally act in a true endocrine fashion with release from a distant site to regulate physiologic functions of specific target organs. In general, GI hormones bind to their G-protein-coupled receptors (GPCRs) to produce their endocrine effects. In addition to effects on physiologic functions of the GI tract and pancreas, selected GI hormones can act in an endocrine, paracrine, and/or autocrine fashion to stimulate the proliferation of normal and neoplastic GI tissues as well as non-GI tissues. This review will focus on effects of GI hormones on neoplastic tissues concentrating on the hormones that have been best characterized for these effects.

Topics: Biomarkers, Tumor; Colorectal Neoplasms; Female; Gastrins; Gastrointestinal Hormones; Gastrointestinal Neoplasms; Growth Substances; Humans; Male; Pancreatic Neoplasms; Prognosis; Receptors, Gastrointestinal Hormone; Risk Assessment; Sensitivity and Specificity; Signal Transduction; Stomach Neoplasms; Survival Analysis

Inhibitors of gastric acid secretion are efficient drugs in the treatment of acid-related diseases. However, by reducing gastric acidity, hypergastrinemia develops. Gastrin regulates its target cell, the enterochromaffin (ECL) cell, both functionally and tropicaly. Long-term hypergastrinemia in whatever species studied, has been shown to induce tumors originating from the ECL cell. In man, at least 10 years of hypergastrinemia, accompanied by high or reduced gastric acidity is necessary to induce ECL cell carcinoids. There are reports indicating development of ECL cell carcinoids after long-term treatment with proton pump inhibitors. Moreover, the ECL cell may give rise to gastric carcinomas of diffuse type, which have increased during the last decades. Furthermore, most of the carcinomas developing in patients with long-lasting hypergastrinemia are of ECL cell origin. Therefore, long-lasting iatrogenic hypergastrinemia induced by potent inhibitors of acid secretion may be expected to increase the occurrence of gastric carcinomas in the future.

Topics: Anti-Ulcer Agents; Carcinoma; Drug Administration Schedule; Enterochromaffin Cells; Gastric Acid; Gastrins; Humans; Stomach Neoplasms

Topics: Gastric Acid; Gastrins; Gastritis, Atrophic; Helicobacter Infections; Helicobacter pylori; Humans; Polyps; Stomach Neoplasms

Topics: DNA Damage; Gastric Acid; Gastric Mucosa; Gastrins; Gastritis, Hypertrophic; Helicobacter Infections; Helicobacter pylori; Hepatocyte Growth Factor; Humans; Interleukin-1; Risk; Stomach Neoplasms

In 1984, Reg protein was shown to be stimulated during the regeneration of pancreatic islets. Since then, many Reg-related proteins have been identified in humans and other animals. These Reg-related proteins are classified into four subfamilies according to their amino-acid sequences, but they share a similar structure and physiological function. The role of Reg in gastric tissue was investigated, and Reg I was found to be expressed mainly in gastric fundic enterochromaffin-like (ECL) cells. Reg I production in ECL cells is stimulated by gastrin, as well as by the proinflammatory cytokine, cytokine-induced neutrophil chemoattractant (CINC)-2Beta. In patients with chronic hypergastrinemia, Reg production is stimulated, with the increased proliferation of gastric mucosal cells. Patients with Helicobacter pylori infection also showed increased Reg production in the gastric mucosa, partly via increased plasma gastrin concentration and partly via increased proinflammatory cytokine production. Thus, Reg protein induced by H. pylori infection may be partly responsible for the increased proliferation of gastric epithelial cells in H. pylori-infected patients. Reg protein is also produced in many gastric cancer cells, especially in poorly differentiated and advanced cancers. Reg protein stimulates the proliferation of several gastric cancer cell types, and gastric cancers with Reg protein expression tend to show a poorer clinical outcome. In summary, Reg protein may be a growth factor that regulates the proliferation and differentiation of normal and neoplastic gastric epithelial cells.

Topics: Animals; Cell Division; Chronic Disease; Enterochromaffin-like Cells; Gastric Mucosa; Gastrins; Gastritis; Helicobacter Infections; Helicobacter pylori; Humans; Immunohistochemistry; In Situ Hybridization; Stomach Neoplasms

The gastrointestinal peptide hormones gastrin and cholecystokinin (CCK) are well known for their ability to stimulate gastric acid secretion and pancreatic enzyme secretion, respectively. The suggestion that gastrin and CCK might also promote the development of cancers of the gastrointestinal tract has been controversial, but an increasing body of evidence now supports the view that the amidated and non-amidated forms of gastrin act as growth factors via different receptors in different regions of the gut. For example, animal experiments indicate that amidated gastrins are involved in cellular differentiation and repair in the gastric mucosa, and synergize with Helicobacter pylori infection in the development of gastric carcinoma. In contrast, non-amidated gastrins stimulate colonic mucosal growth, accelerate the early steps in colorectal carcinoma formation, and are elevated in the tumour and circulation of patients with colorectal cancer. Although human pancreatic carcinomas express CCK-1 and CCK-2 receptors, the role of gastrins and CCK in pancreatic carcinogenesis is yet to be established. Further investigation of the possible role of the CCK-2 receptor in gastric and pancreatic neoplasia, and of the hypothesis that gastrin precursors act as autocrine growth factors in colorectal carcinoma, is warranted. However, therapies aimed at the gastrins must be targeted to the relevant gastrin/gastrin receptor combination.

Topics: Cholecystokinin; Colorectal Neoplasms; Gastrins; Gastrointestinal Neoplasms; Humans; Pancreatic Neoplasms; Receptors, Cholecystokinin; Stomach Neoplasms; Tumor Cells, Cultured

Gastric carcinoids are rare neuroendocrine tumors, usually classified as type I, if associated with atrophic body gastritis; type II, if associated with Zollinger-Ellison syndrome and multiple endocrine neoplasia type I, and type III, in the absence of any gastric pathology (sporadic tumors). The pathological features, as well as the prognosis of the tumor and the patient's survival strictly depend on this classification. The correct management of the patient with gastric carcinoid can only be proposed when the tumor has been classified by an accurate pathological and clinical evaluation of the patient. While the therapeutic approach in types I and II is based on a conservative strategy, including endoscopic resection, an adequate follow-up program, and the possible use of somatostatin analogues, an aggressive surgical approach is required in type III.

Topics: Enterochromaffin Cells; Gastrins; Gastritis, Atrophic; Humans; Neuroendocrine Tumors; Stomach Neoplasms

Despite general awareness of Zollinger-Ellison syndrome (ZES) by most physicians and more than 3000 articles written about it since 1955, the diagnosis of ZES is still delayed for a mean of 5 years. Recent studies show it is being delayed even more with the widespread use of proton pump inhibitors. A number of tumor markers, in addition to assessing serum gastrin, such as chromogranin A, neuron-specific enolase, and subunits of chorionic gonadotropin, have been proposed for use in either the diagnosis of pancreatic endocrine tumors, such as gastrinomas, or for assessment of tumor extent and growth. In this article important recent insights into the diagnosis of ZES as well as the clinical usefulness of assessing tumor markers for diagnosis and determination of disease extent and growth are discussed. Approximately 25% of ZES cases are due to multiple endocrine neoplasia type 1 (MEN1). A number of important studies in this group of patients are also reviewed. Finally, almost every patient with ZES has marked gastric acid hypersecretion, and its current treatment as well as the long-term possible side effects are reviewed briefly.

Topics: Algorithms; Biomarkers, Tumor; Carcinoid Tumor; Chorionic Gonadotropin; Chromogranin A; Chromogranins; Gastric Acid; Gastrinoma; Gastrins; Gastrointestinal Agents; Humans; Hyperparathyroidism; Multiple Endocrine Neoplasia Type 1; Octreotide; Pancreatic Neoplasms; Phosphopyruvate Hydratase; Proton Pump Inhibitors; Stomach Neoplasms; Zollinger-Ellison Syndrome

Aphton is developing an anti-gastrin vaccine [Anti-gastrin 17 immunogen, G17DT, Gastrimmune], which neutralises the gastrin 17 hormone and the Gly-G17 hormone. Gastrin 17 is a growth factor for pancreatic, stomach and colorectal cancers, and a potent stimulator of gastric acid secretion.The anti-gastrin immunogen, G17DT, consists of a large carrier protein, called Diptheria Toxoid (DT). A synthetic peptide, which is similar to a portion of the gastrin 17 hormone (GT), is attached to the carrier protein. These are then contained in a liquid suspension vehicle. When administered to patients, G17DT induces an immune response producing antibodies, which cross-react and neutralise the target hormone thus preventing its interaction with disease-causing or -participating cells. Aphton has entered into an agreement with Aventis Pasteur for the marketing of G17DT in all human cancer indications in North America and Europe. Under the terms of the agreement, Aphton is responsible for product development, clinical trials and regulatory agency approvals. The agreement was originally with Pasteur Mérieux Connaught, a subsidiary of Rhône-Poulenc. However, in December 1999, Rhône-Poulenc merged with Hoechst to form Aventis. As a result of the merger, Pasteur Mérieux Connaught underwent a name change to Aventis Pasteur. In July 2002, Aphton announced that it would negotiate with companies wanting to licence the vaccine in territories other than North America and Europe. In February 2003, Aphton announced it had received fast track designation for G17DT in combination with cisplatin and fluorouracil for use in stage IV gastric cancer to improve overall survival. In July 2002, the US FDA granted G17DT orphan drug status for the treatment of gastric cancer, an indication that was broader than the indication Aphton originally sought. The vaccine was also granted orphan drug status in Australia for gastric cancer in December 2002. In July 2002, Aphton announced that the US FDA had granted G17DT orphan drug status for the treatment of adenocarcinoma of the pancreas. In September 2002, the US FDA also granted G17DT, used in combination with gemcitabine, fast track status for the treatment of pancreatic cancer patients. In addition, the vaccine was also granted orphan drug status in Australia for pancreatic cancer in December 2002. In March 2003, Aphton announced that the Committee for Orphan Medicinal Products had recommended to the European Commission that G17DT be granted orph

Topics: Animals; Cancer Vaccines; Clinical Trials as Topic; Colorectal Neoplasms; Gastrins; Humans; Orphan Drug Production; Pancreatic Neoplasms; Peptic Ulcer; Rats; Stomach Neoplasms; Vaccines

Helicobacter pylori (Hp) infection represents a crucial factor in pathogenesis of gastric cancer (GC). Factors emanating from bacterium as well as from environmental contributions such as salt diet and inadequate supply of antioxidants, affect the risk for GC development.. Atrophic gastritis is considered to be a precursor lesion of intestinal type GC that is accompanied by hypergastrinemia with subsequent induction of cyclooxygenase-2 (COX-2), whose products are responsible for slowing apoptosis and for angiogenesis in GC tumor. The involvement of proinflammatory cytokines (especially IL-1 and IL-8) and reactive oxygen species (ROS) due to NF kappa B activation, increased cell proliferation combined with inhibition of apoptosis as well as upregulation of peroxisome proliferation activated receptor gamma (PPAR gamma) and inducible nitric oxide synthase (iNOS) appear to be major molecular biology alterations in pathogenesis of GC.. These results suggest the therapeutic usefulness of inhibitors of gastrin expression and release such as powerful somatostatin analogs (Sandostatin) or blockers of COX-2 (coxibs) in the control of GC development and progression as chemopreventive agents. Comparative genomic and proteomic is the key in identifying biomarkers in host and bacterium for the prediction of gastric cancer in Hp-infected patients.

Topics: Animals; Apoptosis; Bacterial Proteins; Cyclooxygenase 2; Cytokines; Gastrins; Gastritis, Atrophic; Gene Expression Regulation, Neoplastic; Helicobacter Infections; Helicobacter pylori; Humans; Isoenzymes; Membrane Proteins; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Prostaglandin-Endoperoxide Synthases; Receptors, Cytoplasmic and Nuclear; Stomach Neoplasms; Survival Rate; Transcription Factors

Helicobacter infection is the single most common cause of gastric cancer worldwide. Although infection prevention and eradication of established infection offer the potential for cure, these strategies are neither feasible nor practical for widespread implementation. Patients most at risk need to be identified and targeted for treatment. For disease to occur, bacterial, environmental, and nutritional factors require a genetically susceptible host. Consequently, it is important to understand how the organism interacts with the host to cause disease. Only through an understanding of what places a patient at risk can we hope to identify susceptible patients early enough in disease to have an impact on their outcome. The immune response is the single most important determinant of disease. Single nucleotide polymorphisms within the promoter region of several critical proinflammatory genes dramatically increase the risk of Helicobacter-associated gastric cancer. Additionally, environmental and dietary factors may modulate the immune response or directly influence key apoptotic and proliferative signaling cascades to alter disease presentation. Lastly, concurrent disease states may have a dramatic impact on the host response to Helicobacter infection and influence disease. An understanding of the immune signaling pathways responsible for disease and the ways in which environmental risk factors influence these pathways will allow identification of populations that are most at risk and targeted prevention and treatment strategies.

Topics: Animals; Cadherins; Disease Susceptibility; Gastrins; Helicobacter Infections; Helicobacter pylori; Humans; Polymorphism, Single Nucleotide; Precancerous Conditions; Stomach Neoplasms

On the basis of the levels of serum pepsinogen I (S-PGI) and gastrin-17 (S-G-17) as well as Helicobacter pylori - antibodies assayed from a blood sample it is possible to establish with high sensitivity and specificity whether the patient has gastritis, whether the gastritis is atrophic or not and in which part of the stomach the atrophic changes are located. The test enables the identification of patients whose risk of gastric cancer, of the consequences of vitamin B12 deficiency (e.g. elevated levels of homocysteine) or of peptic ulcer is considerably increased and who can then undergo gastroscopy. It also facilitates the diagnosis of non-atrophic Helicobacter gastritis enabling treatment before endoscopy.

Topics: Finland; Gastrins; Gastritis, Atrophic; Helicobacter Infections; Humans; Pepsinogen A; Peptic Ulcer; Stomach Neoplasms; Vitamin B 12 Deficiency

Gastric cancer is the second most common cause of cancer-related mortality worldwide and the 14th overall cause of death. Detection of disease usually occurs at an advanced stage and overall survival rates for gastric cancer are poor. Our current model for gastric cancer progression clearly maintains Helicobacter infection as the primary inducer of gastric metaplastic and neoplastic disease. Helicobacter pylori is a ubiquitous organism, infecting more than half the world's population. It has been suggested that this infection directly contributes to the formation of gastric cancer in up to 80% of cases; however, gastric malignancy develops in only a subset (< 1%) of infected patients. Therefore, predisposition to Helicobacter-associated gastric cancer is most likely multifactorial, including the interaction of bacterial, host and environmental components. Our understanding of how the organism interacts with the gastric mucosa and synergizes with dietary and other environmental factors to induce malignant mucosal changes is evolving. Indeed, H. pylori has direct effects on the gastric mucosa, but the major factor in disease progression appears to be a robust host Th1 immune response in the setting of a permissive environment. In combination, these factors predispose to the formation of atrophy, metaplasia and gastric cancer. Understanding the interaction of the bacterium with the host and the environment can potentially identify patients most at risk. Identifying potentially removable factors (in addition to H. pylori infection) in the acquisition and progression of neoplastic disease may provide targets for early intervention and prevention strategies.

Topics: Animals; Cytokines; Diet; Diffusion of Innovation; Gastric Acid; Gastrins; Growth Substances; Helicobacter Infections; Helicobacter pylori; Humans; Mucins; Muscle Proteins; Neuropeptides; Peptides; Sodium Chloride; Stomach Neoplasms; Trefoil Factor-2; Trefoil Factor-3

G17DT or Gastrimmune, as it was formally known, is an antigastrin 17 immunogen producing neutralising high affinity antibodies directed against gastrin-17 (G17). Preclinical studies, initiated to identify biological functionality of G17DT-induced antibodies, confirmed that the antibodies both reduced G17 stimulated gastric acid secretion and inhibited gastrin from interacting with the CCK-2 receptor. Therapeutic efficacy of both passive and active immunisation with G17DT has been established in a number of tumour systems including both primary and metastatic disease. Furthermore, additive effects with 5-fluorouracil (5-FU)/leucovorin have been confirmed in both colon and gastric tumour models. Phase I/II studies in advanced gastrointestinal (GI) malignancies have shown no systemic or autoimmune reactions to active immunisation with G17DT. Use of an optimised dose has yielded a high proportion of responders (> 80%), with minimal side effects and antibody titres measurable within 2-4 weeks. Taken together these results suggest that the G17DT immunogen is a promising agent for the treatment of GI cancer and Phase III trials, currently underway, will definitively evaluate this early promise.

Topics: Adenocarcinoma; Animals; Antibodies; Antigens; Cancer Vaccines; Clinical Trials as Topic; Colonic Neoplasms; Diphtheria Toxoid; Gastrins; Gastrointestinal Neoplasms; Humans; Immunotherapy; Multicenter Studies as Topic; Neoplasm Metastasis; Stomach Neoplasms

The decline in duodenal ulcer disease and the established relation of peptic ulcer to Helicobacter pylori have virtually abolished the need for elective ulcer surgery. However, a substantial proportion of the population around retirement age has previously been subjected to partial gastric resection due to peptic ulcer, and the long-term outcome of these patients is of continuing relevance. Patients subjected to elective surgery could represent a selected group of healthy subjects with a lower overall morbidity, but reports indicate that patients operated on for peptic ulcer have more advanced disease associated with excess smoking and a different pattern of social behavior. The surgical procedure induces enterogastric reflux, leading to profound changes in the remnant mucosa and the formation of carcinogens in the gastric juice. In addition, metabolic abnormalities are common, especially fat malabsorption. Evaluation of the impact of these factors on morbidity and mortality is difficult. Increased mortality in gastrointestinal tumors (especially gastric stump carcinoma), respiratory diseases and other smoking-related malignancies, and suicide are found in the long-term follow-up after partial gastric resection due to peptic ulcer. However, these hazards to life are offset by a decreased mortality in cardiovascular disease. Preventive measures against suicide and especially tobacco smoking are recommended to improve th outcome for this cohort.

Topics: Bile Reflux; Cardiovascular Diseases; Female; Gastrectomy; Gastrins; Helicobacter Infections; Helicobacter pylori; Humans; Male; Nutrition Disorders; Peptic Ulcer; Prognosis; Risk Factors; Sex Factors; Smoking; Stomach Neoplasms; Suicide; Time Factors

Fundic gland polyps (FGPs) are tiny multiple sessile polyps of the acid-secreting gastric mucosa. They have been described both in a sporadic form, mainly in middle-aged females, and in a syndromic form, associated with familial adenomatous polyposis (FAP)-Gardner's syndrome and attenuated variants (AFAP). They share the same histology, characterised by superficial and deep cystic dilatations, shortened gastric pits, with an inconspicuous lamina propria. They have been for a long time described as innocuous lesions, but some recent reports have shown that FGPs may harbour dysplastic foci and ultimately (particularly syndromic polyps) gastric cancer. Factors influencing their genesis are unknown. A circulating factor in FAP patients has been postulated and a role of female hormones has been suggested for sporadic FGPs. Whereas patients with sporadic FGPs have normal basal acid output, normal fast serum levels of gastrin and pepsinogen I, the role of gastrin seems crucial for the development of cystic changes in flat body-fundus mucosa, and for the appearance of FGPs in patients with Zollinger-Ellison syndrome. A role of H. pylori induced gastritis has been excluded. Actually, patients with both sporadic and syndromic FGPs appear consistently free from H. pylori colonisation, again for an unknown factor(s). Some recent reports have claimed a role for omeprazole in the genesis of FGPs, a highly controversial issue. Ultimately, the nature of FGPs is still debated: some have interpreted them as hamartomatous lesions, others as a peculiar form of hyperplastic polyp.

Topics: Adenomatous Polyposis Coli; Anti-Ulcer Agents; Female; Gardner Syndrome; Gastric Fundus; Gastric Mucosa; Gastrins; Helicobacter pylori; Humans; Male; Omeprazole; Pepsinogen A; Polyps; Stomach Neoplasms; Syndrome; Zollinger-Ellison Syndrome

Helicobacter pylori, infecting more than 50% of the world population, results in gastritis, usually located in the antral portion of the stomach, accompanied by hypergastrinemia, the key factor in gastric and colorectal carcinogenesis. Excessive mucosal cell proliferation for many years may eventually result in gastric atrophy, cell mutation and transformation of gastric mucosal cells into gastrin-producing cells, which also express gastrin receptors serving to stimulate cell proliferation and tumor growth. These processes may be completed by the expression of cyclooxygenase-2 (COX-2) as an inflammation enzyme to release excessive amounts of PGE(2), leading to further proliferation, reduction in apoptosis, angiogenesis and tumor growth. H. pylori eradication results in complete regression of MALT lymphoma and subsequent normalisation of excessive gastrin release and COX-2 expression. Reduction of gastrin by active immunisation (gastrimmune), blocking of gastrin receptors with specific blockers and suppression of COX-2 might be helpful in inhibiting tumor growth and invasion.

Topics: Animals; Colorectal Neoplasms; Cyclooxygenase 2; Gastrins; Helicobacter Infections; Helicobacter pylori; Humans; Isoenzymes; Lymphoma, B-Cell, Marginal Zone; Membrane Proteins; Mice; Prostaglandin-Endoperoxide Synthases; Stomach Neoplasms

Helicobacter pylori infection affects the concentration of regulatory peptides such as gastrin, somatostatin and cholecystokinin and the concentration and activity of glutathione and glutathione S-transferases in the gastric mucosa.. Literature review.. Although some of these peptides have been known since the beginning of this century, their action has changed since the discovery of H. pylori infection in 1983. Chronic infection with H. pylori might lead to an increased risk in developing gastric cancer. Glutathione S-transferases are involved in the cellular detoxification of xenobiotics and other toxic compounds. Since there is a close inverse relationship between the activity of glutathione S-transferase and incidence of malignancies in the gastrointestinal tract, the possible relation between H. pylori infection and activity of glutathione S-transferases in the gastric mucosa is discussed.. The effect of H. pylori infection on regulatory peptides and glutathione/glutathione S-transferases might play a role in the development of neoplastic changes of the H. pylori-infected gastric mucosa.

Topics: Animals; Biomarkers; Cholecystokinin; Chronic Disease; Disease Progression; Gastric Mucosa; Gastrins; Gastritis; Glutathione; Glutathione Transferase; Helicobacter Infections; Helicobacter pylori; Humans; Somatostatin; Stomach Neoplasms

Topics: Adenoma; Carcinoid Tumor; Gastrins; Humans; Male; Middle Aged; Multiple Endocrine Neoplasia Type 1; Neoplasms, Multiple Primary; Parathyroid Glands; Parathyroid Neoplasms; Stomach; Stomach Neoplasms; Zollinger-Ellison Syndrome

The recent recognition of the nature of gastric carcinoids and the elucidation of the biological events associated with enterochromaffin-like cell transformation has provided an opportunity to advance the understanding of this particular type of neuroendocrine tumour. The relationship between hypergastrinaemia present in low acid disease states and the development of gastric carcinoids has led to an appreciation of the role of gastrin as a growth mediator in the evolution of this type of neoplasia. In addition, evidence exists to support a genetic predisposition to this tumour type in individuals with Multiple Endocrine Neoplasia type 1 syndrome, and in an experimental model--the African rodent species, Mastomys. The recent development of an isolated pure enterochromaffin-like cell preparation has facilitated the elucidation of the molecular physiology of the naive enterochromaffin-like cell and, in addition, allowed the evaluation of the cellular events associated with enterochromaffin-like cell transformation from the naive state to the neoplastic phenotype. This synopsis seeks to present information relevant to both the animal model and the human disease state. The aim is to facilitate an appreciation of the regulatory mechanisms of the enterochromaffin-like cell and delineate the changes consequent to the development of the neoplastic phenotype.

Topics: Animals; Apoptosis; Carcinoid Tumor; Cell Transformation, Neoplastic; Cytoplasm; Enterochromaffin-like Cells; Gastric Mucosa; Gastrins; Histamine Release; Histidine Decarboxylase; Humans; Immunohistochemistry; Rats; Receptors, Growth Factor; Rodentia; Sensitivity and Specificity; Somatostatin; Stomach Neoplasms

An analysis carried out in 1994 by the WHO International Agency for Research on Cancer (IARC) resulted in Helicobacter pylori being designated as a Group 1 carcinogen and thus clearly having an association with the development of gastric cancer. In the case of H. pylori, the evaluation was made solely on the basis of epidemiological results. In Japan, in 1993, only 235,000 of the 60 million people with H. pylori had gastric cancer. This represents only 0.4% of the infected population. Each individual reacts in a unique way to H. pylori infection in terms of the inflammatory response. The probability of developing cancer will be determined by environmental factors such as diet, duration of or age at acquisition of H. pylori infection, the virulence of H. pylori strains, and host factors including genetic make-up.

Topics: Antibodies, Bacterial; Diet; Environment; Gastrins; Gastritis; Helicobacter Infections; Helicobacter pylori; Humans; Prevalence; Stomach Neoplasms

The safety of proton-pump inhibitors (PPIs) for long-term use is reviewed. PPIs are being used with increasing frequency to inhibit secretion of gastric acid in order to treat acid-related disorders such as gastroesophageal reflux disease and peptic ulcer disease. Some patients may require long-term acid suppressive treatment to control the symptoms of their disease, which raises questions about the long-term safety of PPIs. A thorough literature search was conducted, and the clinical consequences of sustained hypergastrinemia induced by all antisecretory therapy, the consequences of atrophic gastritis in patients infected with Helicobacter pylori, the effects of hypochlorhydria on bacterial overgrowth and nutrient absorption, and possible interactions of PPIs with other drugs were identified as areas of concern with long-term use of PPIs. Short- and long-term studies showed that PPIs have a wide safety margin and a favorable adverse-event profile with few drug interactions. Available data support the short- and long-term safety of PPIs.

Topics: Anti-Ulcer Agents; Colonic Neoplasms; Drug Interactions; Enterochromaffin Cells; Gastric Acid; Gastrins; Gastritis, Atrophic; Humans; Hyperplasia; Proton Pump Inhibitors; Stomach Neoplasms

Topics: Betazole; Duodenal Ulcer; Gastric Acidity Determination; Gastric Juice; Gastrins; Gastritis; Humans; Stomach Neoplasms; Stomach Ulcer; Zollinger-Ellison Syndrome

Helicobacter pylori infection is now recognized to be an important acquired factor in the pathogenesis of duodenal ulcer disease. There is also an association between H pylori and the subsequent development of gastric cancer. The mechanism of the association between the infection and those disorders is incompletely understood but there is increasing evidence that H pylori-induced disturbances of gastric function play a pivotal role. In this article we review the role of H pylori infection in the pathophysiology of these important upper gastrointestinal diseases.

Topics: Ascorbic Acid; Duodenal Ulcer; Gastric Acid; Gastrins; Helicobacter Infections; Helicobacter pylori; Humans; Stomach Neoplasms

Helicobacter pylori is now recognized as the major acquired factor in the pathogenesis of duodenal ulcer disease (DU). There is also an association between H. pylori infection and the subsequent development of gastric cancer. The mechanisms by which such infection predisposes the host to these diseases are incompletely understood, but disorders induced by the bacterium in gastric function play a pivotal role. In most patients, H. pylori infection stimulates acid secretion, leading to a predisposition to DU development. However, in some patients, the infection is associated with a significant decrease in acid secretion, a predisposition to gastric cancer. These divergent effects of H. pylori on gastric acid secretion explain the early conflicting reports on changes in acid secretion associated with the infection. The reason why H. pylori infection produces divergent effects on gastric acid secretion is unclear, but may be related to differences in bacterial strains or genetic, dietary or other environmental factors.

Topics: Duodenal Ulcer; Gastric Acid; Gastrins; Helicobacter Infections; Helicobacter pylori; Humans; Stomach; Stomach Neoplasms

Helicobacter pylori is probably the commonest bacterial infection worldwide and is now accepted as the cause of chronic active type B gastritis. Most patients continue through life with a chronic superficial gastritis while some develop either duodenal or gastric ulcer. In a very small proportion the lymphoid reaction to H. pylori infection appears to progress to become a mucosal associated lymphoid tissue (MALT) lymphoma, while in others the evidence suggests that chronic superficial gastritis progresses to atrophy, the loss of gastric acid secretory capacity and the development of gastric cancer. The mechanisms involving H. pylori infection in peptic ulceration are increasingly well understood and H. pylori is now accepted as having a critical role in duodenal ulcer, where the prevalence of infection is 90 to 95%. More important is the dramatic reduction in duodenal ulcer recurrence after successful eradication of the organism to about 4% in a year compared to recurrences of up to 80% in those who ulcers have been healed but in whom the infection persists. There is also increasing evidence for the involvement of H. pylori in gastric ulcer, where infection is seen in between 60 and 80%, and there is a similar dramatic reduction in recurrence following cure of H. pylori infection. The progression of H. pylori gastritis from the acute infection to chronic superficial gastritis, predominantly antral gastritis or a pangastritis with increasing atrophy appears to be associated with the differing outcomes seen in this disease. Moreover, there is increasing data on the roles played by bacterial heterogeneity and the virulence of the organism, host factors such as the HLA genotype and immune response, environmental factors and the age of acquisition of infection play in determining these clinical outcomes of the disease.

Topics: Gastric Acid; Gastrins; Gastritis; Gastrointestinal Diseases; Helicobacter Infections; Helicobacter pylori; Humans; Lymphoma, B-Cell, Marginal Zone; Somatostatin; Stomach Neoplasms

Gastrin is a well known endogenous stimulator of gastric acid. In addition, recent studies have revealed that gastrin has a growth promoting effect on gastric ECL cells. Indeed, development of ECL carcinoid tumor occurs almost exclusively in patients with hypergastrinemia such as autoimmune gastritis and Zollinger-Ellison syndrome with MEN type I. We have recently cloned human gastrin receptor gene, and by using it, we found that both gastric carcinoid tumor and endocrine cell carcinoma of the stomach express significant amount of gastrin receptor gene whereas none of gastric cancer tissue shows gastrin receptor gene expression. Thus, it is clear that gastrin plays important roles in the development of gastric carcinoid tumor as well as endocrine cell carcinoma of the stomach.

Topics: Animals; Carcinoid Tumor; Duodenal Ulcer; Gastrins; Helicobacter Infections; Helicobacter pylori; Humans; Receptors, Cholecystokinin; Stomach Neoplasms

The major clinicopathologic aspects of 55 gastric neuroendocrine tumors were analyzed. Forty-six of 55 cases were well-differentiated tumors and 9 were poorly differentiated gastric neuroendocrine carcinomas. Well-differentiated gastric neuroendocrine tumors comprised 1 gastrinoma and 45 enterochromaffin-like (ECL)-cell tumors. ECL tumors were grouped depending on their clinical background. Type 1, associated with chronic atrophic gastritis of the acidopeptic mucosa (A-CAG), included 28 cases with tumor growths mainly restricted to the mucosa and submucosa, with no metastasis. Type 2, associated with hypertrophic gastropathy, included seven cases, six of which were associated with Zollinger-Ellison syndrome (ZES) and multiple endocrine neoplasia type 1 (MEN-1), including two cases with local metastasis. Type 3, not associated with any significant clinicopathologic condition (sporadic), included 10 cases, 7 of which were deeply invasive and 5 metastatic. The nine gastric neuroendocrine carcinomas were highly aggressive metastatic tumors. At follow-up, no tumor-related death was observed for type 1 and type 2 ECL tumors. Type 3 (sporadic) ECL tumors were fatal in 3 of 10 cases, and 6 of 9 patients with gastric neuroendocrine carcinomas died of their tumor disease. It is concluded that type 1 and type 2 well-differentiated ECL tumors are benign or low-grade tumors, whereas type 3 well-differentiated ECL tumors and the poorly differentiated neuroendocrine carcinomas are malignant neoplasms.

Topics: Adult; Aged; Female; Gastrins; Humans; Male; Middle Aged; Neuroendocrine Tumors; Stomach Neoplasms

The enterochromaffin-like (ECL) cell of the oxyntic, acid-secreting mucosa is at present the most extensively studied endocrine cell type in the gastrointestinal tract. It is functionally related to acid secretion through paracrine release of histamine. Its ability to undergo proliferation in response to the trophic stimulus of hypergastrinemia has important implications in pathology, being involved in the development of ECL-cell carcinoid tumors of rodents treated with powerful inhibitors of acid secretion as well as in that of most human gastric carcinoids which, with rare exceptions, are composed of ECL cells. The various aspects of the ECL-cell response to hypergastrinemia in humans are discussed in this review. The trophic effect of gastrin is specific for ECL cells and its sensitivity is enhanced by the female sex and by the genetic background of the multiple endocrine neoplasia type 1 (MEN-1) syndrome. Exposure of ECL cells to hypergastrinemia induces peculiar changes in the structure of cytoplasmic granules and triggers the phenotypic expression of a novel protein, the alpha subunit of glycoprotein hormones, absent in normal cells. The ECL-cell hyperplasia driven by hypergastrinemia may influence the hypersecretory gastric state of patients with Zollinger-Ellison syndrome (ZES) by inappropriate intramucosal secretion of histamine and may contribute to the high circulating levels of basic fibroblast growth factor (bFGF), an ECL-cell product responsible for parathyroid mitogenic effects in MEN-1 patients. However, hypergastrinemia per se cannot promote evolution of hyperplasia into carcinoid tumors, for which additional unknown factors, particularly associated with atrophic gastritis or MEN-1 syndrome, are required. ECL-cell carcinoids developing within these backgrounds have a strikingly more favorable course than their gastrin-independent counterpart. Suppression of hypergastrinemia, either by antrectomy or treatment with somatostatin analogues, may induce regression of both ECL-cell hyperplasia and gastrin-sensitive ECL-cell carcinoids.

Topics: Carcinoid Tumor; Enterochromaffin Cells; Gastric Mucosa; Gastrins; Gastritis, Atrophic; Humans; Hyperplasia; Stomach Neoplasms; Zollinger-Ellison Syndrome

In the Zollinger-Ellison syndrome, fundic argyrophil carcinoid tumors occur almost exclusively in the small subgroup of patients who also have multiple endocrine neoplasia type 1. In these patients, tumor development seems related to the same genetic alterations as those observed in other endocrine tumors related to multiple endocrine neoplasia type 1. We report here the second detailed case of a patient with sporadic Zollinger-Ellison syndrome who developed an argyrophil carcinoid tumor in nonatrophic fundic mucosa, suggesting that chronic hypergastrinemia may lead to fundic carcinoid development in nongenetically predisposed patients.

Topics: Aged; Biopsy; Carcinoid Tumor; Chronic Disease; Diagnosis, Differential; Female; Gastric Fundus; Gastric Mucosa; Gastrins; Humans; Multiple Endocrine Neoplasia Type 1; Silver Staining; Stomach Neoplasms; Zollinger-Ellison Syndrome

Gastric carcinoid tumors were previously believed to be rare lesions, representing less than 2% of all carcinoid tumors and less than 1% of all stomach neoplasms. More recent studies have demonstrated that they may constitute as much as 10-30% of carcinoid tumors. Patients with conditions associated with hypergastrinemia, such as chronic atrophic gastritis, Zollinger-Ellison syndrome with multiple endocrine neoplasia type 1 (ZES-MEN-1), and pernicious anemia, display a markedly elevated incidence of gastric carcinoid tumor formation. A classification system distinguishing three types of gastric carcinoid tumor has been proposed: 1) tumors associated with chronic atrophic gastritis, 2) tumors associated with Zollinger-Ellison syndrome, and 3) sporadic lesions. Tumors that develop in association with hypergastrinemia are usually composed of enterochromaffin-like (ECL) cells, in contrast to sporadic lesions that contain a variety of endocrine cell types (enterochromaffin, ECL, X). In both intact animal models such as the rat and Praomys (mastomys) natalensis and in isolated purified ECL cell preparations, gastrin has been demonstrated to exert a powerful trophic effect on ECL cells, in addition to stimulating histamine secretion. It is apparent that hypergastrinemia-associated gastric carcinoids display relatively benign biological behavior. Sporadic lesions require aggressive surgical management on diagnosis. Type I and type II (hypergastrinemia-associated) lesions can be managed initially by endoscopic excision of accessible tumors, followed by endoscopic surveillance. If tumors recur, antrectomy and local excision may be used to remove the source gastrin, resulting in cure in the vast majority of patients.

Topics: Animals; Carcinoid Tumor; Decision Trees; Gastric Mucosa; Gastrins; Gastritis, Atrophic; Humans; Incidence; Multiple Endocrine Neoplasia Type 1; Stomach Neoplasms; Zollinger-Ellison Syndrome

Topics: Duodenal Diseases; Duodenal Ulcer; Gastrins; Gastritis; Helicobacter Infections; Helicobacter pylori; Humans; Models, Biological; Somatostatin; Stomach Diseases; Stomach Neoplasms; Stomach Ulcer

ECL cells are argyrophilic endocrine cells of the stomach. Their distribution is species specific, however they are consistently located in the oxyntic mucosa and, in particular, in very close contact with the adenomeres of acidopeptic glands. ECL cells store histamine and are considered a key element in the mechanisms of gastric acid secretion as controlled by gastrin stimulus. Their peculiar anatomical disposition and secretory properties strongly suggest that ECL cells exert their function by a paracrine mechanism, i.e. by releasing histamine in the extracellular spaces surrounding acid-producing parietal cells. ECL cell activity is strongly stimulated by gastrin, which, once applied as a long-standing stimulus, also exerts a potent proliferating effect. Long-lasting hypergastrinaemia has been demonstrated to elicit ECL cell proliferation in laboratory animals, inducing ECL cell hyperplasia, dysplasia and ECL cell tumours, i.e. argyrophilic gastric carcinoids. However, in experimental rodents it is believed that hypergastrinaemia is not per se a stimulus capable of inducing ECL cell transformation, a predisposing genetic background being required for tumour development in endocrine organs. In man, long-standing hypergastrinaemia exerts the same proliferative pressure on ECL cells and is associated with hyperplasia with or without dysplastic changes and carcinoid development. Clinical evidence suggests that other factors, both genetic and environmental, are required to induce ECL cell transformation and carcinoid development. For this reason human gastric argyrophilic ECL carcinoids are subdivided into three main groups depending on their clinical background: (1) gastric carcinoids in patients with chronic atrophic gastritis; (2) gastric carcinoids in patients with Zollinger-Ellison and multiple endocrine neoplasia type 1 syndrome (MEN-ZES); and (3) solitary, sporadic gastric carcinoids. The clinical assessment of carcinoid-bearing patients is strongly recommended for better diagnosis and management of patients.

Topics: Animals; Carcinoid Tumor; Enterochromaffin Cells; Gastric Acid; Gastric Mucosa; Gastrins; Gastritis; Histamine Release; Humans; Multiple Endocrine Neoplasia; Omeprazole; Parietal Cells, Gastric; Stomach Neoplasms; Zollinger-Ellison Syndrome

The polypeptide hormone, gastrin, is known to promote both the in vitro and in vivo growth of human gastric cancer. This proliferative activity has been shown to be mediated by high affinity, membrane-associated receptors. This has led to the development of agents with the ability to antagonise gastrin receptor binding, which have been evaluated for their potential clinical value. Other anti-gastrin therapies have been investigated. As gastrin may act as an autocrine mediator of gastric tumor cell proliferation, anti-secretory agents have been evaluated, as have agents which induce the production of neutralising anti-gastrin antibodies in situ.

Topics: Animals; Antineoplastic Agents; Gastrins; Humans; Receptors, Cholecystokinin; Stomach Neoplasms

During the early experience with omeprazole, it was recommended that plasma gastrin levels be monitored to identify patients with 4-5-fold increases above baseline. Such patients were thought to be at an increased risk of developing gastric carcinoid tumours. Studies have established that plasma gastrin levels usually rise 2-4-fold during omeprazole therapy, there being considerable inter- and intra-individual variation. Approximately 3.3% of patients have plasma gastrin levels above 400 pg/ml when treated continuously for 1 year. In clinical practice, it is not cost-effective to screen all patients to detect such a small percentage, particularly given the paucity of realistic treatment options in such patients, and the growing evidence that hypergastrinaemia during omeprazole treatment is of little, if any, clinical significance.

Topics: Colonic Neoplasms; Drug Monitoring; Fasting; Gastric Mucosa; Gastrins; Humans; Omeprazole; Ranitidine; Recurrence; Stomach Neoplasms; Vagotomy, Proximal Gastric

A 42-yr-old woman presented with multiple carcinoid tumors in her stomach and a markedly elevated serum gastrin level. Total gastrectomy was performed, and 22 small carcinoid tumors were found in the gastric fundus and body. A high serum gastrin level was revealed in the gastric drainage veins; still more gastrin was detected in the carcinoid tumors by the immunohistochemical method, and many secretory granules were found in the tumor cells with an electron microscope. The fundic gland showed marked atrophy, and there was some conglobation of endocrine cells (ECL cells). This case suggests a hypothetic sequence of anacidity due to atrophic gastritis----hypergastrinemia----proliferation of ECL cells----multiple carcinoids. A search of the Japanese literature revealed that 26 cases of multiple carcinoid tumors in the stomach have been reported so far, and most of them support this hypothesis.

Topics: Adult; Carcinoid Tumor; Female; Gastrins; Humans; Neoplasms, Multiple Primary; Stomach Neoplasms

Achlorhydria has been discussed as a possibly dangerous consequence of therapeutic inhibition of gastric acid secretion since the introduction of H2-receptor antagonists. The risk of long-term hypergastrinaemia has only been considered for about 5 years. The reason for this was the demonstration that gastric carcinoids (ECLomas) observed after life-long treatment of rats with the proton pump inhibitor omeprazole could also be produced in rats by other methods leading to long-lasting profound hypergastrinaemia. Such methods were the 80% resection of the oxyntic mucosa or feeding of ranitidine (2000 mg/day) for 2 years. The endocrine tumours corresponded to the gastric carcinoids found in patients with long-lasting hypergastrinaemia due to pernicious anaemia or with a gastrinoma as part of the MEN I syndrome. Neither in animals nor in man could other endocrine tumours or adenocarcinomas of the gastrointestinal tract be related to hypergastrinaemia. Epidemiologic data do not support gastrin dependence of adenocarcinoma of the stomach or the colon. Experimental findings of gastrin effects on tumour growth in vivo and in vitro have been contradictory and may be explained by the presence of gastrin receptors on tumour cells and the role of gastrin as an autocrine growth factor in some of these tumours. Since acid blockade by proton pump inhibitors or H2-receptor blockers dose-dependently increase serum gastrin levels, patients with ranitidine-resistant peptic ulceration receiving long-term treatment with high-dose omeprazole have been followed up with serial gastric biopsy specimens for up to 5 years. Complete healing, moderate hypergastrinaemia, and a slight hyperplasia but no dysplasia of the ECL cells in the oxyntic mucosa have been observed, which seemed to be correlated to chronic gastritis progressing over the years. Despite these negative findings excessive hypergastrinaemia by overdosage of potent drugs for inhibition of gastric secretion should be avoided and monitoring of plasma gastrin levels is recommended in case of long-term treatment.

Topics: Achlorhydria; Adenocarcinoma; Colonic Neoplasms; Enterochromaffin Cells; Gastric Acid; Gastric Mucosa; Gastrins; Gastritis; Histamine H2 Antagonists; Humans; Stomach Neoplasms

Topics: Animals; Clofibric Acid; Enterochromaffin Cells; Female; Fibric Acids; Gastric Mucosa; Gastrins; Growth Substances; Hypolipidemic Agents; Male; Neoplasms, Experimental; Omeprazole; Portacaval Shunt, Surgical; Rats; Somatostatin; Stomach Neoplasms

Topics: Achlorhydria; Carcinoid Tumor; Gastrectomy; Gastrins; Gastritis, Atrophic; Humans; Stomach Neoplasms

Topics: Carcinoid Tumor; Enterochromaffin Cells; Female; Gastrins; Humans; Male; Omeprazole; Pyloric Antrum; Sex Factors; Stomach Neoplasms; Zollinger-Ellison Syndrome

Topics: Adenocarcinoma; Carcinoid Tumor; Enterochromaffin Cells; Gastric Mucosa; Gastrins; Gastritis, Atrophic; Humans; Omeprazole; Stomach Neoplasms; Zollinger-Ellison Syndrome

Of 44 patients with the Zollinger-Ellison syndrome treated at our institution, nine appeared to have undergone "regression" of their gastrinomas. Six of the nine patients had sporadic gastrinomas and became permanently eugastrinemic following excision of nodal metastases and total gastrectomy (n = 4), antrectomy (n = 1), or pancreatoduodenectomy (n = 1) (mean survival, 13 years). The other three patients had Zollinger-Ellison syndrome as part of the multiple endocrine adenopathy type 1 syndrome and became temporarily eugastrinemic after total gastrectomy (mean survival, 11 years). Occult submucosal duodenal-wall microgastrinomas (mean size, 3.0 mm) were found to have been serendipitously excised in four patients. Long-term follow-up of these nine patients, as well as of six other patients described in the literature, demonstrates that excision of occult duodenal-wall gastrinomas provides a plausible explanation for the phenomenon of apparent regression of primary gastrinomas and the eugastrinemia that may follow total gastrectomy.

Topics: Adolescent; Adult; Aged; Duodenal Neoplasms; Female; Follow-Up Studies; Gastrectomy; Gastrinoma; Gastrins; Humans; Male; Middle Aged; Neoplasm Regression, Spontaneous; Neoplasms, Multiple Primary; Neoplasms, Unknown Primary; Pancreatic Neoplasms; Stomach Neoplasms; Zollinger-Ellison Syndrome

Novel, powerful and long-acting inhibitors of gastric acid secretion include second generation H2-blockers and so-called proton pump inhibitors, such as omeprazole. Gastric carcinoids were found to develop in experimental animals as a consequence of continuous long-term administration of several of these highly effective anti secretory drugs. This unwanted side effect is now thought to reflect the fact (1) that pharmacological blockade of acid secretion results in hypergastrinaemia, and (2) that long-standing hypergastrinaemia gives rise to hyperplasia of certain endocrine cells, the so-called ECL cells, in the gastric mucosa. The carcinoids that develop in the rat stomach after lifelong treatment with antisecretagogues arise from the ECL cells. The proposed sequence of events is acid blockade--hypergastrinaemia--ECL cell hyperplasia--carcinoid. This concept, referred to as the gastrin hypothesis, maintains that the ECL cell hyperplasia (and possibly the carcinoids) is a consequence of long-term continuous hypergastrinaemia.

Topics: Animals; Anti-Ulcer Agents; Carcinoid Tumor; Endocrine Glands; Gastric Mucosa; Gastrins; Humans; Models, Biological; Stomach Neoplasms

A 42-year-old white woman was seen by her physician because of somatic complaints of the neck and right arm discomfort, difficulty in swallowing, and "heartburn." Findings of the workup led to the diagnosis of metastatic ossified gastric carcinoid. Review of the literature suggests that this is the third report of ossified gastric carcinoid. However, this is the only case in which such a tumor was associated with hypergastrinemia, gastric (antiparietal cell), and thyroid (antimicrosomal) autoantibodies.

Topics: Adult; Autoantibodies; Carcinoid Tumor; Female; Gastrins; Humans; Ossification, Heterotopic; Parietal Cells, Gastric; Stomach Neoplasms

Newer potent and long-acting inhibitors of acid secretion, such as the proton pump inhibitor omeprazole, are becoming available for general use. These drugs promise to control acid-peptic disease effectively in patients who do not respond adequately to conventional short-acting H2-receptor antagonists. The safety of chronic administration of these drugs has come into question, however. Lifelong profound inhibition of acid secretion in rats induced by superpotent inhibitors of acid secretion or subtotal fundectomy is associated with the development of carcinoid tumors of enterochromaffin-like (ECL) cells in the gastric corpus. Available evidence supports a role of gastrin, which becomes chronically elevated in animals subjected to prolonged and profound hypochlorhydria. In humans, hypergastrinemic states such as Zollinger-Ellison syndrome and atrophic gastritis are associated with an increased risk of ECL-cell carcinoid tumors. Such observations have raised concern that humans may also be susceptible to carcinoid tumor formation in response to potent inhibitors of acid secretion. To date, however, no cases of carcinoid tumor have been attributed to the use of omeprazole in humans. If achlorhydric doses are not used, significant hypergastrinemia can be avoided while effectiveness of treatment is maintained. Such measures should minimize any risk of ECL-cell carcinoid tumors in humans taking potent long-term antisecretory drugs.

Topics: Achlorhydria; Animals; Carcinoid Tumor; Cell Transformation, Neoplastic; Enterochromaffin Cells; Gastrins; Humans; Omeprazole; Rats; Stomach Neoplasms

Three cases of gastric carcinoid polypi associated to atrophic gastritis and high levels of seric gastrin, are presented. One of the cases was a multiple micropolyposis the literature regarding this association is reviewed and the therapy discussed. Tumors of greater than 2 cm have to be considered potentially malignant and be treated likewise. The treatment of the micropolyposis is not well established.

Topics: Achlorhydria; Adult; Autoimmune Diseases; Carcinoid Tumor; Female; Follow-Up Studies; Gastrins; Gastritis, Atrophic; Humans; Male; Middle Aged; Neoplasms, Multiple Primary; Polyps; Pyloric Antrum; Stomach Neoplasms

Topics: Colorectal Neoplasms; Gastrins; Gonadal Steroid Hormones; Humans; Neoplasms, Hormone-Dependent; Stomach Neoplasms

Although carcinoid tumors only infrequently (2-6%) have a gastric localization, in recent years several cases have been described of this tpe of neoplasm in association with atrophic gastritis (with or without pernicious anemia). A possible carcinogenetic effect of sustained hypergastrinemia on the enterochromaffin-like cells (ECL) of the gastric mucosa has been postulated. A new case of these characteristics in reported, and a review is made of the pathogenic hypotheses in the literature on this peculiar type of tumors and their possible clinical implications.

Topics: Adult; Carcinoid Tumor; Gastrins; Gastritis; Gastritis, Atrophic; Humans; Male; Stomach Neoplasms

Topics: Achlorhydria; Adenocarcinoma; Animals; Anti-Ulcer Agents; Carcinoid Tumor; Gastric Acid; Gastric Mucosa; Gastrins; Humans; Male; Rats; Serotonin; Stomach Neoplasms

We have described a 40-year-old woman whose classic adrenal insufficiency, achlorhydria, and hypergastrinemia was complicated by the development of a gastric carcinoid. There is now evidence that patients with elevated serum gastrin levels are at increased risk for this rare tumor.

Topics: Achlorhydria; Addison Disease; Adult; Carcinoid Tumor; Female; Gastrins; Humans; Stomach Neoplasms

Recent advances in understanding the physiology and pathophysiology of the gastrointestinal hormone, gastrin, are reviewed. Details of gastrin biosynthesis, secretion, and cellular actions may have broad implications for other peptide hormones. Potentially useful antigastrin drugs are described. Areas of future development are suggested.

Topics: DNA Replication; Gastric Acid; Gastric Mucosa; Gastrins; Humans; Peptic Ulcer; Receptors, Gastrointestinal Hormone; Stomach Neoplasms; Vagotomy; Zollinger-Ellison Syndrome

Topics: Achlorhydria; Animals; Gastric Mucosa; Gastrins; Humans; Rats; Stomach Neoplasms

Topics: Animals; Diagnosis, Differential; Digestive System; Duodenal Ulcer; Enterochromaffin Cells; Fluorescent Antibody Technique; Gastrins; Gastrointestinal Diseases; Gastrointestinal Hormones; Histocytochemistry; Humans; Hyperplasia; Immunologic Techniques; Intestinal Mucosa; Microscopy, Electron; Neural Crest; Regeneration; Stomach Neoplasms

The accumulating evidence of an association between antrum-sparing hypergastrinaemic atrophic gastritis, frequently associated with pernicious anaemia, and the occurrence of gastric carcinoid tumours is briefly reviewed. The development of argyrophil cell carcinoid tumours in the atrophic fundic mucosa seems to be related to argyrophil cell hyperplasia caused by hypergastrinaemia. Epidemiologic considerations indicate that the gastric carcinoid generally is underdiagnosed and that the incidence of this tumour is higher than previously recognized. The clinical relevance of minute gastric carcinoids, or endocrine cell 'adenomas', is obscure. However, larger tumours should be regarded as potentially malignant. These findings are relevant to the aspect of long-term medically induced achlorhydria leading to hypergastrinaemia.

Topics: Achlorhydria; Adenoma; Anemia, Pernicious; Atrophy; Carcinoid Tumor; Cell Division; Epidemiologic Methods; Gastrins; Gastritis; Humans; Stomach Neoplasms

The stomach is rich in endocrine cells, most of which are still unidentified with respect to the peptide hormones they produce. The endocrine cell populations in the antrum usually differ from those in the oxyntic mucosa. Gastrin cells are found in the antrum and respond readily to stimuli from the gastric lumen, such as changes in the pH and the presence of food. In order to study the functional control of the antral gastrin cell, rats were subjected to different kinds of surgery. The serum gastrin concentrations in the various experimental groups were measured 8-10 weeks after the operations. Elevated antral pH raised the serum gastrin concentration. The combination of elevated antral pH and the passage of food over the pyloric glands produced gastrin cell hyperplasia. The operation that was most effective in inducing gastrin cell hyperplasia was removal of the acid-producing part of the stomach. Interestingly, gastrin cell hyperplasia was seen also after bilateral truncal vagotomy, indicating that an intact vagal innervation is not essential for the development of gastrin cell hyperplasia. Enterochromaffin-like (ECL) cells are endocrine/paracrine cells that are numerous in the acid-producing part of the stomach in many species. In the rat, they occur predominantly in the basal half of the oxyntic mucosa and produce and store histamine. The ECL cells have an unknown function and do not seem to respond to stimuli from the gastric lumen. They are activated by circulating gastrin and by vagal excitation. Gastrin mobilises histamine from these cells and activates the histamine-forming enzyme, histidine decarboxylase. Long-term hypergastrinaemia produces diffuse ECL cell hyperplasia, whereas hypogastrinaemia (following removal of the endogenous stores of gastrin by antrectomy) reduces the ECL cell number. Portacaval shunt brings about a marked increase in the number of ECL cells through an unknown mechanism. Also neuronal stimuli are important for the trophic control of the ECL cells. Studies of unilaterally vagotomised rats showed reduced weight and thickness of the oxyntic mucosa as well as a markedly reduced number of ECL cells on the denervated side. Gastric carcinoids in man are rare tumours predominantly made up of ECL cells. The incidence of such tumours is increased in patients with hypergastrinaemia (pernicious anaemia, Zollinger-Ellison syndrome). A diffuse ECL cell hyperplasia is a common finding in such patients, which is in keeping with the know

Topics: Animals; Carcinoid Tumor; Chromaffin System; Enterochromaffin Cells; Gastrins; Humans; Hydrogen-Ion Concentration; Hyperplasia; Microscopy, Electron; Portacaval Shunt, Surgical; Rats; Stomach; Stomach Neoplasms

The value of cimetidine in treatment of duodenal ulcer and the Zollinger-Ellison syndrome appears to be well established. The drug has been enthusiastically embraced and widely used by practicing physicians. As with virtually all drugs used in the practice of medicine, cimetidine is not without its adverse effects. In some instances these effects may result from actions of cimetidine on H2-receptors on many widely distributed and diverse cells other than parietal cells, to which its potent acid-inhibiting properties are directed. Other adverse effects of cimetidine may be idiosyncratic, and, therefore, not predictable on a pharmacologic basis. In some instances the mechanisms responsible for cimetidine's adverse effects hav e yet to be defined. An assortment of abnormalities reported in patients receiving cimetidine have been suggested, but not proven, to represent adverse effects of the drug. Considering its extremely wide use, serious toxicity with cimetidine is rare. However, no potent drug, including cimetidine, used in the practice of medicine is without its adverse effects. Recognizing the present and projected extensive and probably long-term use of cimetidine, physicians and surgeons treating patients with cimetidine must maintain continued surveillance in order to detect and clarify potential undesired consequences of cimetidine administration.

Topics: Agranulocytosis; Animals; Bone Marrow; Central Nervous System; Chemical and Drug Induced Liver Injury; Cimetidine; Creatinine; Duodenal Ulcer; Endocrine Glands; Gastric Juice; Gastrins; Guanidines; Humans; Immunity, Cellular; Intrinsic Factor; Liver; Pancreatitis; Receptors, Histamine H2; Risk; Stomach Neoplasms; Transaminases

Topics: Anemia, Pernicious; Depression, Chemical; Digestive System Physiological Phenomena; Gastric Acid; Gastrins; Hormones; Humans; Pancreatic Juice; Pepsin A; Peptic Ulcer; Somatostatin; Stomach Neoplasms

Topics: Bombesin; Cholecystokinin; Cimetidine; Epidermal Growth Factor; Gastric Inhibitory Polypeptide; Gastrins; Gastrointestinal Hormones; Humans; Motilin; Nerve Tissue; Pancreas; Pancreatic Polypeptide; Pituitary Gland; Secretin; Somatostatin; Stomach Neoplasms; Vasoactive Intestinal Peptide; Zollinger-Ellison Syndrome

Topics: Animals; Gastric Mucosa; Gastrins; Humans; Intestinal Mucosa; Nervous System; Pancreas; Pancreatic Neoplasms; Stomach Neoplasms; Zollinger-Ellison Syndrome

Topics: Adenoma, Islet Cell; Cholecystokinin; Gastric Juice; Gastrins; Gastrointestinal Hormones; Glucagon; Humans; Neoplasms; Pancreatic Neoplasms; Paraneoplastic Endocrine Syndromes; Peptides; Precancerous Conditions; Secretin; Somatostatin; Stomach Neoplasms; Vasoactive Intestinal Peptide; Zollinger-Ellison Syndrome

With combined immunofluorescent, cytochemical and electron microscopic investigations the enterochromaffin cell system has been differentiated into 5 distinct endocrine cell types in the human stomach and into 8 cell types in the intestine. These endocrine cells are probably of neuroectodermal origin and belong to the APUD (amine precursor uptake and decarboxylation)-system. Maximal gastrointestinal hormone concentrations as determined by tissue extracts correlate fairly well to the location of each endocrine cell type in various segments of the gastrointestinal tract. In certain gastroenteropathies the pathophysiological disturbances can be explained by pathomorphological alterations of the disseminated endocrine cells. 1. The gastrin-producing G-cell is the predominating endocrine cell in the gastric antrum. Besides immunocytochemistry the G-cell can be demonstrated with argyrophilic reaction (Grimelius, 1968), masked metachromasia and leadhematoxylin. The ultrastructural features are variable, depending on functional activity. The secretory granules are usually only slightly osmiophilic, measuring 200 till 250 nm in diameter. By some working groups a positive immunofluorescence with gastrin-antisera has been demonstrated in A1- or D-cells of the pancreatic islets. However, numerous negative results have been reported, too. Considering physiological conditions, a gastrin-secretion of the human pancreatic islets has not been secured without doubt. 2. The EC-cell produces serotonin and in the intestine motilin, too. Besides the formaldehyde-induced fluorescence, these cells can be demonstrated with diazonium and argentaffin reactions, less specific with argyrophilic methods. Ultrastructurally the EC-granules are easily differeniated from the other endocrine cells by their pronounced osmiophilia and pleomorphism. In experimental conditions the EC-cells demonstrate species- and site-specific alterations. With reserpine no ultrastructural changes were demonstrable in EC-cells of the rat. However, marked ultrastructural alterations with an increase of the hormone-producing organelle system were noticed after administration of parachlorophenylalanine (PCPA) which interferes with serotonine synthesis; 5. The gastric D-cells are characterized by large secretory granules similar to pancreatic D-cells. They secrete the HCl-inhibitory peptide somatostatin. 4. The D1-cell is a cell type with unknown function. The cytoplasm contains small granules with variable elect

Topics: Adenoma, Islet Cell; Anemia, Pernicious; Chromaffin System; Digestive System; Duodenal Ulcer; Endocrine System Diseases; Enterochromaffin Cells; Esophagitis, Peptic; Gastrectomy; Gastric Mucosa; Gastrins; Gastritis; Gastrointestinal Hormones; Gastrointestinal Neoplasms; Humans; Intestinal Mucosa; Metabolic Diseases; Serotonin; Somatostatin; Stomach Neoplasms; Stomach Ulcer; Syndrome; Zollinger-Ellison Syndrome

Topics: Anemia, Pernicious; Calcium; Dietary Proteins; Duodenal Ulcer; Gastric Juice; Gastrins; Gastritis; Glucagon; Humans; Hyperplasia; Intestine, Small; Kidney Failure, Chronic; Pyloric Antrum; Pyloric Stenosis; Secretin; Stomach Neoplasms; Stomach Ulcer; Vagotomy; Zollinger-Ellison Syndrome

Topics: Adenoma, Islet Cell; Adolescent; Adult; Aged; Child; Duodenal Neoplasms; Duodenal Ulcer; Female; Gastrectomy; Gastric Juice; Gastrins; Humans; Male; Middle Aged; Neoplasm Metastasis; Pancreatic Neoplasms; Peptic Ulcer; Radiography; Radioimmunoassay; Stomach Neoplasms; Zollinger-Ellison Syndrome

Topics: Acetylcholine; Anemia, Pernicious; Atrophy; Calcium; Carcinoma; Catecholamines; Circadian Rhythm; Duodenal Ulcer; Gastric Juice; Gastric Mucosa; Gastrins; Gastritis; Gastrointestinal Diseases; Hormones, Ectopic; Humans; Ligation; Pancreatic Ducts; Secretin; Stimulation, Chemical; Stomach Diseases; Stomach Neoplasms; Stomach Ulcer; Zollinger-Ellison Syndrome

Topics: Animals; Cats; Chronic Disease; Creatinine; Dogs; Duodenal Ulcer; Esophageal Achalasia; Esophageal Diseases; Gastric Mucosa; Gastrins; Gastritis; Humans; Hydrogen-Ion Concentration; Kidney Failure, Chronic; Peptic Ulcer; Pyloric Antrum; Rats; Scleroderma, Localized; Stomach Neoplasms; Vagotomy; Zollinger-Ellison Syndrome

Topics: Animals; Aspirin; Atropine; Bile Acids and Salts; Cell Membrane Permeability; Ethanol; Gastric Juice; Gastric Mucosa; Gastrins; Gastritis; Gastrointestinal Hemorrhage; Humans; Hydrogen; Hydrogen-Ion Concentration; Ion Exchange; Membrane Potentials; Pentagastrin; Pepsin A; Pyloric Antrum; Smoking; Sodium; Stomach Neoplasms

Topics: Adolescent; Adult; Aged; Anemia, Hypochromic; Anemia, Pernicious; Atrophy; Autoantibodies; Autoimmune Diseases; Chronic Disease; Female; Gastrins; Gastritis; Gastrointestinal Hemorrhage; Humans; Male; Middle Aged; Postgastrectomy Syndromes; Stomach Neoplasms; Stomach Ulcer

Topics: Digestion; Gastric Mucosa; Gastrins; Gastritis; Gastrointestinal Diseases; Gastrointestinal Neoplasms; Humans; Intestine, Small; Pancreas; Paraneoplastic Endocrine Syndromes; Stomach Neoplasms; Zollinger-Ellison Syndrome

Topics: Adrenal Cortex Hormones; Anemia, Pernicious; Animals; Antibodies; Autoantibodies; Biopsy; Chronic Disease; Gastric Juice; Gastric Mucosa; Gastrins; Gastritis; Humans; Intrinsic Factor; Schilling Test; Stomach; Stomach Neoplasms; Stomach Ulcer; Vitamin B 12

Topics: Adenoma; Diagnosis, Differential; Gastrectomy; Gastric Juice; Gastrins; Humans; Neoplasm Metastasis; Peptic Ulcer; Radioimmunoassay; Stomach Neoplasms; Zollinger-Ellison Syndrome

Topics: Biliary Tract Diseases; Ceruletide; Cholangiography; Cholelithiasis; Duodenal Ulcer; Endoscopy; Gastrins; Gastrointestinal Diseases; Gastrointestinal Hemorrhage; Gastrointestinal Hormones; Humans; Intestinal Absorption; Lactose Intolerance; Pancreatic Diseases; Peptic Ulcer; Radionuclide Imaging; Secretin; Stomach Neoplasms

Topics: Diagnosis, Differential; Duodenal Ulcer; Gastric Acidity Determination; Gastric Juice; Gastric Mucosa; Gastrins; Gastritis; Humans; Hydrogen-Ion Concentration; Hypertrophy; Intubation, Gastrointestinal; Stomach Neoplasms

Topics: Anemia, Pernicious; Antibodies; Atrophy; Autoimmune Diseases; Capillaries; Chronic Disease; Dyspepsia; Gastrectomy; Gastric Juice; Gastric Mucosa; Gastrins; Gastritis; Humans; Hypertrophy; Intrinsic Factor; Metaplasia; Mitosis; Pentagastrin; Pepsin A; Peptic Ulcer; Pyloric Antrum; Radiography; Stomach; Stomach Neoplasms; Thyroid Diseases; Vagotomy

Topics: Abdomen; Duodenal Diseases; Duodenal Neoplasms; Duodenal Ulcer; Esophageal Achalasia; Esophageal Diseases; Esophageal Neoplasms; Esophagitis; Esophagoplasty; Esophagus; Female; Gastrins; Gastrointestinal Hemorrhage; Hernia, Diaphragmatic; Humans; Male; Peptic Ulcer; Peptic Ulcer Perforation; Postoperative Complications; Rupture, Spontaneous; Stomach Diseases; Stomach Neoplasms; Stomach Ulcer; Stress, Psychological; Vagotomy

Topics: Colitis, Ulcerative; Gastrins; Gastrointestinal Diseases; Gastroscopy; Humans; Lactose Intolerance; Malabsorption Syndromes; Peptic Ulcer; Stomach Neoplasms

Topics: Air; Anemia, Pernicious; Angiography; Barium; Biopsy; Cholangiography; Colonic Diseases; Contrast Media; Cytodiagnosis; Duodenal Diseases; Endoscopy; Enema; Esophageal Diseases; Gastrins; Gastroenterology; Gastrointestinal Diseases; Gastrointestinal Neoplasms; Gastroscopy; Glucose; Glucuronidase; Gold Isotopes; Insulin; Liver Diseases; Methionine; Pancreatic Diseases; Peptic Ulcer; Peptides; Rectal Neoplasms; Rose Bengal; Selenium; Silicones; Stomach Neoplasms; Vagotomy

Topics: Gastric Acidity Determination; Gastric Juice; Gastrins; Gastritis; Histamine; Humans; Inhalation; Intubation, Gastrointestinal; Methods; Peptic Ulcer; Radio; Radioisotopes; Radionuclide Imaging; Stomach; Stomach Neoplasms; Technetium; Vagotomy; Zollinger-Ellison Syndrome

In patients with autoimmune atrophic gastritis and achlorhydria, hypergastrinemia is associated with the development of type 1 gastric neuroendocrine tumors (gNETs). Twelve months of treatment with netazepide (YF476), an antagonist of the cholecystokinin B receptor (CCKBR or CCK2R), eradicated some type 1 gNETs in patients. We investigated the mechanisms by which netazepide induced gNET regression using gene expression profiling.. We obtained serum samples and gastric corpus biopsy specimens from 8 patients with hypergastrinemia and type 1 gNETs enrolled in a phase 2 trial of netazepide. Control samples were obtained from 10 patients without gastric cancer. We used amplified and biotinylated sense-strand DNA targets from total RNA and Affymetrix (Thermofisher Scientific, UK) Human Gene 2.0 ST microarrays to identify differentially expressed genes in stomach tissues from patients with type 1 gNETs before, during, and after netazepide treatment. Findings were validated in a human AGS. Levels of pappalysin 2 (PAPPA2) messenger RNA were reduced significantly in gNET tissues from patients receiving netazepide therapy compared with tissues collected before therapy. PAPPA2 is a metalloproteinase that increases the bioavailability of insulin-like growth factor (IGF) by cleaving IGF binding proteins (IGFBPs). PAPPA2 expression was increased in the gastric corpus of patients with type 1 gNETs, and immunohistochemistry showed localization in the same vicinity as CCK2R-expressing enterochromaffin-like cells. Up-regulation of PAPPA2 also was found in the stomachs of INS-GAS mice. Gastrin increased PAPPA2 expression with time and in a dose-dependent manner in gastric AGS. In an analysis of human gNETS and mice, we found that gastrin up-regulates the expression of gastric PAPPA2. Increased PAPPA2 alters IGF bioavailability, cell migration, and tissue remodeling, which are involved in type 1 gNET development. These effects are inhibited by netazepide.

Topics: Animals; Benzodiazepines; Benzodiazepinones; Cell Line, Tumor; Disease Models, Animal; Gastric Mucosa; Gastrins; Gene Knockdown Techniques; Humans; Mice; Mice, Transgenic; Neuroendocrine Tumors; Organoids; Phenylurea Compounds; Pregnancy-Associated Plasma Protein-A; Primary Cell Culture; Receptor, Cholecystokinin B; Stomach Neoplasms; Treatment Outcome

Develop a program to identify, treat, and prevent severe atrophic gastritis to reduce gastric cancer incidence and mortality.. In total, 2,847 people aged > 40 years old underwent serological noninvasive screening for atrophic gastritis by identifying postprandial gastrin-17 and pepsinogen-1 in the fasting state. Anti-H pylori IgG was found in 2,134 patients. Seven years later, 2,220 patientswho had undergone serological noninvasive screening were asked to fill out a questionnaire survey (were interviewed). We could not find any information on 627 of 2,847 patients. Next, 75 patients with multifocal atrophic gastritis who underwent gastroscopy and biopsies (the Updated Sydney System (USS)) were selected. To study gastrin-17 production, morpho-functional correlation was studies in 75 patients with multifocal atrophic gastritis.. During seven years, no reported case of gastric cancer was done among 2,220 persons who underwent serological screening and treatment. In the same population, 4.3 persons who did not receive screening during the same period, developed gastric cancer and died of it. In this study, we can say that 4.3 lives were saved out of 2,220 tested persons. The cost for screening this number of people amounted to €23,750. A comparison of the prevalence rate of the four stages of multifocal atrophic gastritis based on the data of the histopathology tests and noninvasive serologic screening in accordance with OLGA classification showed a strong correlation (the correlation coefficient is 0.812). This finding suggested that using this classification not only for histopathology tests for atrophic gastritis but also for serologic markers of antral mucosa and corpus ventriculi atrophy: gastrin-17 and pepsinogen-1.. Complex pathogenetic treatment of atrophic gastritis significantly reduced gastric cancer risk and incidence for such patients.
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Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Biomarkers; Case-Control Studies; Female; Follow-Up Studies; Gastric Mucosa; Gastrins; Gastritis, Atrophic; Gastroscopy; Helicobacter Infections; Helicobacter pylori; Humans; Male; Mass Screening; Pepsinogen A; Precancerous Conditions; Prognosis; Prospective Studies; Stomach Neoplasms

Helicobacter pylori (Hp) infection affects a substantial proportion of the world population and is a major risk factor of gastric cancer (GC). The caveats of common Hp-tests can be evaded by a serological biomarker test (GastroPanel®, Biohit Oyj, Helsinki), the most comprehensive Hp-test on the market. The clinical validation of Helicobacter pylori IgG ELISA of the new-generation GastroPanel® test is reported. The aim of the study is to validate the clinical performance of the Helicobacter pylori IgG ELISA test in diagnosis of biopsy-confirmed Hp-infection in gastroscopy referral patients.. A cohort of 101 patients (mean age=50.1 years) referred for gastroscopy at the outpatient Department of Gastroenterology (SM Clinic, St. Petersburg) were examined by two test versions to validate the new-generation GastroPanel®. All patients were examined by gastroscopy and biopsies, which were stained with Giemsa for specific identification of Hp in the antrum (A) and corpus (C).. Biopsy-confirmed Hp-infection was found in 64% of patients, most often confined to antrum. The overall agreement between Hp IgG ELISA and gastric biopsies in Hp-detection was 91% (95%CI=84.1-95.8%). Hp IgG ELISA diagnosed biopsy-confirmed Hp (A&C) with sensitivity (SE) of 92.3%, specificity (SP) of 88.6%, positive predictive value (PPV) of 93.8% and negative predictive value (NPV) of 86.1%, with AUC=0.904 (95%CI=0.842-0.967). In ROC analysis for Hp detection (A&C), Hp IgG ELISA shows AUC=0.978 (95%CI=0.956-1.000).. The Hp IgG ELISA test successfully concludes the clinical validation process of the new-generation GastroPanel® test, which retains the unrivalled diagnostic performance of all its four biomarkers, extensively documented for the first-generation test in different clinical settings.

Topics: Adolescent; Adult; Antibodies, Bacterial; Biopsy; Enzyme-Linked Immunosorbent Assay; Female; Gastrins; Gastritis, Atrophic; Gastroscopy; Helicobacter Infections; Helicobacter pylori; Humans; Immunoglobulin G; Male; Middle Aged; Pepsinogen A; Pepsinogen C; Referral and Consultation; Stomach; Stomach Neoplasms; Young Adult

Helicobacter-induced atrophic gastritis with a hypochlorhydric milieu is a risk factor for gastric cancer. Microbes colonising acid-free stomach oxidise ethanol to acetaldehyde, a recognised group 1 carcinogen.. To assess gastric production of acetaldehyde and its inert condensation product, non-toxic 2-methyl-1,3-thiazolidine-4-carboxylic acid (MTCA), after alcohol intake under treatment with slow-release L-cysteine or placebo.. Seven patients with biopsy-confirmed atrophic gastritis, low serum pepsinogen and high gastrin-17 were studied in a cross-over single-blinded design. On separate days, patients randomly received 200 mg slow-release L-cysteine or placebo with intragastric instillation of 15% (0.3 g/kg) ethanol. After intake, gastric concentrations of ethanol, acetaldehyde, L-cysteine and MTCA were analysed.. Administration of L-cysteine increased MTCA (p < .0004) and decreased gastric acetaldehyde concentrations by 68% (p < .0001). The peak L-cysteine level was 7552 ± 2687 μmol/L at 40 min and peak MTCA level 196 ± 98 μmol/L at 80 min after intake. Gastric L-cysteine and MTCA concentrations were maintained for 3 h. The AUC for MTCA was 11-fold higher than acetaldehyde, indicating gastric first-pass metabolism of ethanol. With placebo, acetaldehyde remained elevated also at low ethanol concentrations representing 'non-alcoholic' beverages and food items.. After gastric ethanol instillation, slow-release L-cysteine eliminates acetaldehyde to form inactive MTCA, which remains in gastric juice for up to 3 h. High acetaldehyde levels indicate a marked gastric first-pass metabolism of ethanol resulting in gastric accumulation of carcinogenic acetaldehyde. Local exposure of the gastric mucosa to acetaldehyde can be mitigated by slow-release L-cysteine capsules.

Topics: Acetaldehyde; Adult; Carbolines; Carcinogenesis; Cross-Over Studies; Cysteine; Delayed-Action Preparations; Ethanol; Female; Gastric Juice; Gastric Mucosa; Gastrins; Gastritis, Atrophic; Helicobacter; Humans; Male; Middle Aged; Single-Blind Method; Stomach Neoplasms; Sweden

Autoimmune chronic atrophic gastritis (CAG) causes hypochlorhydria and hypergastrinaemia, which can lead to enterochromaffin-like (ECL) cell hyperplasia and gastric neuroendocrine tumours (type 1 gastric NETs). Most behave indolently, but some larger tumours metastasise. Antrectomy, which removes the source of the hypergastrinaemia, usually causes tumour regression. Non-clinical and healthy-subject studies have shown that netazepide (YF476) is a potent, highly selective and orally-active gastrin/CCK-2 receptor antagonist. Also, it is effective in animal models of ECL-cell tumours induced by hypergastrinaemia.. To assess the effect of netazepide on tumour biomarkers, number and size in patients with type I gastric NETs.. We studied 8 patients with multiple tumours and raised circulating gastrin and chromogranin A (CgA) concentrations in an open trial of oral netazepide for 12 weeks, with follow-up 12 weeks later. At 0, 6, 12 and 24 weeks, we carried out gastroscopy, counted and measured tumours, and took biopsies to assess abundances of several ECL-cell constituents. At 0, 3, 6, 9, 12 and 24 weeks, we measured circulating gastrin and CgA and assessed safety and tolerability.. Netazepide was safe and well tolerated. Abundances of CgA (p<0.05), histidine decarboxylase (p<0.05) and matrix metalloproteinase-7(p<0.10) were reduced at 6 and 12 weeks, but were raised again at follow-up. Likewise, plasma CgA was reduced at 3 weeks (p<0.01), remained so until 12 weeks, but was raised again at follow-up. Tumours were fewer and the size of the largest one was smaller (p<0.05) at 12 weeks, and remained so at follow-up. Serum gastrin was unaffected.. The reduction in abundances, plasma CgA, and tumour number and size by netazepide show that type 1 NETs are gastrin-dependent tumours. Failure of netazepide to increase serum gastrin further is consistent with achlorhydria. Netazepide is a potential new treatment for type 1 NETs. Longer, controlled trials are justified.. European Union EudraCT database 2007-002916-24 https://www.clinicaltrialsregister.eu/ctr-search/search?query=2007-002916-24ClinicalTrials.gov NCT01339169 http://clinicaltrials.gov/ct2/show/NCT01339169?term=yf476&rank=5.

Topics: Aged; Antineoplastic Agents; Benzodiazepinones; Biomarkers; Biopsy; Chromogranin A; Female; Gastric Mucosa; Gastrins; Gastritis, Atrophic; Gastroscopy; Humans; Male; Middle Aged; Neuroendocrine Tumors; Phenylurea Compounds; Receptor, Cholecystokinin B; Stomach Neoplasms; Treatment Outcome; Tumor Burden

Patients with chronic atrophic gastritis have long-term gastric hypoacidity, and secondary hypergastrinaemia. Some also develop gastric ECL cells carcinoids (type 1 GC). Most type 1 GC remain indolent, but some metastasise. Patients undergo surveillance, and some are treated with somatostatin analogues, endoscopic resection or surgery. Netazepide (YF476) is a highly selective, potent and orally active gastrin receptor antagonist, which has anti-tumour activity in various rodent models of gastric neoplasia driven by hypergastrinaemia. Netazepide has been studied in healthy volunteers.. To assess the effect of netazepide on type 1 GC.. Eight patients with multiple type 1 GC received oral netazepide once daily for 12 weeks, with follow-up at 12 weeks in an open-label, pilot trial. Upper endoscopy was performed at 0, 6, 12 and 24 weeks, and carcinoids were counted and measured. Fasting serum gastrin and chromogranin A (CgA) and safety and tolerability were assessed at 0, 3, 6, 9, 12 and 24 weeks.. Netazepide was well tolerated. All patients had a reduction in the number and size of their largest carcinoid. CgA was reduced to normal levels at 3 weeks and remained so until 12 weeks, but had returned to pre-treatment levels at 24 weeks. Gastrin remained unchanged throughout treatment.. The gastrin receptor antagonist netazepide is a promising new medical treatment for type 1 gastric carcinoids, which appear to be gastrin-dependent. Controlled studies and long-term treatment are justified to find out whether netazepide treatment can eradicate type 1 gastric carcinoids.

Topics: Aged; Benzodiazepinones; Carcinoid Tumor; Chromogranin A; Female; Gastrins; Humans; Male; Middle Aged; Phenylurea Compounds; Receptor, Cholecystokinin B; Stomach Neoplasms; Treatment Outcome

Chromogranin A (CgA) is a neuroendocrine tumor (NET) marker. Modest CgA elevation is found in subjects with enterochromaffin-like (ECL) cell hyperplasia due to hypergastrinemia. Somatostatin analogs reduce CgA levels in patients with NET. Meals may affect serum CgA levels. The aims of the study were to investigate meal-induced CgA release and the short-term effect of octreotide on serum CgA levels. Four groups were studied: group A, seven patients with ECL cell hyperplasia secondary to use of proton pump inhibitors (PPIs); group B, six patients with gastric carcinoid type 1/ECL hyperplasia due to chronic atrophic gastritis (CAG); group C, six patients with nongastric NETs; group D, seven controls. The subjects were studied on three separate days with the use of three exposures: a test meal, pentagastrin subcutaneously (not group C), and octreotide intravenously. Serum CgA and gastrin were analyzed. A test meal induced a significant CgA increase in long-term PPI users and in healthy controls. The meal did not affect CgA levels in patients with gastric carcinoid type 1 or patients with NETs. The test meal increased gastrin levels in all groups except in those with CAG. Pentagastrin increased CgA levels in all groups tested except in those with CAG, while octreotide, reduced CgA and gastrin levels in all groups. Serum CgA should be determined in fasting individuals. A test meal may distinguish between increased CgA levels in PPI users from nongastric NET patients. Concomitant gastrin determination may help to discriminate between nongastric NETs and CAG. Intravenous octreotide rapidly reduces serum CgA.

Topics: Aged; Biomarkers, Tumor; Carcinoid Tumor; Carcinoma, Neuroendocrine; Chromogranin A; Diagnostic Techniques, Digestive System; Enterochromaffin-like Cells; Female; Gastrins; Gastrointestinal Agents; Humans; Hyperplasia; Male; Middle Aged; Octreotide; Pentagastrin; Proton Pump Inhibitors; Radioimmunoassay; Stomach Neoplasms

Gastrin hormone is trophic to in vitro gastric cancer, and the antigastrin antibodies (AGAs) are antiproliferative and antimetastatic. Human gastric cancers overexpress gastrin genes and receptors that react to gastrin's trophic effects. Immunogen G17DT elicits a specific and high-affinity AGA. The authors evaluated G17DT vaccination given with cisplatin plus 5-fluorouracil for the treatment gastric adenocarcinoma.. In this multicenter, Phase II study, patients received G17DT vaccination intramuscularly on Weeks 1, 5, 9 and 25 and cisplatin plus 5-fluorouracil every 28 days. Eligible patients had untreated, metastatic, or unresectable gastric or gastroesophageal adenocarcinoma with near-normal organ function. The primary endpoint of the study was the over response rate (ORR), and secondary endpoints included overall survival (OS), safety, and the impact of successful vaccination on patient outcome.. In total, 103 patients were enrolled in 5 countries. Seven patients who were overdosed inadvertently with 5-fluorouracil (a major protocol violation) were removed from the analysis. The confirmed ORR was 30% in 79 patients who were evaluated for response. The median time-to-progression (TTP) was 5.4 months, and the median survival (MS) was 9.0 months (n = 96 patients). Sixty-five of 94 patients who were vaccinated (69%) had 2 consecutive AGA titers of > or =1 units (successfully vaccinated patients or immune-responders). The TTP was longer in immune-responders than in immune-nonresponders (P = .0005). Similarly, the MS was longer in immune-responders than in immune-nonresponders (10.3 months vs. 3.8 months; P < or =.0001). In a multivariate analysis, successful vaccination was an independent OS prognosticator (P = .0001). G17DT did not have an adverse effect on safety.. The results demonstrated that successful G17DT vaccination was correlated with longer TTP and MS. AGA response was an independent OS prognosticator. A Phase III evaluation of G17DT in gastric cancer is warranted.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cancer Vaccines; Cisplatin; Esophageal Neoplasms; Female; Fluorouracil; Gastrins; Humans; Male; Middle Aged; Multivariate Analysis; Stomach Neoplasms; Vaccination

G17DT is a gastrin immunogen, raising antibodies that blockade gastrin-stimulated growth. The aim of the study was to characterise antibody response and assess safety and tolerability of G17DT given to patients with gastric cancer.. G17DT was administered to 52 patients with gastric adenocarcinoma at weeks 0, 2 and 6 by intramuscular injection at doses of 10, 100 and 250 microg. Antibody levels were measured by an ELISA assay. A radioligand displacement assay determined the ability of G17DT-immunised patients' sera to inhibit binding of 125IG17 to cholecystokinin (CCK)-2 receptors.. By week 12 of the study, 6/12 evaluable stage I-III patients achieved an antibody response in the 10 microg group, 7/11 in the 100 microg group, and 11/12 in the 250 microg group. Stage IV patients dosed at 250 microg achieved a similar response rate to stage I-III patients dosed at 10 or 100 microg. G17DT was well tolerated in 47/52 patients. Two patients suffered significant adverse reactions including injection site pain and abscess. G17DT antibodies displaced iodinated gastrin from CCK-2 receptors, with the level of displacement correlating with antibody titre.. G17DT immunisation is a well-tolerated method of raising functional antibodies to 17 amino acid gastrin forms in patients with gastric carcinomas.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antibody Formation; Cancer Vaccines; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Gastrins; Humans; Immune Sera; Immunization, Secondary; Injections, Intramuscular; Male; Middle Aged; Neoplasm Staging; Receptor, Cholecystokinin B; Statistics as Topic; Stomach Neoplasms; Treatment Outcome

Patients with chronic atrophic gastritis (CAG) and hypergastrinaemia are at risk of developing hyperplasia of the enterochromaffin-like (ECL) cells and ECL-cell-derived tumours. The effect of the somatostatin analogue octreotide on ECL cell carcinoids is examined.. Five patients with hypergastrinaemia and ECL cell carcinoids were enrolled in a 1-year study of octreotide LAR (long-acting release) 20 mg given at monthly intervals. Biopsies from tumours and from flat oxyntic mucosa were done at the start and 3, 6 and 12 months thereafter. Sections were stained with haematoxylin-erythrosin, immunostained with chromogranin A (CgA) and doublestained with CgA and Ki-67. Serum gastrin and CgA were measured.. The number of visible tumours was reduced by more than 50 %. Sections from both tumours and flat mucosa showed a reduced number of CgA immunoreactive cells. Mean serum gastrin decreased from 421 to 186 pM (normal <40 pM); P > 0.05, and serum CgA from 73 to 25 ng/ml (normal < 30 ng/ml); P < 0.001.. During treatment the patients were still markedly hypergastrinaemic, whereas the serum CgA showed normalization. A diminished tumour load and reduced ECL cell density were found, indicating an antiproliferative effect of octreotide directly on the ECL cells.

Topics: Aged; Antineoplastic Agents, Hormonal; Carcinoid Tumor; Cell Proliferation; Chromogranin A; Chromogranins; Delayed-Action Preparations; Enterochromaffin-like Cells; Female; Gastric Mucosa; Gastrins; Gastroscopy; Humans; Male; Middle Aged; Octreotide; Stomach Neoplasms; Time Factors

To find an ideal reconstruction method after total gastrectomy.. With 12 healthy persons as control, a total of 120 gastric cancer patients received their digestive tract reconstruction after total gastrectomy were randomized into Roux-en-y esophagojejunostomy group (A), P pouch with Roux-en-y esophagojejunostomy group (B), Hunt-Lawrence esophagojejunostomy group (C), and jejunal interposition esophagojejunostomy group (D). After operation, quality of life, prognosis nutrition index (PNI), body weight, serum nutritional parameters, gastrointestinal hormone level and immunological state were evaluated.. The quality of life, PNI, body weight and serum nutritional parameters (SI, TS and Hb) were better in group D than those in groups A, B and C (P < 0.05). The cholecystokinin (CCK) level and NK cell, CD(4)(+) cell, CD(8)(+) cell and CD(4)/CD(8) ratio in group D, being similar to the control group, were significantly higher than groups A, B and C (P < 0.05).. Modified jejunal interposition esophagojejunostomy is a reasonable reconstruction method. The construction of "P" pouch, reserving foods as the stomach, can preserve the duodenal passage and secretion of the gastrointestinal hormones, which results in better digestion of the food and absorption of the nutrients. This method simplifies the operation and guarantee the blood supply of interpositioned jejunum without causing ischemia at the anastomotic orifice.

Topics: Esophagus; Gastrectomy; Gastrins; Humans; Jejunum; Plastic Surgery Procedures; Prospective Studies; Stomach Neoplasms

: To investigate the effect of the eradication of Helicobacter pylori on histological gastritis.. : Twenty-six patients with moderate to severe atrophy received successful eradication therapy of H.pylori. Four patients dropped out and 22 were followed up prospectively for 5 years. The grades of gastritis were estimated from gastric biopsy specimens. The grade of intestinal metaplasia was also evaluated by dye-endoscopy using methylene blue (methylthioninium chloride). The serum levels of pepsinogen, gastrin and anti-parietal cell antibody were also determined.. : The grades of atrophy decreased in patients with successful eradication therapy in the gastric corpus (before vs. 5 years after eradication, 2.09 +/- 0.15 vs. 0.91 +/- 0.17; P < 0.01) and in the antrum (2.14 +/- 0.17 vs. 1.36 +/- 0.17; P < 0.01). The levels of intestinal metaplasia were also decreased in the corpus (0.91 +/- 0.24 vs. 0.50 +/- 0.16; P < 0.05) and in the antrum (1.41 +/- 0.20 vs. 1.00 +/- 0.16; P < 0.05), which was also demonstrated by the methylene blue (methylthioninium chloride) staining method (33.4 +/- 8.2% vs. 23.0 +/- 6.5%; P < 0.05). The improvement of corpus atrophy correlated well with the high serum level of pepsinogen I (P = 0.005), but showed no correlation with the levels of anti-parietal cell antibody.. : These results suggest that gastric atrophy and intestinal metaplasia are reversible events in some patients.

Topics: Adult; Aged; Anti-Bacterial Agents; Biomarkers; Drug Therapy, Combination; Female; Follow-Up Studies; Gastrins; Gastritis, Atrophic; Helicobacter Infections; Helicobacter pylori; Humans; Intestines; Male; Metaplasia; Methylene Blue; Middle Aged; Pepsinogens; Precancerous Conditions; Prognosis; Prospective Studies; Stomach Neoplasms

Topics: Antineoplastic Combined Chemotherapy Protocols; Cancer Vaccines; Cisplatin; Diphtheria Toxoid; Fluorouracil; Gastrins; Humans; Stomach Neoplasms

Helicobacter pylori causes gastric adenocarcinoma. We assessed the success of H. pylori eradication therapy in a medically underserved population in Chiapas, Mexico, that is at high risk for gastric cancer risk.. Healthy volunteers with both antibodies to CagA and gastrin levels > or = 25 ng/ml were randomly assigned to receive either a combination of omeprazole, amoxicillin, and clarithromycin or matched placebo for 1 wk. Endoscopy with seven biopsies was performed at baseline, at 6 wk, and 1 yr after treatment. Treatment success was defined as loss of H. pylori by histological analysis. Cure was assessed using change in serology based on the standardized absorbance of a H. pylori ELISA.. H. pylori eradication rates were high (intent-to-treat analysis: 76.3% [95% CI = 68.7-84.0%] after 6 wk and 76.1% [95% CI = 67.7-84.6%] after 1 yr; per protocol analysis: 77.8% [95% CI = 70.1-85.4%] after 6 wk and 75.2% [95% CI = 66.5-84.0%] after 1 yr). Nine subjects on active treatment and one subject on placebo who were without H. pylori at 6 wk were infected at 1 yr (recurrence rates 10.7% and 33.3%, respectively, p = 0.31). Median changes in standardized absorbance at 1 yr were 47% and 1% for successfully and unsuccessfully treated patients, respectively. A 10% decline in standardized absorbance after 1 yr had 84% sensitivity and 100% specificity for H. pylori eradication.. Even with a short course of treatment against H. pylori, a high rate of eradication rate can be achieved in populations at high risk for stomach cancer. Serum antibodies are useful in assessing efficacy of therapy.

Topics: Adenocarcinoma; Adult; Amoxicillin; Anti-Bacterial Agents; Anti-Ulcer Agents; Antibodies, Bacterial; Antigens, Bacterial; Bacterial Proteins; Clarithromycin; Drug Therapy, Combination; Enzyme-Linked Immunosorbent Assay; Female; Gastrins; Gastritis, Atrophic; Helicobacter Infections; Helicobacter pylori; Humans; Immunoglobulin G; Male; Middle Aged; Omeprazole; Penicillins; Precancerous Conditions; Recurrence; Risk Factors; ROC Curve; Stomach Neoplasms

Body-predominant atrophic gastritis is considered a risk factor for gastric cancer and carcinoid. Timing of follow-up for patients with this disorder has not been defined. This study was undertaken to determine the optimal time for the first endoscopic/histologic follow-up in patients with body-predominant atrophic gastritis.. Forty-two patients with body-predominant atrophic gastritis were randomly assigned to 1 of 2 follow-up intervals: group A (n = 22) at 24 months and group B (n = 20) at 48 months. At baseline and follow-up patients underwent gastroscopy at which biopsies were obtained from the antrum and body for histopathology and evaluation for enterochromaffin-like cells.. In group A patients, 2 antral hyperplastic polyps (9.1%) were present at baseline and 4 antral hyperplastic polyps (18.2%) were found at follow-up. In group B patients, baseline gastroscopy revealed 2 antral hyperplastic polyps (10%) and follow-up 2 antral hyperplastic polyps (10%) and 1 carcinoid tumor (5%) in the body. Atrophy and intestinal metaplasia scores in gastric body and antral mucosa in both groups did not change significantly between baseline and follow-up, except an increase in antral mucosa atrophy in group B patients (p = 0.02) was revealed.. The results of this study indicate that performing the first follow-up in patients with body-predominant atrophic gastritis need not be earlier than at 4 years after diagnosis. This interval is satisfactory for detection of potential neoplastic lesions.

Topics: Adult; Aged; Anemia, Pernicious; Biopsy; Carcinoid Tumor; Enterochromaffin-like Cells; Female; Follow-Up Studies; Gastric Mucosa; Gastrins; Gastritis, Atrophic; Gastroscopy; Helicobacter Infections; Helicobacter pylori; Humans; Male; Middle Aged; Pepsinogen A; Polyps; Prospective Studies; Pyloric Antrum; Random Allocation; Stomach Neoplasms; Time Factors

There is accumulating evidence for the role of Helicobacter pylori in the development of gastric cancer as well as of lymphomas that arise in mucosa-associated lymphoid tissue (MALT). We reported recently that gastric cancer patients show high prevalence of cagA-positive H. pylori and express gastrin and gastrin receptors enabling them to stimulate tumour growth in autocrine fashion.. Since the H. pylori infection is considered to be more strongly associated with MALT lymphoma than with gastric cancer, we decided to determine the gastrin and its receptors' mRNA expression and gastrin content in this tumour as well as the release of this hormone both into plasma and gastric lumen. Twenty MALT lymphoma patients were compared with 100 age- and gender-matched controls with similar dyspeptic symptoms.. The overall H. pylori seropositivity in MALT lymphoma was about 90% and CagA positivity was 70%, compared to 56% and 33%, respectively, in controls. The serum gastrin in MALT lymphoma was about sixfold higher than in controls while gastric luminal gastrin in these patients was over 70 times higher than in controls. Gastrin content in tumour was about 10-fold higher than in antral mucosa. Gastrin and gastrin-receptor (CCKB-receptor) mRNA were detected by reverse transcriptase-polymerase chain reaction in cancer tissue whilst in the fundic and antral mucosa, only enhanced expression of CCKB-receptor mRNA and gastrin mRNA was detected, respectively. Histamine stimulation in MALT lymphoma induced acid secretion that was only about 30% of control value due to atrophic gastritis. This study confirms an important role of CagA-positive H. pylori in the pathogenesis of MALT lymphoma and shows that this lymphoma is capable of synthesizing and releasing potent growth promoting gastrin, possibly due to the action on G-cells of H. pylori-originated Nalpha-methyl histamine and cytokines (tumour necrosis factor alpha and interleukin-8).. Gastric MALT lymphoma is closely linked to CagA-positive H. pylori infection. Gastrin and its receptors may be implicated in the pathogenesis of gastric lymphoma.

Topics: Adult; Aged; Antigens, Bacterial; Bacterial Proteins; Cytokines; Female; Gastric Acid; Gastric Mucosa; Gastrins; Helicobacter Infections; Helicobacter pylori; Histamine; Humans; Interleukin-8; Lymphoma, B-Cell, Marginal Zone; Male; Middle Aged; Radioimmunoassay; Receptors, Cholecystokinin; Reverse Transcriptase Polymerase Chain Reaction; Stomach Neoplasms

Serum chromogranin A levels (CgA) are reported by some authors to be of clinical utility for assessing the presence or absence of a pancreatic endocrine tumor and tumor extent or growth. The aim of the current study was to assess this finding and compare the results with those from serum gastrin determinations (FSG) in a large cohort of patients with gastrinomas.. In 112 consecutive patients with the Zollinger-Ellison syndrome serum CgA and FSG levels were measured and correlated with disease activity, extent of disease, and the presence of multiple endocrine neoplasia type-1 (MEN-1) or gastric carcinoid tumors.. Serum CgA levels drawn on 2 consecutive days correlated closely (P < 0.00001) as did serum gastrin levels. Serum CgA levels correlated significantly with FSG levels (P < 0.00001). Serum CgA and FSG levels were significantly higher in patients with active disease than in disease free patients (P < 0.00001). The sensitivity for the presence of disease was higher for CgA compared with FSG (92% vs. 80%; P = 0.021). However, the specificity of CgA was 67%. Serum CgA levels were not significantly different in the four disease categories (stable extrahepatic disease, increasing extrahepatic disease, stable liver metastases, and increasing liver metastases). FSG levels were significantly lower in patients with stable extrahepatic disease compared with those with increasing extrahepatic disease. However, both tumor markers decreased significantly with a gastrinoma resection in five patients. The presence of MEN-1 or a gastric carcinoid tumor did not influence the results.. The results of the current study showed that serum CgA and FSG levels both are sensitive tumor markers for the detection of a gastrinoma; however, CgA levels have a relatively low specificity. Neither the magnitude of the serum CgA nor gastrin level correlated with tumor growth or tumor extent and therefore cannot be used to determine these variables. However, in contrast to some other studies, the results of the current study show that changes in serum CgA or gastrin in a given patient with time are related to the tumor extent and not to gastric mucosal changes due to hypergastrinemia.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Carcinoid Tumor; Chromogranin A; Chromogranins; Female; Gastrinoma; Gastrins; Humans; Liver Neoplasms; Male; Middle Aged; Multiple Endocrine Neoplasia Type 1; Prospective Studies; Sensitivity and Specificity; Stomach Neoplasms; Zollinger-Ellison Syndrome

Helicobacter pylori infection is common in patients with hyperplastic gastric polyps.. To study the effect of eradication of H. pylori on the clinical course of patients with hyperplastic gastric polyps.. Single-blind, randomized, controlled trial.. University-based gastroenterology outpatient clinic.. 35 patients with H. pylori infection and hyperplastic gastric polyps at least 3 mm in diameter.. Patients were randomly assigned to a treatment group (n = 17), which received a proton-pump inhibitor (omeprazole or lansoprazole), amoxicillin, and either clarithromycin or ecabet sodium, or to a control group (n = 18), which received no treatment.. Patients underwent endoscopy before enrollment and 12 to 15 months after the end of treatment. Serum gastrin levels and titers of IgG to H. pylori were measured.. In the treatment group, the polyps had disappeared by 3 to 15 months (average, 7.1 +/- 1.2 months) after the end of treatment in 12 of all 17 patients (71%) and in 12 of the 15 patients (80%) in whom H. pylori was eradicated. However, 12 to 15 months after the start of the study, no change in polyps or H. pylori status was seen in any controls (P < 0.001). Histologic findings of inflammation and activity, serum gastrin levels, and titers of IgG to H. pylori showed significant regression in the treatment group compared with the control group (P < 0.01).. Most hyperplastic polyps disappeared after eradication of H. pylori. Thus, eradication should be attempted before endoscopic removal is done in patients with hyperplastic gastric polyps and H. pylori infection.

Topics: 2-Pyridinylmethylsulfinylbenzimidazoles; Abietanes; Adult; Aged; Amoxicillin; Anti-Bacterial Agents; Clarithromycin; Diterpenes; Drug Therapy, Combination; Female; Gastrins; Helicobacter Infections; Helicobacter pylori; Humans; Hyperplasia; Immunoglobulin G; Lansoprazole; Male; Middle Aged; Omeprazole; Penicillins; Polyps; Proton Pump Inhibitors; Single-Blind Method; Statistics, Nonparametric; Stomach Neoplasms

To evaluate the response of endocrine cells of the gastric oxyntic mucosa in hypergastrinaemic patients to either antrectomy or treatment with the somatostatin analogue octreotide.. (a) Two patients with enterochromaffin-like (ECL) cell carcinoid and chronic atrophic gastritis, treated with antrectomy; (b) four patients with Zollinger-Ellison syndrome, treated with octreotide.. Oxyntic endocrine cells were examined by ultrastructural morphometry on full thickness biopsy specimens taken: (a) before and four months after antrectomy, (b) before and after three months' treatment with octreotide 200 micrograms daily.. Both treatments induced prompt, significant reduction of gastrinaemia and a significant decrease of the volume density of the whole endocrine cell mass and of the cross sectional area of all nucleated endocrine cell profiles (antrectomy: -38%, p < 0.04 and -31%, p < 0.04, respectively; octreotide: -59%, < 0.007 and -26%, < 0.04, respectively). Assessment of the relative proportion of individual endocrine cell types showed a different response to antrectomy or octreotide. After antrectomy, in fact, only the volume fraction of ECL cells was significantly reduced, from 56.5% to 22.5% (-60%, p < 0.04). After octreotide treatment, in contrast, the proportion of all endocrine cell types remained remarkably constant, showing that all cell types took part in the observed overall decrease.. Postantrectomy reduction of oxyntic endocrine cells mostly reflects the withdrawal of the specific trophic stimulus of hypergastrinaemia on ECL cells. In contrast, the inhibitory response to octreotide seems to be exerted on virtually all types of oxyntic endocrine cells, probably reflecting a universal occurrence of somatostatin receptors.

Topics: Adult; Aged; Carcinoid Tumor; Female; Gastrins; Gastritis, Atrophic; Gastrointestinal Agents; Humans; Male; Microscopy, Electron; Middle Aged; Octreotide; Parietal Cells, Gastric; Pyloric Antrum; Stomach Diseases; Stomach Neoplasms; Zollinger-Ellison Syndrome

Topics: Adolescent; Adult; Aged; Clinical Trials as Topic; Dyspepsia; Female; Gastric Acidity Determination; Gastric Juice; Gastrins; Histamine; Humans; Injections, Subcutaneous; Male; Middle Aged; Peptic Ulcer; Secretory Rate; Stomach Neoplasms

Topics: Adult; Aged; Anemia, Pernicious; Carcinoma; Clinical Trials as Topic; Duodenal Ulcer; Female; Gastric Juice; Gastrins; Hernia, Diaphragmatic; Histamine; Humans; Male; Middle Aged; Secretory Rate; Stomach; Stomach Neoplasms; Stomach Ulcer

Stomach cancer is a leading cause of cancer death. Helicobacter pylori is a bacterial gastric pathogen that is the primary risk factor for carcinogenesis, associated with its induction of inflammation and DNA damage. Dicarbonyl electrophiles are generated from lipid peroxidation during the inflammatory response and form covalent adducts with amine-containing macromolecules. 2-hydroxybenzylamine (2-HOBA) is a natural compound derived from buckwheat seeds and acts as a potent scavenger of reactive aldehydes. Our goal was to investigate the effect of 2-HOBA on the pathogenesis of H. pylori infection. We used transgenic FVB/N insulin-gastrin (INS-GAS) mice as a model of gastric cancer. First, we found that 2-HOBA is bioavailable in the gastric tissues of these mice after supplementation in the drinking water. Moreover, 2-HOBA reduced the development of gastritis in H. pylori-infected INS-GAS mice without affecting the bacterial colonization level in the stomach. Further, we show that the development of gastric dysplasia and carcinoma was significantly reduced by 2-HOBA. Concomitantly, DNA damage were also inhibited by 2-HOBA treatment in H. pylori-infected mice. In parallel, DNA damage was inhibited by 2-HOBA in H. pylori-infected gastric epithelial cells in vitro. In conclusion, 2-HOBA, which has been shown to be safe in human clinical trials, represents a promising nutritional compound for the chemoprevention of the more severe effects of H. pylori infection.

Topics: Animals; Gastric Mucosa; Gastrins; Gastritis; Helicobacter Infections; Helicobacter pylori; Humans; Mice; Stomach Neoplasms

A highly sensitive and convenient amplified luminescent proximity homogeneous assay (AlphaLISA) method with high throughput and automation potential was developed for quantitation of serum Gastrin-17 (G-17) levels, which can facilitate the early diagnosis of atrophic gastritis in people at high risk of gastric cancer using a non-invasive approach. In this study, donor and acceptor beads with modified carboxyl groups on the surface were directly coupled to anti-G-17 antibodies through activation was proposed for application in the development of the new AlphaLISA, which can effectively simplify the steps and shorten the reaction time to achieve faster detection. Therefore, the G-17-AlphaLISA only needs to react for 15 min to obtain good analysis results. The proposed method has a wider detection range than commercial enzyme-linked immunosorbent assay (ELISA) kits (0.12-112.8 pmol/L > 0.5-40 pmol/L). In addition, results of G-17-AlphaLISA and ELISA had good correlation and agreement (ρ = 0.936). Importantly, the developed method may be more suitable for the large-scale screening of people at high risk for gastric cancer than traditional ELISA and provides a novel solution for other biomarkers that require accurate, highly sensitive, and high throughput detection.

Topics: Antibodies; Enzyme-Linked Immunosorbent Assay; Gastrins; Humans; Luminescent Measurements; Stomach Neoplasms

Gastric polyps represent an abnormal proliferation of the gastric mucosa. Chronic atrophic autoimmune gastritis (CAAG) targets parietal cells and results in hypo-achlorhydria and hypergastrinemia, which exerts a proliferative effect on the gastric mucosa.. We investigate the incidence of gastric polyps in CAAG patients.. This is a single-center retrospective study examining patients with confirmed CAAG from January 1990 until June 2022. Demographic, clinical, biochemical, and serological data were collected for each included patient. The histopathological characteristics of the detected polyps were recorded.. A total of 176 CAAG patients were included. Eighty-nine (50.5%) had 163 incidental polyps. Seventy-six patients (85%) had 130 non-endocrine lesions, among which 118 (90.7%) were inflammatory, 6 (4.6%) adenomatous, and 4 (3%) fundic; 33 patients (37%) had gastric neuroendocrine neoplasms (gNENs), and 21 (23.6%) both; one had MALToma and one gastric adenocarcinoma. Higher circulating levels of gastrin and chromogranin A were observed among patients with polyps (median 668 vs 893 pg/ml p = 0.0237, 146 vs 207 ng/ml p = 0.0027, respectively).. CAAG implies a high incidence of gNENs and exocrine lesions. Gastrin plays a possible trophic role on the mucosa. Further evidence is needed to validate its predictive role for increased polyp risk in CAAG.

Topics: Autoimmune Diseases; Gastric Mucosa; Gastrins; Gastritis; Gastritis, Atrophic; Humans; Polyps; Precancerous Conditions; Retrospective Studies; Stomach Neoplasms

The aim of the study was to determine the proportion of gastric cancer patients with decreased levels of pepsinogen and gastrin-17 in plasma, with the goal of providing indirect evidence of the sensitivity of these biomarkers when applied in a cancer screening setting.. The levels of pepsinogens I and II, gastrin-17, and Helicobacter pylori immunoglobulin antibodies in plasma samples of gastric cancer patients were evaluated using the GastroPanel test system (Biohit Oyj, Helsinki, Finland). A decreased level of the pepsinogen I/II ratio was defined as less than three, while a decrease in gastrin-17 was defined as less than 1 pmol/L. Univariate analysis using non-parametric tests was used to investigate differences between normal and low concentrations of biomarkers.. In total, 481 plasma samples from patients (59.9% male) with a median age of 64 years (ranging from 27 to 88 years) were analyzed. Out of the 400 cases of gastric cancer (83.2% of the total), 182 were categorized as the intestinal type, 141 as the diffuse type, 60 as the mixed type, and 17 as indeterminate according to the Lauren classification system. The H. pylori immunoglobulin test was positive in 74.0% of the patients. Pepsinogen I/II ratio was decreased in 32.4% (36.8% of the intestinal type); gastrin-17 in 12.3% (10.1% of the antral region) of all cases.. The majority of gastric cancer patients had normal levels of pepsinogen and gastrin-17, suggesting that these biomarkers have limited application as screening tools in the Caucasian population.

Topics: Antibodies, Bacterial; Biomarkers; Female; Gastrins; Helicobacter Infections; Helicobacter pylori; Humans; Male; Middle Aged; Pepsinogen A; Stomach Neoplasms

The pathogenesis for non-type 1/2 gastric neuroendocrine tumors (G-NETs) remains unclear. The aim of this study was to examine the clinicopathologic features of G-NETs and associated mucosal changes.. The electronic health records of patients with non-type 1/2 G-NETs were reviewed. H&E slides were reviewed for pathologic features and mucosal changes. The t test and Fisher exact test were used for statistical analysis.. In total, 33 patients were assigned to either group 1 (n = 23) or group 2 (n = 10). Group 1 included patients with a history of proton pump inhibitor (PPI) use, increased gastrin levels, or significant PPI effect (PPI/gastrin-associated). All other patients were assigned to group 2. There was no significant difference in age and sex between the 2 groups. Group 2 tumors were more likely to be larger, invade deeper, and develop metastases (P < .05). Tumors in patients with cirrhosis tended to be larger. Peritumoral mucosal changes included loss of oxyntic glands, foveolar hyperplasia, and intestinal metaplasia. Background mucosa in group 1 patients showed PPI effect and neuroendocrine hyperplasia or dysplasia.. Although PPI/gastrin-associated non-type 1/2 G-NETs were smaller and more indolent than typical type 3 G-NETs, tumors in patients with cirrhosis tended to be larger. Additionally, peritumoral mucosal changes could mimic chronic atrophic gastritis.

Topics: Gastric Mucosa; Gastrins; Humans; Hyperplasia; Neuroendocrine Tumors; Proton Pump Inhibitors; Stomach Neoplasms

The ABC method, which combines the pepsinogen method and anti-Helicobacter pylori antibody titers, has been used for risk screening for gastric cancer in Japan. However, it has been reported that there are cases of gastritis and carcinogenesis risk even in group A, which is considered to be a low-risk group based on the ABC method. Currently, in group A, endoscopic examination is needed to strictly discriminate "patients without gastritis" (defined as true A patients) from those "with gastritis." A simple and minimally invasive diagnostic criterion for gastritis using serological markers is desirable. In this study, we aimed to identify the normal serum gastrin concentrations in normal stomach cases based on pathological diagnosis and investigate the usefulness of serum gastrin concentrations in diagnosing gastritis.. Patients who underwent endoscopy and blood tests at Hiroshima University Hospital were enrolled in the study and categorized into the "pathologically-evaluated group" and "endoscopically-evaluated group," according to the evaluation method of atrophic gastritis. Initially, we measured serum gastrin concentrations in the normal stomach cases in the pathologically-evaluated group and calculated the normal range of serum gastrin concentrations. We used the upper limit of this normal range of serum gastrin concentrations and performed a validation study to determine its usefulness as a diagnostic marker for distinguishing between cases of gastritis and true A in the endoscopically-evaluated group.. The 95th percentile of serum gastrin concentrations in pathologically-evaluated normal stomach cases was 34.12-126.03 pg/mL. Using the upper limit of this normal range of serum gastrin concentrations, the sensitivity, specificity, positive predictive value, and negative predictive value for gastritis were 52.8%, 92.6%, 97.0%, and 31.0%, respectively. Additionally, the receiver operating characteristic (ROC) curve for the endoscopically-evaluated group showed an area under the ROC curve of 0.80.. The gastrin cut-off value of 126 pg/mL has a good positive predictive value (97.0%) for detecting gastritis positing its use as a marker for cases requiring endoscopy. However, the identification of patients with gastritis having normal serum gastrin concentrations due to insufficient sensitivity remains a challenge for the future.

Topics: Biomarkers; Gastrins; Gastritis; Gastritis, Atrophic; Helicobacter Infections; Humans; Pepsinogen A; Reference Values; Retrospective Studies; Stomach Neoplasms

We report here a case of a 62-year-old woman with multiple gastric enterochromaffin-like cell neuroendocrine tumor caused by hypergastrinemia due to parietal cell dysfunction that was successfully treated with somatostatin analogue. Esophagogastroduodenoscopy revealed several G1 neuroendocrine tumors, 10 mm in diameter, in the body of the stomach. No evidence of autoimmune gastritis, Helicobacter pylori infection, neuroendocrine neoplasia type 1, or Zollinger-Ellison syndrome was identified. The pattern of immunohistochemical staining of the background gastric mucosa was suggestive of parietal cell dysfunction. She was treated with long-acting release octreotide acetate. Complete response was confirmed after 9 months and was maintained for 22 months.

Topics: Enterochromaffin-like Cells; Female; Gastric Mucosa; Gastrins; Helicobacter Infections; Helicobacter pylori; Humans; Middle Aged; Neuroendocrine Tumors; Somatostatin; Stomach Neoplasms

Von Hippel-Lindau (VHL) disease is a rare inherited familial syndrome complicated with various neoplasms, including neuroendocrine tumors (NETs). We herein report the first case of multiple gastric NETs in a 45-year-old man with VHL. He had multiple gastric polyps, and several endoscopic resected lesions were diagnosed as NETs. The serum gastrin level was elevated because he was taking a proton pump inhibitor (PPI). We suspected that gastrin had played a role in the development of NETs, and the remaining polyps were followed up with discontinuation of the PPI. The NETs gradually reduced in size until they became hard to notice on endoscopy and have remained nearly invisible for over eight years.

Topics: Gastrins; Humans; Male; Middle Aged; Neuroendocrine Tumors; Proton Pump Inhibitors; Stomach Neoplasms; von Hippel-Lindau Disease

The aim of this study was to clarify the correlation between gastrin receptor (GR) expression in the gastric oxyntic mucosa and fundic gland polyps (FGPs) and the histological and immunohistochemical findings of the mucosa as well as the history of proton pump inhibitor (PPI) administration. The unique membranous linear positivity of GR in parietal cells was reproducibly observed by immunohistochemistry, which was also validated by immunofluorescence. Further histological and immunohistochemical examination of 34 oxyntic mucosae and 43 FGPs revealed the following: 1) parietal cells (PCs) with membranous linear GR expression (mGR) were observed to be limited to the isthmus-neck region in the normal state; 2) appearance of PCs with mGR in the deep oxyntic gland regions was significantly related to the PPI medication history; 3) PCs with mGR were more frequently observed in the deep oxyntic gland regions when the oxyntic mucosa showed derangement of mucosal component cell compartmentalization revealed by MUC5AC and MUC6 immunohistochemistry, which was also significantly related to the PPI use; and 4) PCs with intense membranous linear positivity of GR were observed to be diffusely distributed in all of the cases of FGPs. In conclusion, the distribution of unique GR membranous linear expression in PCs of the oxyntic mucosa under PPI medication and FGPs could reflect the pathologic mucosal state characterized by derangement of the compartmentalization of mucosal component cells, which could be another basis for evaluating physiologic and/or pathophysiologic conditions of the gastric mucosa.

Topics: Adenomatous Polyps; Gastric Mucosa; Gastrins; Humans; Parietal Cells, Gastric; Polyps; Proton Pump Inhibitors; Receptor, Cholecystokinin B; Stomach Neoplasms

Gastric intestinal metaplasia (GIM) is a premalignant lesion, highly associated with Helicobacter pylori infection. Previous studies have shown that H. pylori is able to induce the expression of programmed death ligand 1 (PD-L1), an inhibitory immune modulator, in gastric cells. Our aim was to investigate whether tissues from GIM patients may exploit PD-L1 expression upon H. pylori infection to evade immunosurveillance.. Immunohistochemistry was performed for PD-L1 and enteroendocrine markers somatostatin and gastrin on samples derived from a cohort of patients with known GIM, both before and after H. pylori eradication. To determine the identity of any observed PD-L1-positive cells, we performed multiplex immunofluorescent staining and analysis of single-cell sequencing data.. GIM tissue was rarely positive for PD-L1. In normal glands from GIM patients, PD-L1 was mainly expressed by gastrin-positive G-cells. While the D-cell and G-cell compartments were both diminished 2-fold (p = .015 and p = .01, respectively) during H. pylori infection in the normal antral tissue of GIM patients, they were restored 1 year after eradication. The total number of PD-L1-positive cells was not affected by H. pylori, but the percentage of PD-L1-positive G-cells was 30% higher in infected subjects (p = .011), suggesting that these cells are preferentially rescued from destruction.. Antral G-cells frequently express PD-L1 during homeostasis. G-cells seem to be protected from H. pylori-induced immune destruction by PD-L1 expression. GIM itself does not express PD-L1 and is unlikely to escape immunosurveillance via expression of PD-L1.

Topics: B7-H1 Antigen; Gastric Mucosa; Gastrins; Helicobacter Infections; Helicobacter pylori; Humans; Inflammation; Metaplasia; Precancerous Conditions; Somatostatin; Stomach Neoplasms

In Mongolia, gastric cancer morbidity and mortality are high, and more than 80 percent of cases are diagnosed at an advanced stage. This study aimed to evaluate pepsinogens (PGIs) and gastrin-17 (G-17) levels and to determine the diagnostic performances for gastric cancer and chronic atrophic gastritis among Mongolian individuals. We enrolled a total of 120 subjects, including gastric cancer (40), atrophic gastritis (40), and healthy control (40), matched by age (±2) and sex. Pepsinogen I (PGI), Pepsinogen II (PGII), G-17, and H. pylori IgG levels were measured using GastroPanel ELISA kit (Biohit, Helsinki, Finland). Also, PGI to PGII ratio (PGR) was calculated. For atrophic gastritis, when the optimal cut-off value of PGI was ≤75.07 ng/ml, the sensitivity and specificity were 75% and 50%, respectively; when the optimal cut-off value of PGR was ≤6.25, sensitivity and specificity were 85% and 44.7%, respectively. For gastric cancer, when the optimal cut-off value of PGI was ≤35.25 ng/ml, the sensitivity and specificity were 47.2% and 86.8%, respectively; when the optimal cut-off value of PGR was ≤5.27, sensitivity and specificity were 75% and 60.5%, respectively. Combinations of biomarkers with risk factors could improve diagnostic accuracy (AUC for atrophic gastritis 74.8, 95% CI 64.0-85.7, p<0.001; AUC for gastric cancer 75.5, 95% CI 64.2-86.8, p<0.001). PGI, PGR biomarkers combined with the risk of age, family history of gastric cancer, and previous gastric disease could not be an alternative test for upper endoscopy but might be a supportive method which is identifying individuals at medium- and high risk of gastric cancer and precancerous lesions who may need upper endoscopy.

Topics: Biomarkers; Gastrins; Gastritis, Atrophic; Helicobacter Infections; Helicobacter pylori; Humans; Immunoglobulin G; Pepsinogen A; Pepsinogen C; Stomach Neoplasms

gastric cancer is the fifth most prevalent cancer and the fourth cause of death because of cancer. In Iran, northern and northwestern regions are considered gastric cancer hot spots. Identifying serum biomarkers could be helpful in early diagnosis of patients with gastric adenocarcinoma (GAC). Increase in progastrin level has been reported in different cancers. Given the diagnostic value of this biomarker, this study aimed to determine the diagnostic role of progastrin serum biomarker in patients with gastric cancer.. In this case-control study, forty patients with gastric cancer who were diagnosed by endoscopy and pathologic findings and visited Mazandaran Comprehensive Cancer Center. The participants had received no treatment yet and entered this study. The participants in case group were compared with the control group including forty-two individuals with no history of gastrointestinal cancer in their first-degree relatives and visiting the lab for routine tests. Progastrin serum level was assessed using ELISA kit. The Kruskal-Wallis test and Mann Whitney test, both non-parametric) were used for statistical analysis and the relation between the variables was examined using Pearson's correlation coefficient at 95% confidence level in SPSS 16.. In this study, progastrin serum level was significantly higher in patients with gastric cancer compared with normal participants (P = 0.035). Progastrin serum level had no significant relation with tumor clinicopathologic parameters (p-value > 0.05).. Increase in progastrin may be utilized as a predictive factor for gastric cancer.

Topics: Biomarkers, Tumor; Case-Control Studies; Gastrins; Humans; Stomach Neoplasms

PPI use,

Topics: Aged; Amino Acid Sequence; Animals; Arthropod Proteins; Cloning, Molecular; Endoscopy, Digestive System; Fasting; Female; Gastrins; Gastritis; Helicobacter Infections; Helicobacter pylori; Humans; Invertebrate Hormones; Male; Middle Aged; Nerve Tissue Proteins; Ovary; Penaeidae; Precancerous Conditions; Proton Pump Inhibitors; Stomach Neoplasms; Vitellogenesis; Vitellogenins

The incidence of proximal gastric adenocarcinoma is increasing among younger adults. Rodent models have shown that hypergastrinemia causes carcinogenesis in the proximal stomach. The aim of our study was therefore to assess if hypergastrinemia was associated with an increased risk of developing gastric adenocarcinoma also in humans. A prospective population-based nested case-control study within the Nord-Trøndelag Health Study (HUNT) cohort, Norway, was used to assess this association. Serum was collected from 78 962 participants in 1995 to 1997 and 2006 to 2008. In the cohort, 181 incident gastric adenocarcinoma cases were identified from the Norwegian Cancer and Patient Registries through 2015 and matched with 359 controls. The risk of gastric adenocarcinoma was compared between participants with prediagnostic hypergastrinemia (>60 pmol/L) and normal serum gastrin (≤60 pmol/L). Logistic regression provided odds ratios (ORs) with 95% confidence intervals (CIs), adjusted for body mass index, tobacco smoking and comorbidity. Hypergastrinemia was associated with increased risk of gastric adenocarcinoma overall (OR 2.2, 95% CI 1.4-3.4) and in particular for gastric adenocarcinoma with proximal location (OR 6.1, 95% CI 2.7-13.8), but not with gastric adenocarcinoma with distal location (OR 1.7, 95% CI 0.9-3.4). Moreover, hypergastrinemia was associated with an increased risk of gastric adenocarcinoma of intestinal histological type (OR 3.8, 95% CI 1.8-7.9), but not for diffuse histological type (OR 1.6, 95% CI 0.7-3.7). In conclusion, hypergastrinemia was associated with an increased risk of proximal and intestinal type gastric adenocarcinoma.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Case-Control Studies; Female; Gastrins; Humans; Incidence; Logistic Models; Male; Middle Aged; Norway; Population Surveillance; Prospective Studies; Registries; Risk Factors; Stomach Neoplasms

We herein report a case of gastric hyperplastic polyps after argon plasma coagulation (APC) for gastric antral vascular ectasia (GAVE) in the antrum of a 65-year-old man with liver cirrhosis and hypergastrinemia induced by long-term proton pump inhibitor (PPI) use. Two years after APC therapy, endoscopy demonstrated multiple gastric polyps in the antrum and angle. A gastric polyp biopsy indicated foveolar epithelium hyperplasia, which was diagnosed as gastric hyperplastic polyps. One year after switching to an H2 blocker antagonist, endoscopy revealed that the polyps and GAVE had disappeared, with normal gastrin levels suggesting that PPI-induced hypergastrinemia had caused gastric hyperplastic polyps after APC therapy, and the polyps had disappeared after discontinuing PPIs.

Topics: Aged; Argon Plasma Coagulation; Gastric Antral Vascular Ectasia; Gastrins; Humans; Liver Cirrhosis; Male; Polyps; Stomach Neoplasms

Immune checkpoint inhibitors have limited efficacy in many tumors. We investigated mechanisms of tumor resistance to inhibitors of programmed cell death-1 (PDCD1, also called PD-1) in mice with gastric cancer, and the role of its ligand, PD-L1.. Gastrin-deficient mice were given N-methyl-N-nitrosourea (MNU) in drinking water along with Helicobacter felis to induce gastric tumor formation; we also performed studies with H/K-ATPase-hIL1B mice, which develop spontaneous gastric tumors at the antral-corpus junction and have parietal cells that constitutively secrete interleukin 1B. Mice were given injections of an antibody against PD-1 or an isotype control before tumors developed, or anti-PD-1 and 5-fluorouracil and oxaliplatin, or an antibody against lymphocyte antigen 6 complex locus G (also called Gr-1), which depletes myeloid-derived suppressor cells [MDSCs]), after tumors developed. We generated knock-in mice that express PD-L1 specifically in the gastric epithelium or myeloid lineage.. When given to gastrin-deficient mice before tumors grew, anti-PD-1 significantly reduced tumor size and increased tumor infiltration by T cells. However, anti-PD-1 alone did not have significant effects on established tumors in these mice. Neither early nor late anti-PD-1 administration reduced tumor growth in the presence of MDSCs in H/K-ATPase-hIL-1β mice. The combination of 5-fluorouracil and oxaliplatin reduced MDSCs, increased numbers of intra-tumor CD8. In mouse models of gastric cancer, 5-fluorouracil and oxaliplatin reduce numbers of MDSCs to increase the effects of anti-PD-1, which promotes tumor infiltration by CD8

Topics: Administration, Oral; Animals; Carcinogenesis; Gastric Mucosa; Gastrins; Helicobacter felis; Helicobacter Infections; Humans; Immune Checkpoint Inhibitors; Methylnitrosourea; Mice; Mice, Knockout; Myeloid-Derived Suppressor Cells; Neoplasms, Experimental; Programmed Cell Death 1 Receptor; Signal Transduction; Stomach Neoplasms; Tumor Microenvironment

Depending on etiology, prognosis and malignant potential, recent S2k guideline differentiates gastric neuroendocrine tumors (gNET) in 4 types with different treatment implications.We report on a 55-year-old patient with the accidental finding of a 15 mm gNET. Apart from a prolonged use of proton pump inhibitors (PPI) for 20 years as a treatment for gastroesophageal reflux disease, there were no other associations or risk factors for gNETs. Formally, this patient would have been classified as a type III gNET, implicating gastric surgery. From a pathophysiological point of view, however, the assumed prolonged gastrin hypersecretion would have justified an assignment as a type I gNET. The gNET was resected by ESD, but histology showed an R1 situation. After cessation of PPIs, there is no recurrence so far. Besides, the initially documented numerous and large gland polyps showed an impressive regression only a few weeks after cessation of PPI.This case points to a probably underestimated gap in the present gNET classification. On the basis of present literature, the therapeutic dilemma of PPI-associated gNETs is discussed. A new assignment of PPI associated gNETs as type Ib could help to overcome this dilemma.. Die aktuelle S2k Leitlinie unterteilt neuroendokrine Tumore des Magens (gNETs) abhängig von der Genese, Prognose und dem Malignitätsgrad in therapeutisch unterschiedlich anzugehende 4 Typen.Wir berichten über einen 55-jährigen Patienten, bei dem sich als Zufallsbefund ein 15 mm großer gNET fand; einziger Risikofaktor war eine zwanzigjährige Therapie mit Protonenpumpenblockern (PPI) aufgrund einer gastroösophagealen Refluxerkrankung. Rein formal hätte dieser Fall als ein Typ III NET gewertet und operiert werden müssen, pathophysiologisch entsprach er durch die anzunehmende langjährige Gastrinüberstimulation aber eher einem Typ I NET. Der gNET konnte via ESD entfernt werden, allerdings mit einer R1 Situation. Nach Absetzen der PPIs zeigte sich bislang kein Tumorrezidiv; darüber hinaus bildeten sich die zuvor bestehenden großen Drüsenkörpercysten wenige Wochen nach Absetzen der PPI eindrucksvoll zurück.Der Fall demonstriert eine vermutlich unterschätzte Lücke in der aktuellen gNET Klassifikation. Anhand der aktuellen Literatur wird das therapeutische Dilemma bei PPI-assoziierten gNETs diskutiert, dem durch eine Benennung von PPI-assoziierten gNETs als Typ I b Rechnung getragen werden könnte.

Topics: Gastrins; Gastroesophageal Reflux; Humans; Middle Aged; Neuroendocrine Tumors; Proton Pump Inhibitors; Stomach Neoplasms

Gastric enterochromaffin-like cell (ECL) tumours can occur in patients with multiple endocrine neoplasia type 1 (MEN1), especially in those affected by Zollinger Ellison syndrome (ZES). Since the prevalence of ECL lesions is not well defined yet, the present study evaluated the presence and extent of ECL lesions in MEN1 patients with and without ZES.. Multiple endocrine neoplasia type 1 patients being part of a regular screening program (2014-2018) underwent gastroduodenoscopies with biopsies of the stomach and determination of serum gastrin and chromogranin A levels. Haematoxylin- and immunostaining with chromogranin A, gastrin and VMAT I and II (vesicular monoamine transporter I and II) of the biopsies were performed.. Thirty-eight MEN1 patients, of whom 16 (42%) were diagnosed and treated earlier for ZES, were analysed. In ten of 16 (62.5%) ZES patients, a locally scattered, mixed image of diffuse, linear and micronodular mild hyperplasia was present. In addition, two of these patients (13%) showed small (max 1.5 mm in size) intramucosal ECL tumours. Neither ECL changes, nor tumours were found in MEN1 patients without ZES (n = 22). In MEN1/ZES patients, the median serum gastrin level was significantly elevated compared to MEN1 patients without ZES (206 pg/ml vs. 30.5 pg/ml, p < .001). A subgroup analysis of the serum gastrin and chromogranin A levels of MEN1/ZES patients with or without ECL hyperplasia did not show significant differences (gastrin level: p = .302, chromogranin A: p = .464).. Enterochromaffin-like cell hyperplasia and gastric carcinoids occur only in MEN1 patients with ZES, but less frequently than reported.

Topics: Carcinoid Tumor; Enterochromaffin-like Cells; Gastrins; Humans; Multiple Endocrine Neoplasia Type 1; Stomach Neoplasms; Zollinger-Ellison Syndrome

Gastric cancer (GC) is one of the most common cancers, with most patients often succumbing to death as a result of tumor metastasis. Recent work has demonstrated that gastrin is closely associated with GC metastasis. However, the specific molecular mechanisms underlying this relationship remain to be unveiled. In this study, we assessed the impact of gastrin and the Wnt/β-catenin inhibitor XAV939 on the epithelial-mesenchymal transition (EMT) of the SGC-7901 and MKN45 GC cell lines, and we determined that gastrin-17 significantly decreased E-cadherin expression and upregulated the expression of Snail1 and N-cadherin in GC cells. In addition, gastrin 17 also significantly increased the expression of Wnt3α in a dose-dependent manner. Consistent with these results, gastrin-17 promoted GC cell invasion, proliferation, and migration in a dose-dependent fashion, and these effects were inhibited by XAV939. Together, these results indicated that gastrin-17 induced GC cell EMT, migration, and invasion via the Wnt/β-catenin signaling pathway, which suggests that this gastrin/Wnt/β-catenin signaling axis may represent a therapeutic target for the prevention of GC metastasis.

Topics: Cell Line, Tumor; Cell Movement; Cell Proliferation; Epithelial-Mesenchymal Transition; Gastrins; Humans; Snail Family Transcription Factors; Stomach Neoplasms; Wnt Signaling Pathway

Overexpressed gastrin is reported to promote oncogenesis and development of gastric cancer by inhibiting apoptosis of cancer cells; however, the underlying mechanism remains unclear. Our study is aimed at revealing the mechanism underlying the effect of gastrin on apoptosis of gastric cancer cells. Gastrin-interfering cell line was constructed by stably transfecting gastrin-specific pshRNA plasmid to gastric cancer cell line BGC-823. Then, differentially expressed proteins between untreated BGC-823 and gastrin-interfering BGC-823 cell lines were detected by the iTRAQ technique. GO and KEGG analysis was used to analyze the differentially expressed genes that code these differentially expressed proteins. The Annexin V-FITC staining assay was used to detect gastric cancer cell apoptosis. The DCFH-DA fluorescent probe staining assay was used to measure intracellular ROS. Mitochondrial membrane potential was detected by flow cytometry. Western blot was used to analyze the mitochondria respiratory chain proteins and apoptosis-related proteins. A total of 107 differentially expressed proteins were identified by iTRAQ. GO and KEGG analysis showed that proteins coded by the corresponding differentially expressed genes were mainly enriched in the mitochondrial oxidative respiratory chain, and the expression of three proteins (COX17, COX5B, ATP5J) was upregulated. The three proteins with higher scores were verified by Western blot. The apoptosis rate of the gastrin knockdown cancer cell was significantly increased; meanwhile, gastrin knockdown leads to increase of membrane potential and decrease of intracellular ROS production. Additionally, Bax was significantly increased, whereas NF-

Topics: Apoptosis; Cell Line, Tumor; Gastrins; Humans; Mitochondria; NF-kappa B; Reactive Oxygen Species; Stomach Neoplasms

In order to explore the changes of intestinal flora and serum levels of relevant substances in patients with gastric cancer before and after surgery with carbon nanoparticle laparoscopy, a total of 180 patients with early distal gastric cancer who adopted laparoscopic radical gastrectomy for distal gastric cancer in the general surgery department of TCM Hospital of Shi Jia Zhuang City from January 2018 to January 2020 were selected and randomly divided into two groups: traditional laparoscopic operation (control group) and carbon nanoparticle laparoscopic operation (experimental group) were adopted for treatment for the two groups, respectively. Postoperative evaluation included the difference between the two groups in the operative time, the efficiency of intraoperative lymph node dissection, and the number of lymph node detection. The adverse reactions, changes of intestinal flora before and after surgery in the two groups, and the serum levels of epidermal growth factor receptor (EGFR), interleukin-32 (IL-32), and gastrin 17 were evaluated. In the experimental group, the success rate of carbon nanoparticle tracer black staining reached 100%, and the operation time of the experimental group was significantly shorter than that of the control group (

Topics: Carbon; Dissection; ErbB Receptors; Female; Gastrectomy; Gastrins; Gastrointestinal Microbiome; Humans; Interleukins; Laparoscopy; Lymph Node Excision; Lymph Nodes; Lymphatic Metastasis; Male; Middle Aged; Nanoparticles; Sentinel Lymph Node; Stomach Neoplasms

Topics: Area Under Curve; Disease Progression; Early Detection of Cancer; Ethnicity; Gastrins; Gastroscopy; Humans; Male; Middle Aged; Neoplasm Staging; Pepsinogen A; Pepsinogen C; ROC Curve; Stomach Neoplasms

Analysis of serum biomarkers for the assessment of atrophic gastritis (AG), considered as gastric precancerous lesion, is of growing interest and recommended by current guidelines. Our aim was to evaluate the diagnostic performance of a panel of biomarkers (GastroPanel®) for the detection of AG in France, a country of a low gastric cancer (GC) incidence.. In this prospective, multicenter, cross-sectional study, consecutive patients considered at increased risk of GC and undergoing upper endoscopy with gastric biopsies were included. Blood samples were collected for the analysis of GastroPanel® (association of Pepsinogens I and II, Gastrin-17, and Helicobacter pylori serology) using ELISA. The results of GastroPanel® were compared to the results of histology considered as the reference.. Between 2016 and 2019, 344 patients (148 cases with AG, 196 controls without AG) were included. Sensitivity, specificity, positive, and negative predictive values for the detection of AG by GastroPanel® were of 39.9% (95% CI 31.9; 48.2), 93.4% (95% CI 88.9; 96.4), 81.9 (95% CI 71.1; 90.0), and 67.3 (95% CI 61.4; 72.8), respectively. The sensitivity was significantly higher for the detection of severe AG [60.8% (95% CI 46.1; 74.6) P = .015] and corpus AG [61.0% (95% CI 49.2; 72.0), P = .004]. Diagnostic performances of GastroPanel® tended to be better than those of Pepsinogen I alone, but the difference did not reach statistical significance (P = .068).. Serum pepsinogen and GastroPanel® tests show promising results for the detection of AG, especially of corpus AG and severe AG, in patients at high risk of GC in France.

Topics: Adult; Aged; Antibodies, Bacterial; Biomarkers; Cross-Sectional Studies; Enzyme-Linked Immunosorbent Assay; Female; France; Gastrins; Gastritis, Atrophic; Helicobacter Infections; Humans; Incidence; Male; Middle Aged; Pepsinogen A; Pepsinogen C; Prospective Studies; Sensitivity and Specificity; Stomach Neoplasms

Proton pump inhibitor (PPI) therapy causes hypergastrinemia, which could promote the development and progression of neuroendocrine tumors (NETs). Concerns have been raised about the safety of long-term PPI use due to a possible increased risk of NETs. This study aimed to investigate the association between hypergastrinemia and the risk of NETs. Twenty outpatients presenting with serum gastrin levels greater than 400 pg/mL after long-term PPI treatment were registered in this study. Immunohistochemical analyses for chromogranin A (CgA), Ki67, gastrin and CCK/B gastrin receptor (CCKBR) were performed, and positive cell numbers were counted. There were no NET or gastric epithelial neoplasia cases observed among any of the 20 patients examined throughout the PPI treatment period. Histologically, ECL cell hyperplasia were shown in all patients. However, no relationship was found between serum gastrin levels and the number of CgA positive ECL cells. There was also no relationship between serum gastrin levels and the proportion of Ki67 positive cells or the density of CCKBR positive cells. The data indicate no relationship may exist between NETs and hypergastrinemia secondary to PPI treatment in patients having no, or mild, atrophic gastritis.

Topics: Aged; Aged, 80 and over; Carcinogenesis; Enterochromaffin-like Cells; Female; Gastric Mucosa; Gastrins; Gastritis, Atrophic; Humans; Male; Middle Aged; Neuroendocrine Tumors; Proton Pump Inhibitors; Stomach Neoplasms

Chronic atrophic autoimmune gastritis (CAAG) can lead to the development of gastric neuroendocrine tumors (gNETs) and can be accompanied by other autoimmune diseases. This study aimed to determine, in CAAG patients, the association of gNET development, the prevalence of autoimmune diseases other than CAAG, the association of autoimmunity, and gNET development with pepsinogen I, II, gastrin-17, and Helicobacter pylori infection analysis.. We determined the prevalence of gNETs and other autoimmune diseases and analyzed pepsinogen I and II, gastrin-17 serum levels, and H. pylori infection in all patients diagnosed with CAAG at our hospital between 2013 and 2017.. A total of 156 patients were studied and in 15.4% was observed concomitant gNET. Approximately 68.6% had at least 1 other autoimmune disease at diagnosis of CAAG. Approximately 60.9% had autoimmune thyroiditis, followed by diabetes (19.9%) and autoimmune polyendocrine syndrome (12.8%). CAAG patients with and without gNET had similar rates of comorbidity with other autoimmune diseases, but the pepsinogen I/II ratio was lower in patients with gNET (1.6 vs 4.5, P = 0.018). Receiver operating characteristic curve analyses identified a pepsinogen I/II ratio <2.3 and gastrin-17 levels >29.6 pmol/L as cutoffs distinguishing CAAG patients with gNET from those without. The combined use of these cutoff correctly identified 16 of the 18 CAAG patients with gNET (P = 0.007). H. pylori infection was observed in 28.7% of cases tested but did not associate with gNET.. This study suggests that a low pepsinogen I/II ratio and high gastrin-17 levels characterize patients with CAAG and gNET and confirms the frequent coexistence of CAAG with other autoimmune diseases.

Topics: Adolescent; Adult; Aged; Autoimmune Diseases; Biomarkers; Diagnosis, Differential; Female; Gastrins; Gastritis, Atrophic; Helicobacter Infections; Helicobacter pylori; Humans; Male; Middle Aged; Neuroendocrine Tumors; Pepsinogen A; Pepsinogen C; Prevalence; Retrospective Studies; ROC Curve; Stomach Neoplasms; Young Adult

Screening and timely treatment of precancerous gastric cancer diseases or of gastric cancer in the early stages has important significance in reducing the incidence and mortality of gastric cancer. Gastroscopy and histopathological biopsy are still the gold standards for the diagnosis of gastric diseases. But the application of astroscopy for the screening and diagnosis of gastric diseases is limited. In recent years, serum pepsinogen (PG), gastrin, and Helicobacter pylori (H. pylori) IgG antibodies have become indicators for "serological biopsy" of the gastric mucosa.. From January 2016 to January 2018, a total of 2,394 patients with digestive tract symptoms underwent gastroscopy. According to the endoscopic examination and pathological diagnosis, there were four case groups: 1,376 cases of chronic non-atrophic gastritis, 708 cases of chronic atrophic gastritis, 265 cases of gastric ulcer, and 45 cases of gastric cancer. Serological gastric biopsies were performed and analyzed.. The serum levels of PGI in the chronic atrophic gastritis group was significantly lower than that in the chronic non-atrophic gastritis group, gastric ulcer group, and gastric cancer group (p < 0.05). The serum levels of PGII and G-17 in the gastric cancer group were significantly higher than those in the chronic non-atrophic Gastritis group, chronic atrophic gastritis group, and gastric ulcer group (p < 0.05). The PGR in the gastric cancer group was significantly lower than that in the chronic non-atrophic gastritis group, chronic atrophic Gastritis group, and gastric ulcer group (p < 0.05). The H. pylori positive rates in the chronic atrophic gastritis group and gastric cancer group were higher than those in the chronic non-atrophic gastritis group and gastric ulcer Group (p < 0.05).. Serological gastric biopsy is closely correlated to gastric mucosal disease and can be used as a Screening tool in gastric disease.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Bacterial; Biomarkers; Biopsy; Female; Gastric Mucosa; Gastrins; Helicobacter Infections; Helicobacter pylori; Humans; Male; Middle Aged; Pepsinogen A; Sensitivity and Specificity; Stomach Neoplasms; Young Adult

Autoimmune atrophic gastritis (AAG) is an immune-mediated disorder characterised by destruction of gastric oxyntic mucosa AIM: To explore gastric histopathological evolution in a cohort of AAG patients over a prolonged follow-up METHODS: Single centre prospective study enrolling consecutive patients with histologically confirmed AAG between 2000 and 2018. All AAG patients undergoing endoscopic follow-up every 1-3 years were classified as having stages 1, 2 or 3 according to atrophy severity (mild, moderate and severe). AAG patients with either glandular or neuroendocrine dysplasia/neoplasia were classified as having stage 4. Disease stage progression, and changes in serum anti-parietal cell antibody (PCA), chromogranin A and gastrin-17 were assessed.. In total, 282 AAG patients (mean age 60.3 years; F:M ratio 2.4:1; median follow-up 3 years, interquartile range 1-7) were enrolled. All patients with stages 1 or 2 progressed to stage 2 or 3 over time with a steady trend (P = .243) and regression from a severe to a milder stage was never noticed. Disease progression of patients with stages 1 or 2 occurred within the first 3 years. PCA positivity rate did not change over time. Stage 3 patients had higher gastrin-17 levels compared to patients with stages 1 and 2 (median 606 vs 295 pg/mL; P < .001). In stage 3, the hazard ratio for the risk of developing stage 4 was 6.6 (95% CI 1.5-29; P = .001).. AAG is a steadily progressive disease, in which stages 1 and 2 always progress to stage 3. The risk of developing a complicated disease stage is greater in patients with more severe gastric lesions.

Topics: Adult; Aged; Autoimmune Diseases; Disease Progression; Female; Gastric Mucosa; Gastrins; Gastritis, Atrophic; Humans; Male; Middle Aged; Neuroendocrine Tumors; Prospective Studies; Severity of Illness Index; Stomach Neoplasms

International guidelines recommend endoscopic surveillance of premalignant gastric lesions. However, the diagnostic yield and preventive effect require further study. We therefore aimed to assess the incidence of neoplastic progression and to assess the ability of various tests to identify patients most at risk for progression.. Patients from the Netherlands and Norway with a previous diagnosis of atrophic gastritis (AG), intestinal metaplasia (IM) or dysplasia were offered endoscopic surveillance. All histological specimens were assessed according to the updated Sydney classification and the operative link on gastric intestinal metaplasia (OLGIM) system. In addition, we measured serum pepsinogens (PG) and gastrin-17.. 279 (mean age 57.9 years, SD 11.4, male/female 137/142) patients were included and underwent at least one surveillance endoscopy during follow-up. The mean follow-up time was 57 months (SD 36). Four subjects (1.4%) were diagnosed with high-grade adenoma/dysplasia or invasive neoplasia (ie, gastric cancer) during follow-up. Two of these patients were successfully treated with endoscopic submucosal dissection, while the other two underwent a total gastrectomy. Compared with patients with extended AG/IM (PGI/II≤3 and/or OGLIM stage III-IV), patients with limited AG/IM (PG I/II>3 and OLGIM stage 0-II) did not develop high-grade adenoma/dysplasia or invasive neoplasia during follow-up (p=0.02).. In a low gastric cancer incidence area, a surveillance programme can detect gastric cancer at an early curable stage with an overall risk of neoplastic progression of 0.3% per year. Use of serological markers in endoscopic surveillance programmes may improve risk stratification.

Topics: Biomarkers, Tumor; Disease Progression; Female; Gastrins; Gastroscopy; Humans; Incidence; Male; Middle Aged; Netherlands; Norway; Pepsinogen A; Population Surveillance; Precancerous Conditions; Risk Assessment; Risk Factors; Stomach Neoplasms

Functional outcomes were prospectively compared between two types of reconstruction [double tract (L-DT; n = 15) and jejunal interposition (L-JIP; n = 15)] following laparoscopic half-proximal gastrectomy (LPG), including laparoscopic total gastrectomy (L-TG; n = 30) as a control group, at 1 year after surgery.. Clinical investigations were performed in each patient, and functional evaluations, involving the swallowing of an alimentary liquid containing acetaminophen (AAP), followed by measurements of the concentrations of AAP and hormones in the sitting (n = 5) and in the supine positions (n = 5), were carried out in each group.. The post-/preoperative body weight ratios were significantly higher in the L-DT and L-JIP groups than in the L-TG group. The AAP levels were significantly lower in the LPG group than in the LTG group. The AAP, insulin, and gastrin levels in the L-JIP group were markedly increased in the sitting position compared with the supine position, while those in the L-DT and L-TG groups were stable in both positions.. L-JIP and L-DT are procedures that maintain gradual intestinal absorption and help improve the quality of life. Intestinal absorption and hormonal secretion were relatively unaffected by the posture of the meal intake after L-DT, so L-DT might be the procedure providing the most stable results.

Topics: Acetaminophen; Aged; Body Weight; Female; Gastrectomy; Gastrins; Humans; Insulin; Intestinal Absorption; Jejunum; Laparoscopy; Male; Middle Aged; Perioperative Period; Plastic Surgery Procedures; Posture; Prospective Studies; Quality of Life; Stomach; Stomach Neoplasms; Time Factors

Our group observed the first case of synchronous gastric neuroendocrine tumor (NET) and duodenal gastrinoma with autoimmune chronic atrophic gastritis (CAG), in the absence of Helicobacter pylori infection. Demographic, clinical, endoscopic, and pathologic data were abstracted from the electronic medical record at Mount Sinai Hospital from 2013 to 2015. The patient's anonymity was carefully protected, and informed consent was obtained for publication of protected health information. A 53-year-old woman with hypertension presented to Mount Sinai Hospital in June 2013 for a second opinion for management of gastric and duodenal NETs. After evaluation by gastroenterology and surgery, repeat upper endoscopy with ultrasound and fine-needle aspiration revealed multiple diminutive type I gastric NETs and 2 duodenal NETs, against a background of autoimmune CAG, with biopsy pathology negative for H. pylori. She subsequently underwent a transduodenal resection of the duodenal NETs, confirming low-grade, gastrin-positive, stage T2 duodenal NET. On routine follow-up over the next 2 years, clinical, radiographic, and endoscopic surveillance revealed no recurrent or metastatic gastric or duodenal disease. This first report of synchronous duodenal gastrinoma and gastric NET in the setting of autoimmune CAG can broaden our understanding of gastric NET pathophysiology.

Topics: Autoimmune Diseases; Chronic Disease; Duodenal Neoplasms; Female; Gastrinoma; Gastrins; Gastritis, Atrophic; Humans; Hypertension; Middle Aged; Neuroendocrine Tumors; Stomach Neoplasms

Gastric neuroendocrine tumors are rarely seen in the gastric tumors, because there are few case reports and the clinical diagnosis rate is low. There is no consensus treatment method in the world. However, with the benefit of esophagogastrodenoscopy and widespread use of proton pump inhibitors, the diagnostic rate of gastric neuroendocrine tumors is on the increase, which gives us an updated understanding for the pathogenesis and pathophysiology of the disease. By studying its pathogenesis, scholars have found that hypergastrinemia caused by various causes is closely related to its occurrence. Gastric neuroendocrine tumors are classified into different types or pathological grades depending on the state of progression of the disease and the unique clinical manifestations. Clinically used diagnostic methods include gastroscopy, medical imageology, nuclear medicine, gastrin, CgA, etc. There are also differences in treatments depending on the clinical classification. If the disease progresses rapidly and the grade is high, surgical resection of the lesion plus postoperative adjuvant chemotherapy should be actively performed. Other better treatments are still being explored.. 胃神经内分泌肿瘤是临床较少见的一类肿瘤性病变，由于病例报道少，临床诊断率较低，在国内外尚无统一的诊疗方法。得益于内镜技术的发展以及临床上广泛应用的质子泵抑制剂，胃神经内分泌肿瘤的发病率和诊断率呈现上升的趋势。通过研究其发病机制，学者发现其发生与各种原因引起的高胃泌素血症密切相关。根据疾病的进展状态和临床表现，学者对胃神经内分泌肿瘤进行了分型和病理分级。临床上运用的诊断方法有胃镜、影像学、核医学、胃泌素、CgA等检查。根据临床分型的不同，治疗手段也存在差异，如果疾病进展迅速且分级较高，则应积极行外科手术切除病灶加术后辅助化学药物治疗。其他更好的治疗方法还在不断探索中。.

Topics: Gastrins; Gastroscopy; Humans; Neuroendocrine Tumors; Proton Pump Inhibitors; Stomach Neoplasms

To develop a gastric cancer (GC) risk prediction rule as an initial prescreening tool to identify individuals with a high risk prior to gastroscopy.. This was a nationwide multicentre cross-sectional study. Individuals aged 40-80 years who went to hospitals for a GC screening gastroscopy were recruited. Serum pepsinogen (PG) I, PG II, gastrin-17 (G-17) and anti-. The novel GC risk prediction rule comprised seven variables (age, sex, PG I/II ratio, G-17 level,. The developed and validated prediction rule showed good performance on identifying individuals at a higher risk in a Chinese high-risk population. Future studies are needed to validate its efficacy in a larger population.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Bacterial; Biomarkers, Tumor; Diet; Early Detection of Cancer; Female; Gastrins; Gastroscopy; Helicobacter Infections; Helicobacter pylori; Humans; Male; Mass Screening; Middle Aged; Pepsinogen A; Pepsinogen C; Predictive Value of Tests; Random Allocation; Reproducibility of Results; Risk Factors; Secondary Prevention; Stomach Neoplasms

Angiogenesis is recognized as a sign of cancer and facilitates cancer progression and metastasis. Suppression of angiogenesis is a desirable strategy for gastric cancer (GC) management. In this study, we showed a novel role of gastrin in angiogenesis of GC. We observed that treatment with gastrin 17 (G17) increased the proliferation of AGS cells and enhanced tube formation during normoxia and hypoxia. The expression level of VEGF were increased by G17 treatment as well. Experiments on the mechanism showed that G17 promoted HIF-1α expression, which subsequently enhanced β-catenin nuclear localization and activation of TCF3 and LEF1 and finally resulted in angiogenesis by upregulating VEGF. An in vivo experiment confirmed that G17 enhanced GC cell proliferation and angiogenesis in the resultant tumor. In conclusion, our findings indicate that gastrin promotes angiogenesis via activating HIF-1α/β-catenin/VEGF axis in GC.

Topics: Animals; beta Catenin; Cell Proliferation; Cells, Cultured; Gastrins; Human Umbilical Vein Endothelial Cells; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Mice; Mice, Inbred BALB C; Mice, Nude; Neovascularization, Pathologic; Oxygen; Signal Transduction; Stomach Neoplasms; Tumor Hypoxia; Vascular Endothelial Growth Factor A

The aim of the study was to estimate the value of detecting pepsinogen (PG) I, PGII, and gastrin-17 (G-17) levels in serum for chronic atrophic gastritis (CAG) screening and to determine the clinical applicability of combined measurement of serum G-17, pepsinogens (PGI, PGII) and PGI/PGII ratio (PGR) as a screening test for CAG. The PGI, PGII, and G-17 levels were detected by ELISA in 68 patients with CAG and 86 healthy volunteers who underwent gastroscopy for gastroduodenal diseases at Taizhou Municipal Hospital between January 2016 and December 2016. Concentrations of all measured serum markers were lower in patients with CAG in comparison to healthy volunteers and achieved statistical significance (P<0.01) in PGI (93.25 vs 126.98) and PGR (12.67 vs 17.09). Receiver operating characteristic (ROC) curve analysis revealed the optimal cut-off values for PGI, PGII, PGR, and G-17 at 98.10 μg/l, 6.92 ng/l, 15.77 and 1.94 pmol/l, with sensitivities of 72.10%, 58.10%, 61.60%, and 59.30% and specificities of 61.8%, 51.50%, 77.90%, and 55.90%, respectively. The areas under the curve (AUCs) of PGI, PGR, and G-17 were 0.728, 0.726, and 0.556, respectively. The increase of AUC was observed only in PGR and G-17 combination (0.741) with increased sensitivity (69.10% vs 61.60%) of screening for CAG, whereas the specificity was reduced (72.10% vs 77.90%) in comparison to PGR alone. Combination of serum indicators can raise the diagnosis accuracy of CAG in some respects. However, further research including a larger sample size is necessary in order to accurately determine the sensitivity and specificity of combined detection of serum indicators.

Topics: Case-Control Studies; Early Detection of Cancer; Gastrins; Humans; Pepsinogen A; Pepsinogen C; Stomach Neoplasms

To investigate the correlations of Homocysteine (Hcy), vascular endothelial growth factor (VEGF), and serum gastrin 17 (G17) with gastric cancer and precancerous lesions.. A total of 56 patients with gastric cancer (gastric cancer group) and 53 patients with precancerous lesions (precancerous lesion group) admitted to Heze Municipal Hospital from January 2017 to October 2018 were selected, and 50 healthy subjects undergoing the physical examination in the same period were selected as control group. The levels of serum Hcy, VEGF, and G17 in the three groups were compared, and the relations of each index with clinicopathological characteristics of gastric cancer were analyzed.. The levels of serum Hcy, VEGF-A, VEGF-C, VEGF-D, and G17 in gastric cancer group and precancerous lesion group were higher than in control group, and those in gastric cancer group were higher than in precancerous lesion group (p<0.05). Besides, the high expression levels of serum Hcy, VEGF, and G17 had evident correlations with the tumor-node-metastasis (TNM) stage, Lauren type, infiltration depth, and lymph node metastasis of gastric cancer (p<0.05).. Hcy, VEGF, and G17 can exhibit different levels of expressions in precancerous lesions. They are also highly expressed in gastric cancer. Besides, they are involved in the occurrence and development of gastric cancer and can be regarded as crucial indexes with clinical significance for the differential diagnosis of gastric cancer and precancerous lesions in the early stage.

Topics: Case-Control Studies; Diagnosis, Differential; Female; Gastrins; Genes, Tumor Suppressor; Homocysteine; Humans; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Staging; Precancerous Conditions; Stomach Neoplasms; Vascular Endothelial Growth Factor A

The aim of our study was to assess clinico-pathological and biochemical parameters of Type 1 Gastric Neuroendocrine Neoplasms (GNEN1) with respect to tumours propensity for recurrence and metastasis.. Hospital charts of GNEN1 patients were reviewed at a single tertiary referral centre.. We included 114 consecutive patients (74 women; age at baseline 54.5 ± 12.7 years [mean ± SD]) with GNEN1. All tumours (n = 114) were well differentiated; Grade 1 (G1) accounted for 56 patients (49%), whereas 46 (40%) were Grade 2 (G2) and 12 (11%) of unknown Grade. Overall follow-up encompassed 45.3 ± 46 (mean ± SD) months in 84 patients who were subjected to annual surveillance; 44 (52%) developed recurrence in the stomach during follow-up with 22 experiencing multiple recurrences; three (2.6%) presented with metastases in locoregional lymph nodes (n = 3) and/or the liver (n = 2); No metastasis or death was reported during follow-up. Median recurrence-free survival (RFS) was 31 months (95% CI: 7.6-54.4). Among clinico-pathological and biochemical parameters investigated, endoscopic intervention compared with surgery (P-value = .009) and higher serum-gastrin levels (s-gastrin) at baseline and first-year follow-up were associated with recurrence (P-value = .022 and .003 respectively) and also shorter RFS (log-rank P = .009 for type of intervention and .014 for s-gastrin, respectively). Receiver Operator Curve analysis of s-gastrin levels at first-year follow-up for recurrence demonstrated an area under the curve of 0.702.. Despite the relatively high prevalence of G2 tumours, endoscopically and/or surgically treated GNEN1 remains an indolent disease with a low metastatic propensity and no disease-specific mortality reported in our series. Many patients though will experience local recurrence, warranting long-term endoscopic surveillance with s-gastrin biomarker being a complementary tool in recurrence prediction.

Topics: Adult; Aged; Disease-Free Survival; Female; Gastrins; Humans; Male; Middle Aged; Neoplasm Recurrence, Local; Neuroendocrine Tumors; ROC Curve; Stomach Neoplasms

Topics: Adult; Endoscopy, Gastrointestinal; Enterochromaffin Cells; Gastrins; Humans; Male; Neuroendocrine Tumors; Parietal Cells, Gastric; Stomach Neoplasms

The aim of this study was to determine the risk factors of multiple gastric polyps according to the histological classification of gastric polyps.. Subjects with multiple gastric polyps (at least three) during endoscopy were enrolled prospectively. They were assigned to a fundic gland polyp (FGP) group and hyperplastic polyp (HP) group based on a histological classification of gastric polyps.. HPs arise from inflammation caused by

Topics: Adenomatous Polyps; Adult; Aged; Cohort Studies; Endoscopy, Digestive System; Female; Gastric Mucosa; Gastrins; Helicobacter Infections; Humans; Male; Middle Aged; Multivariate Analysis; Neutrophil Infiltration; Prospective Studies; Proton Pump Inhibitors; Risk Factors; Stomach Neoplasms

Gastric cancer is an important disease due to its high mortality. Despite the decline in frequency, most cases are discovered late in its course, and most of the cancer patients die within a few years of diagnosis. In addition to Helicobacter pylori gastritis, gastrin is considered an important factor in the development of this disease, and thus, cholecystokinin-B receptor (CCKBR) becomes of interest. The aim of our study was to explore whether CCKBR is expressed in stomach cancers. Thirty-seven tumors from 19 men and 18 women diagnosed with either adenocarcinoma or neuroendocrine neoplasm (NENs) were included in this study. The tumors were classified into 29 adenocarcinomas and eight NENs. Immunohistochemistry with antibodies against chromogranin A (CgA), synaptophysin and CCKBR, and in situ hybridization with probes against CgA, CCKBR and histidine decarboxylase were used to further explore these tumors. Thirty-three (89%) of the tumors expressed CCKBR protein, whereas only 20 (54%) of all tumors expressed CCKBR mRNA. Of the 20 tumors expressing CCKBR mRNA, eight were NENs and 12 were adenocarcinoma. The highest amount of CCKBR was expressed in NEN. Interestingly, a high degree of co-expression of CCKBR and CgA was observed when the two markers were examined together with in situ hybridization. In conclusion, we found that all eight NENs expressed CCKBR and neuroendocrine markers in a majority of tumor cells. The same markers were also expressed in a proportion of adenocarcinomas supporting the view that gastrin is important in the development of gastric cancer.

Topics: Adenocarcinoma; Adult; Aged; Chromogranin A; Female; Gastrins; Gene Expression Regulation, Neoplastic; Humans; Male; Middle Aged; Neuroendocrine Tumors; Receptor, Cholecystokinin B; Stomach Neoplasms; Synaptophysin

Peritoneal metastasis is a major cause of recurrence of gastric cancer and integrins are key molecules involved in gastric cancer cells attachment to the peritoneum. The peptide hormone, gastrin, initially identified for its role in gastric acid secretion is also a growth factor for gastric mucosa. Gastrin has also been shown to contribute to gastric cancers progression. Here, we provide the first evidence that gastrin increases the adhesion of gastric cancer cells. Gastrin treatment induces the expression of α2 integrin subunit through a mechanism that involves the ERK pathway. We also observed in response to gastrin an increase in the amount of α2 integrin associated with β1subunit. In addition, gastrin-stimulated cell adhesion was blocked with an anti-α2β1 integrin neutralizing antibody. We also show that gastrin activates the integrin pathway via the phosphorylation of β1 integrin by a Src family kinase. This mechanism may contribute to the enhancement of cell adhesion observed in response to gastrin since we found an inhibition of gastrin-mediated cell adhesion when cells were treated with a Src inhibitor. By regulating one of the key step of the metastatic process gastrin might contribute to increase the aggressive behaviour of human gastric tumours.

Topics: Cell Adhesion; Cell Line, Tumor; Gastrins; Humans; Integrin alpha2beta1; MAP Kinase Signaling System; Neoplasm Metastasis; Peritoneal Neoplasms; Peritoneum; Phosphorylation; Signal Transduction; Stomach Neoplasms

To test the hypothesis that activated extracellular signal-regulated kinase (ERK) regulates P65-miR23a/27a/24 axis in gastric cancer (GC) and the ERK-P65-miR23a/27a/24 axis plays an important role in the development of GC, and to evaluate the role of gastrin in GC progression and ERK-P65-miR23a/27a/24 axis.. The component levels of the ERK-P65-miR23a/27a/24 axis in four fresh GC tissues, 101 paraffin-embedded GC tissues and four GC cell lines were determined by Western blotting, immunohistochemistry (IHC) or qRT-PCR. The effects of gastrin on GC were first evaluated by measuring gastrin serum levels in 30 healthy and 70 GC patients and performing a correlation analysis between gastrin levels and survival time in 27 GC patients after eight years of follow-up, then evaluated on GC cell lines, GC cell xenograft models, and patient-derived xenografts (PDX) mouse models. The roles of ERK-P65-miR23a/27a/24 axis in GC progression and in the effects of gastrin on GC were examined.. ERK- P65-miR23a/27a/24 axis was proved to be present in GC cells. The levels of components of ERK-P65-miR23a/27a/24 axis were decreased in GC tissue samples and PGC cells. The decreased levels of components of ERK-P65-miR23a/27a/24 axis were associated with poor prognosis of GC, and ERK-P65-miR23a/27a/24 axis played a suppressive role in GC progression. Low blood gastrin was correlated with poor prognosis of the GC patients and decreased expression of p-ERK and p-P65 in GC tissues. Gastrin inhibited proliferation of poorly-differentiated GC (PGC) cells through activating the ERK-P65-miR23a/27a/24 axis. Gastrin inhibited GC growth and enhanced the suppression of GC by cisplatin in mice or PGC cell culture models through activating the ERK-P65-miR23a/27a/24 axis or its components.. ERK-P65-miR23a/27a/24 axis is down-regulated, leading to excess GC growth and poor prognosis of GC. Low gastrin promoted excess GC growth and contributed to the poor prognosis of the GC patients by down-regulating ERK-P65-miR23a/27a/24 axis. Gastrin inhibits gastric cancer growth through activating the ERK-P65-miR23a/27a/24 axis.

Topics: Animals; Cell Line, Tumor; Cisplatin; Disease Models, Animal; Disease Progression; Extracellular Signal-Regulated MAP Kinases; Female; Gastrins; Gene Expression; Gene Expression Regulation, Neoplastic; Genes, Reporter; Heterografts; Humans; Mice; MicroRNAs; RNA Interference; Signal Transduction; Stomach Neoplasms; Transcription Factor RelA

With the widespread use of endoscopy, small and low-grade type 3 gastric neuroendocrine tumours (NETs) are increasingly being detected. The clinicopathological features, biological behaviour and appropriate treatment strategy for these NETs remain unclear.. Patients with biopsy-proven gastric NET and a normal fasting serum gastrin level were identified from a prospectively maintained database. Clinicopathological features and long-term outcome of local resection for type 3 NETs were reviewed retrospectively and compared according to tumour grade.. Some 32 patients with type 3 gastric NETs were included (25 patients with NET grade G1, 5 with G2 and 2 with G3). Pathological tumour size was 2·0 cm or less in 30 patients. All tumours were well differentiated, even G3 lesions, and all tumours but one were confined to the submucosal layer. G1 NETs were significantly smaller and had a significantly lower lymphovascular invasion rate than G2 and G3 NETs. Twenty-two patients with a G1 NET without lymphovascular invasion were treated with wedge or endoscopic resection. After a median follow-up of 59 (range 6-102) months, no patient with a G1 NET of 1·5 cm or smaller developed recurrence and one patient with a G1 NET larger than 1·5 cm had recurrence in a perigastric lymph node. Among seven patients with a G2 or G3 NET, two had lymph node metastasis and one had liver metastases.. Low-grade type 3 gastric NET has non-aggressive features and a favourable prognosis. Wedge or endoscopic resection may be a valid option for patients with type 3 gastric G1 NET no larger than 1·5 cm without lymphovascular invasion.

Topics: Adult; Aged; Biomarkers, Tumor; Biopsy; Endoscopy, Gastrointestinal; Female; Follow-Up Studies; Gastrectomy; Gastrins; Humans; Intestinal Neoplasms; Male; Middle Aged; Neoplasm Grading; Neoplasm Recurrence, Local; Neuroendocrine Tumors; Pancreatic Neoplasms; Prognosis; Prospective Studies; Stomach Neoplasms; Time Factors

DNA methylation is a regulatory mechanism in epigenetics that is frequently altered during human carcinogenesis. To detect critical methylation events associated with gastric cancer (GC), we compared three DNA methylomes from gastric mucosa (GM), intestinal metaplasia (IM), and gastric tumor (GT) cells that were microscopically dissected from an intestinal-type early gastric cancer (EGC) using methylated DNA binding domain sequencing (MBD-seq) and reduced representation bisulfite sequencing (RRBS) analysis. In this study, we focused on differentially methylated promoters (DMPs) that could be directly associated with gene expression. We detected 2,761 and 677 DMPs between the GT and GM by MBD-seq and RRBS, respectively, and for a total of 3,035 DMPs. Then, 514 (17%) of all DMPs were detected in the IM genome, which is a precancer of GC, supporting that some DMPs might represent an early event in gastric carcinogenesis. A pathway analysis of all DMPs demonstrated that 59 G protein-coupled receptor (GPCR) genes linked to the hypermethylated DMPs were significantly enriched in a neuroactive ligand-receptor interaction pathway. Furthermore, among the 59 GPCRs, six GI hormone receptor genes (NPY1R, PPYR1, PTGDR, PTGER2, PTGER3, and SSTR2) that play an inhibitory role in the secretion of gastrin or gastric acid were selected and validated as potential biomarkers for the diagnosis or prognosis of GC patients in two cohorts. These data suggest that the loss of function of gastrointestinal (GI) hormone receptors by promoter methylation may lead to gastric carcinogenesis because gastrin and gastric acid have been known to play a role in cell differentiation and carcinogenesis in the GI tract.

Topics: Carcinogenesis; Cell Differentiation; Cell Line, Tumor; DNA Methylation; Gastric Acid; Gastric Mucosa; Gastrins; Humans; Metaplasia; Neurotransmitter Agents; Promoter Regions, Genetic; Receptors, G-Protein-Coupled; Receptors, Gastrointestinal Hormone; Signal Transduction; Stomach Neoplasms; Sulfites; Whole Genome Sequencing

We aimed to assess a serological biopsy using five stomach-specific circulating biomarkers-pepsinogen I (PGI), PGII, PGI/II ratio, anti-Helicobacter pylori (H. pylori) antibody, and gastrin-17 (G-17)-for identifying high-risk individuals and predicting risk of developing gastric cancer (GC).. Among 12,112 participants with prospective follow-up from an ongoing population-based screening program using both serology and gastroscopy in China, we conducted a multi-phase study involving a cross-sectional analysis, a follow-up analysis, and an integrative risk prediction modeling analysis.. In the cross-sectional analysis, the five biomarkers (especially PGII, the PGI/II ratio, and H. pylori sero-positivity) were associated with the presence of precancerous gastric lesions or GC at enrollment. In the follow-up analysis, low PGI levels and PGI/II ratios were associated with higher risk of developing GC, and both low (<0.5 pmol/l) and high (>4.7 pmol/l) G-17 levels were associated with higher risk of developing GC, suggesting a J-shaped association. In the risk prediction modeling analysis, the five biomarkers combined yielded a C statistic of 0.803 (95% confidence interval (CI)=0.789-0.816) and improved prediction beyond traditional risk factors (C statistic from 0.580 to 0.811, P<0.001) for identifying precancerous lesions at enrollment, and higher serological biopsy scores based on the five biomarkers at enrollment were associated with higher risk of developing GC during follow-up (P for trend <0.001).. A serological biopsy composed of the five stomach-specific circulating biomarkers could be used to identify high-risk individuals for further diagnostic gastroscopy, and to stratify individuals' risk of developing GC and thus to guide targeted screening and precision prevention.

Topics: Adenocarcinoma; Adult; Aged; Antibodies, Bacterial; Biomarkers; Biopsy; Cross-Sectional Studies; Female; Follow-Up Studies; Gastric Mucosa; Gastrins; Gastroscopy; Helicobacter pylori; Humans; Logistic Models; Male; Middle Aged; Pepsinogen A; Pepsinogen C; Precancerous Conditions; Proportional Hazards Models; Risk Assessment; ROC Curve; Stomach Neoplasms

Gastrin, which induces gastric acid secretion, and a structurally similar hormone, cholecystokinin (CCK)-a potent acid inhibitor, may each play a role in gastric cancer. However, few studies have investigated this hypothesis in humans. We therefore investigated whether serum gastrin or CCK concentrations at baseline were associated with the incidence of gastric non-cardia adenocarcinomas (GNCA), oesophagogastric junctional adenocarcinomas (EGJA) or gastric carcinoid tumours over 24 years of follow-up in a study nested within the all-male Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study of Finnish smokers.. Totals of 283 incident GNCA, 96 EGJA and 10 gastric carcinoid cases, and 778 matched controls, were included in our analysis. Gastrin and CCK were measured using specific radioimmunoassays. Odds ratios (OR) and 95% confidence intervals (95% CI) were estimated by multivariable logistic regression with adjustment for all known or suspected confounding factors, including Helicobacter pylori seropositivity.. Those with high gastrin (Q4 vs Q1), had an increased risk of GNCA (fully adjusted OR: 1.92; 95% CI: 1.21, 3.05) and gastric carcinoids, though the small number of carcinoid cases meant the fully adjusted model was unstable (age-adjusted continuous model OR: 4.67; 95% CI: 2.67, 8.15). CCK was associated with risk of GNCA only for those in Q3 relative to Q1 (OR: 0.56; 95% CI: 0.33, 0.96), and no significant trend was observed.. Our data suggest that high serum concentrations of gastrin may be associated independently with an increased risk of gastric cancer; the role of CCK in cancer risk is less clear.

Topics: Adenocarcinoma; Case-Control Studies; Cholecystokinin; Esophageal Neoplasms; Finland; Follow-Up Studies; Gastrins; Helicobacter Infections; Helicobacter pylori; Humans; Incidence; Logistic Models; Male; Middle Aged; Multivariate Analysis; Prospective Studies; Risk Factors; Smokers; Stomach Neoplasms

Neuroendocrine tumors (NETs) represent uncommon tumors arising from the excessive proliferation of enterochromaffin-like (ECL) cells (so-called Kulchitsky cell). Gastric NETs (GNET) represent less than 2% of all NETs and less than 1% of all stomach neoplasms. In particular, gastric NETs type 1 (associated to chronic atrophic gastritis and hypergastrinaemia) is the more frequent one, accounting for 70-80% of all GNET. A macrocytic anemia is a frequent manifestation of GNET type 1. The possibility that macrocytic anemia appear during therapy with methotrexate (MTX) is widely documented. Similarly, MTX can determine gastric atrophy. We describe the case of a patient with rheumatoid factor-positive early arthritis (EA) in which the appearance of macrocytic anemia during treatment with MTX led to the recognition of a GNET type 1, until then asymptomatic. The endoscopic eradication of polypoid formations forming the GNET, the immediate suspension of MTX and therapy with octreotide long-action determined the complete remission of arthritis. This remission is maintained until today. According to our knowledge, the possibility that an EA may represent a paraneoplastic manifestation of GNET has never been described.

Topics: Anemia, Macrocytic; Antimetabolites, Antineoplastic; Antineoplastic Agents, Hormonal; Arthritis; Enterochromaffin Cells; Erythrocytes; Gastrins; Gastritis, Atrophic; Humans; Male; Methotrexate; Middle Aged; Neuroendocrine Tumors; Octreotide; Rheumatoid Factor; Stomach Neoplasms

Parietal cells play a fundamental role in stomach maintenance, not only by creating a pathogen-free environment through the production of gastric acid, but also by secreting growth factors important for homeostasis of the gastric epithelium. The gastrointestinal hormone gastrin is known to be a central regulator of both parietal cell function and gastric epithelial cell proliferation and differentiation. Our previous gene expression profiling studies of mouse stomach identified parathyroid hormone-like hormone (PTHLH) as a potential gastrin-regulated gastric growth factor. Although PTHLH is commonly overexpressed in gastric tumors, its normal expression, function, and regulation in the stomach are poorly understood. In this study we used pharmacologic and genetic mouse models as well as human gastric cancer cell lines to determine the cellular localization and regulation of this growth factor by the hormone gastrin. Analysis of

Topics: Animals; Cell Line, Tumor; Gastrins; Gene Expression Regulation, Neoplastic; Genotype; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Parathyroid Hormone-Related Protein; Parietal Cells, Gastric; Phenotype; RNA Processing, Post-Transcriptional; RNA Stability; RNA, Messenger; Stomach Neoplasms; Time Factors; Transcriptional Activation; Up-Regulation

Serum pepsinogen (PG) test, as an indicator of gastric mucosal atrophy, reflects the functional and morphologic status of gastric mucosal and it is suggested to serve as a useful predictive marker for patients with gastric cancer (GC). The available classifications of gastritis, known as the Operative Link on Gastritis Assessment (OLGA) and Operative Link on Gastritis Intestinal Metaplasia (OLGIM), integrating the severity and topography of atrophy/intestinal metaplasia (IM), have been gradually accepted and used in screening for GC in recent years.. To assess whether serum pepsinogen test, including PGI, PGII, PGI/PGII and gastrin-17 (G-17) could reflect the extent and topography of gastric mucosal atrophy/IM. Furthermore, to discuss the relationship between OLGA/OLGIM staging system and serum pepsinogen test in assessment of gastric atrophy/IM.. A total of 177 non-atrophic gastritis and 154 atrophic gastritis were analyzed, among which 40 were antrum atrophy, 32 were corpus atrophy and 82 were pan-atrophy. All patients were assessed applying the OLGA/OLGIM criteria with a mean age of 54.7 ± 10.8 years. Patients among OLGA/OLGIM Stage III-IV were presented with a lower level of serum PGI and PGI/PGII (p < .05), especially for Stage IV (p = .01). For both Hp-positive patients and Hp-negative patients according to OLGA system, PGI/PGII level correlated inversely with the rising stage (p = .022; p = .028). As for OLGIM system, similar difference can be seen in PGI/PGII level in either Hp-positive patients, or Hp-negative patients (p = .036; p = .013). In addition, the percentage of G-17 <1 pmol/L combined with PG-negative in antrum atrophy group was much higher than that of non-atrophy group and corpus atrophy group (25 versus 15.8 versus 6.3%) (p = .029). The proportion of G-17 > 15 pmol/L combined with PG-positive was apparently higher in corpus atrophy group, compared with other two groups (25 versus 11.3 versus 8.1%) (p = .023). Logistic regression modeling showed there exist significant connections between OLGA/OLGIM stages and serum pepsinogen test in patient stratification for gastric mucosal atrophy assessment (p < .001, p < .001).. Serum pepsinogen test has a strong correlation with OLGA/OLGIM gastritis stage and could provide important information in assessment of atrophy/intestinal metaplasia.

Topics: Adult; Aged; Antibodies, Bacterial; Biomarkers; China; Female; Gastric Mucosa; Gastrins; Gastritis, Atrophic; Gastroscopy; Helicobacter pylori; Humans; Logistic Models; Male; Metaplasia; Middle Aged; Pepsinogen A; Retrospective Studies; Risk Assessment; Risk Factors; Stomach Neoplasms

The aim of this study was to evaluate the correlation between H. pylori infection and global DNA methylation, as well as the methylation levels of the gastrin promoters.. These results indicate that H. pylori/CagA

Topics: Antigens, Bacterial; Bacterial Proteins; Cell Line; Cell Line, Tumor; CpG Islands; DNA; DNA Methylation; Gastric Mucosa; Gastrins; Gene Expression Regulation, Enzymologic; Genomics; Helicobacter Infections; Helicobacter pylori; Humans; Promoter Regions, Genetic; RNA, Messenger; Stomach Neoplasms; Transfection

Multidrug resistance (MDR) is one of the major reasons for the failure of chemotherapy-based gastric carcinoma (GC) treatments, hence, biologically based therapies are urgently needed. Gastrin (GAS), a key gastrointestinal (GI) hormone, was found to be involved in tumor formation, progression, and metastasis. In this study, quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemical staining analysis revealed a high level of expression of GAS in drug-insensitive GC tissues (P<0.01) and similar results were revealed in GC cell lines SGC7901 and its multidrug-resistant variants SGC7901/VCR and SGC7901/ADR. We constructed a eukaryotic expression vector pCDNA3.1(+)/GAS for GAS overexpression and recombinant lentiviral vectors for specific siRNA (siGAS). Transfection of pCDNA3.1(+)/GAS increased (P<0.05) while transfection of siGAS (P<0.05) and co-treated with paclitaxel (TAX) and vincristine (VCR) combination (TAX-VCR) decreased (P<0.01) the cell viability of SGC7901, SGC7901/VCR and SGC7901/ADR. Apoptosis rates of SGC7901/VCR and SGC7901/ADR were reduced by pCDNA3.1(+)/GAS and increased by siGAS (P<0.05). The apoptosis rates of SGC7901/VCR, SGC7901/ADR and SGC7901 were all upregulated (P<0.01) when cells were co-treated with a combination of siGAS and TAX-VCR. Additionally, siGAS significantly downregulated the expression of Bcl-2 and multidrug-resistant associate protein (MRP1) and P-glycoprotein (Pgp) (P<0.05) in SGC7901/VCR and SGC7901/ADR cells. Moreover, GAS overexpression in SGC7901 cells significantly inhibited p27Kip1 expression but increased phosphorylation levels of p27Kip1 on Thr (187) and Ser (10) sites (P<0.05), as well as increasing nuclear accumulation of S-phase kinase-associated protein 2 (Skp2) and cytoplasmic accumulation of the Kip1 ubiquitination-promoting complex (KPC) (P<0.05). Silencing of Skp2 blocked the promoting effects of pCDNA3.1(+)/GAS on viability, the expression of MRP1 and Pgp and the inhibitory effects of pCDNA3.1(+)/GAS on apoptosis. In conclusion, we suggest that GAS contributes to the emergence of MDR of SGC7901 cells via the degradation of p27Kip1.

Topics: Aged; Camptothecin; Carcinoma; Cell Line, Tumor; Cyclin-Dependent Kinase Inhibitor p27; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Female; Fluorouracil; Gastrins; Gene Expression Regulation, Neoplastic; Humans; Irinotecan; Male; Middle Aged; Multidrug Resistance-Associated Proteins; Phosphorylation; Proteolysis; RNA, Small Interfering; S-Phase Kinase-Associated Proteins; Stomach Neoplasms

The cytoprotective protein clusterin is often dysregulated during tumorigenesis, and in the stomach, upregulation of clusterin marks emergence of the oxyntic atrophy (loss of acid-producing parietal cells)-associated spasmolytic polypeptide-expressing metaplasia (SPEM). The hormone gastrin is important for normal function and maturation of the gastric oxyntic mucosa and hypergastrinemia might be involved in gastric carcinogenesis. Gastrin induces expression of clusterin in adenocarcinoma cells. In the present study, we examined the expression patterns and gastrin-mediated regulation of clusterin in gastric tissue from: humans; rats treated with proton pump (H+/K+-ATPase) inhibitors and/or a gastrin receptor (CCK2R) antagonist; H+/K+-ATPase β-subunit knockout (H/K-β KO) mice; and Mongolian gerbils infected with Helicobacter pylori and given a CCK2R antagonist. Biological function of secretory clusterin was studied in human gastric cancer cells. Clusterin was highly expressed in neuroendocrine cells in normal oxyntic mucosa of humans and rodents. In response to hypergastrinemia, expression of clusterin increased significantly and its localization shifted to basal groups of proliferative cells in the mucous neck cell-chief cell lineage in all animal models. That shift was partially inhibited by antagonizing the CCK2R in rats and gerbils. The oxyntic mucosa of H/K-β KO mice contained areas with clusterin-positive mucous cells resembling SPEM. In gastric adenocarcinomas, clusterin mRNA expression was higher in diffuse tumors containing signet ring cells compared with diffuse tumors without signet ring cells, and clusterin seemed to be secreted by tumor cells. In gastric cancer cell lines, gastrin increased secretion of clusterin, and both gastrin and secretory clusterin promoted survival after starvation- and chemotherapy-induced stress. Overall, our results indicate that clusterin is overexpressed in hypergastrinemic rodent models of oxyntic preneoplasia and stimulates gastric cancer cell survival.

Topics: Aged; Aged, 80 and over; Animals; Carcinogenesis; Cell Line, Tumor; Clusterin; Female; Gastrins; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Gerbillinae; Humans; Male; Mice, Knockout; Middle Aged; Parietal Cells, Gastric; Proton Pump Inhibitors; Rats; Rats, Sprague-Dawley; Receptor, Cholecystokinin B; Stomach Neoplasms

Objective To investigate the expressions and correlations of gastrin and apoptosis-associated proteins involved in mitochondrial apoptotic pathway in gastric cancer tissues, and explore their clinicopathological characteristics. Methods The tissue chip technology and immunohistochemistry (IHC) were used to detect the expressions of gastrin and apoptosis-associated proteins (Bcl2, caspase-9 and caspase-3) in human gastric cancer tissues and their paracancerous tissues. The correlations of these markers and their clinicopathological characteristics were analyzed using Spearman rank correlation analysis and Chi-square test. Results The expressions of gastrin and Bcl2 in gastric cancer tissues were significantly higher than those in the corresponding paracancerous tissues, whereas the expressions of caspase-9 and caspase-3 in gastric cancer tissues was significantly lower than those in the corresponding tissues. There was a significant positive correlation between the expressions of gastrin and Bcl2 in gastric cancer tissues (r=0.237). The expression of gastrin was associated with tumor position, and the expression of Bcl2 was associated with tumor size, TNM stage and lymph node metastasis. Conclusion Gastrin and Bcl2 are highly expressed in gastric cancer tissues, and they are correlated with the clinicopathologic features.

Topics: Adult; Aged; Biomarkers, Tumor; Caspase 3; Caspase 9; Female; Gastrins; Humans; Immunohistochemistry; Male; Middle Aged; Mitochondria; Proto-Oncogene Proteins c-bcl-2; Signal Transduction; Stomach Neoplasms

Gastric carcinoids are slow growing neuroendocrine tumours arising from enterochromaffin-like (ECL) cells in the corpus of stomach. Although most of these tumours arise in the setting of gastric atrophy and hypergastrinemia, it is not understood what genetic background predisposes development of these ECL derived tumours. Moreover, diffuse microcarcinoids in the mucosa can lead to a field effect and limit successful endoscopic removal.. To define the genetic background that creates a permissive environment for gastric carcinoids using transgenic mouse lines.. The multiple endocrine neoplasia 1 gene locus (Men1) was deleted using Cre recombinase expressed from the Villin promoter (Villin-Cre) and was placed on a somatostatin null genetic background. These transgenic mice received omeprazole-laced chow for 6 months. The direct effect of gastrin and the gastrin receptor antagonist YM022 on expression and phosphorylation of the cyclin inhibitor p27. The combination of conditional Men1 deletion in the absence of somatostatin led to the development of gastric carcinoids within 2 years. Suppression of acid secretion by omeprazole accelerated the timeline of carcinoid development to 6 months in the absence of significant parietal cell atrophy. Carcinoids were associated with hypergastrinemia, and correlated with increased Cckbr expression and nuclear export of p27. Gastric carcinoids require threshold levels of hypergastrinemia, which modulates p27

Topics: Adenocarcinoma; Adult; Animals; Benzodiazepines; Carcinogenesis; Carcinoid Tumor; Cell Line, Tumor; Cyclin-Dependent Kinase Inhibitor p27; Female; Gastrins; Gene Deletion; Hormone Antagonists; Hormones; Humans; Male; Mice; Mice, Transgenic; Omeprazole; Phosphorylation; Proto-Oncogene Proteins; Proton Pump Inhibitors; Receptor, Cholecystokinin B; RNA, Messenger; Signal Transduction; Somatostatin; Stomach Neoplasms

Gastric cancer (GC) is one of the most frequent epithelial malignancies worldwide. The gastrointestinal (GI) peptide gastrin is an important regulator of the secretion and release of gastric acid from stomach parietal cells, and it also plays a vital role in the development and progression of GC. The aim of the current study was to investigate the role and underlying mechanism of gastrin and autophagy in regulating GC tumorigenesis. Gastrin-17 amide (G-17) was applied in the GC cell lines SGC7901 and MGC-803. The results showed that G-17 maintained the high viability of SGC7901 and MGC-803. The expression of autophagy marker proteins LC3II and Beclin1 was significantly increased, while the autophagy substrate p62 was obviously decreased in the gastrin group compared with the control group. Moreover, G-17 strengthened the expressions of AMPKα, Ras, Raf, MEK, and ERK1/2. Additionally, administration of AMPKα siRNA counteracted the effect of gastrin in SGC7901 cells. Finally, in an in vivo study of the tumor growth and survival rate of rats, the levels of AMPKα/Ras/Raf/MEK/ERK were significantly increased in the gastrin group and decreased following AMPKα shRNA injection. In conclusion, these findings indicate that gastrin plays a tumorigenic role by promoting autophagy in GC and may provide a novel therapeutic target for GC treatment.

Topics: AMP-Activated Protein Kinases; Animals; Apoptosis; Autophagy; Cell Line, Tumor; Cell Proliferation; Female; Gastrins; Humans; Mice; Signal Transduction; Stomach Neoplasms

In patients with adenoma, assessing premalignant changes in the surrounding mucosa is important for surveillance. This study evaluated atrophic and metaplastic progression in the background mucosa of adenoma or early gastric cancer (EGC) cases.. Among 146 consecutive patients who underwent endoscopic resection for intestinal-type gastric neoplasia, the adenoma group included 56 patients with low-grade dysplasia and the ECG group included 90 patients with high-grade dysplasia or invasive carcinoma. For histology, 3 paired biopsies were obtained from the antrum, corpus lesser curvature (CLC), and corpus greater curvature (CGC). Serological atrophy was determined based on pepsinogen A (PGA), progastricsin (PGC), gastrin-17, and total ghrelin levels. Topographic progression of atrophy and/or metaplasia was staged using the operative link on gastritis assessment (OLGA) and operative link on gastric intestinal metaplasia assessment (OLGIM) systems.. Rates of moderate-to-marked histological atrophy/metaplasia in patients with adenoma were 52.7%/78.2% at the antrum (vs. 58.8%/76.4% in EGC group), 63.5%/75.0% at the CLC (vs. 60.2%/69.7% in EGC group), and 10.9%/17.9% at the CGC (vs. 5.6%/7.8% in EGC group). Serological atrophy indicated by PGA and PGC occurred in 23.2% and 15.6% of cases in the adenoma and ECG groups, respectively (p = 0.25). Mean serum gastrin-17 concentrations of the adenoma group and EGC group were 10.4 and 9.0 pmol/L, respectively (p = 0.54). Mean serum total ghrelin levels were 216.6 and 209.5 pg/mL, respectively (p = 0.71). Additionally, between group rates of stage III-IV OLGA and OLGIM were similar (25.9% vs. 25.0%, p = 0.90; 41.8% vs. 44.9%, p = 0.71, respectively).. Atrophic and metaplastic progression is extensive and severe in gastric adenoma patients. A surveillance strategy for metachronous tumors should be applied similarly for patients with adenoma or EGC.

Topics: Adenoma; Aged; Biomarkers; Disease Progression; Female; Follow-Up Studies; Gastric Mucosa; Gastrins; Gastritis, Atrophic; Humans; Male; Metaplasia; Middle Aged; Neoplasms, Second Primary; Pepsinogen C; Risk Factors; Stomach Neoplasms

The peptide hormone gastrin exerts a growth-promoting effect in both normal and malignant gastrointestinal tissue. Gastrin mediates its effect via the cholecystokinin 2 receptor (CCKBR/CCK2R). Although a substantial part of the gastric adenocarcinomas express gastrin and CCKBR, the role of gastrin in tumor development is not completely understood. Autophagy has been implicated in mechanisms governing cytoprotection, tumor growth, and contributes to chemoresistance. This study explores the role of autophagy in response to gastrin in gastric adenocarcinoma cell lines.. Immunoblotting, survival assays and the xCELLigence system were used to study gastrin induced autophagy. Chemical inhibitors of autophagy were utilized to assess the role of this process in the regulation of cellular responses induced by gastrin. Further, knockdown studies using siRNA and immunoblotting were performed to explore the signaling pathways that activate autophagy in response to gastrin treatment.. We demonstrate that gastrin increases the expression of the autophagy markers MAP1LC3B-II and SQSTM1 in gastric adenocarcinoma cells. Gastrin induces autophagy via activation of the STK11-PRKAA2-ULK1 and that this signaling pathway is involved in increased migration and cell survival. Furthermore, gastrin mediated increase in survival of cells treated with cisplatin is partially dependent on induced autophagy.. This study reveals a novel role of gastrin in the regulation of autophagy. It also opens up new avenues in the treatment of gastric cancer by targeting CCKBR mediated signaling and/or autophagy in combination with conventional cytostatic drugs.

Topics: Adenocarcinoma; Autophagy; Cell Line, Tumor; Cell Movement; Cell Survival; Gastrins; Gene Expression Regulation, Neoplastic; Humans; Microtubule-Associated Proteins; Receptor, Cholecystokinin B; Sequestosome-1 Protein; Signal Transduction; Stomach Neoplasms

We report a case of developing multiple adenocarcinoma foci in multiple hyperplastic polyps in a patient with Helicobacter pylori infection and hypergastrinemia during long-term proton pump inhibitor (PPI) therapy. A 57-year-old man, who was undergoing hemodialysis for chronic renal failure, underwent an upper gastrointestinal endoscopy to elucidate the cause of anemia. Atrophic gastritis with H. pylori infection and multiple adenocarcinoma foci in multiple hyperplastic polyps were found in the endoscopic and histological examinations. Enterochromaffin-like micronests and parietal cell protrusion in the background of the polyps suggested the existence of hypergastrinemia. The serum gastrin level was markedly high-10,206 pg/ml (normal range 37-172 pg/ml). The cause of this marked hypergastrinemia was not autoimmune gastritis and gastrinoma. After discontinuing PPI therapy and successful eradication of H. pylori, the serum gastrin level decreased to normal range. These findings indicate that hypergastrinemia may be caused by long-term PPI therapy in patients with H. pylori infection. This case suggests that hypergastrinemia may mediate gastric carcinogenesis in patients with H. pylori infection.

Topics: Adenocarcinoma; Cocarcinogenesis; Drug Administration Schedule; Gastrins; Gastritis, Atrophic; Gastroscopy; Helicobacter Infections; Helicobacter pylori; Humans; Hyperplasia; Male; Middle Aged; Polyps; Proton Pump Inhibitors; Stomach Neoplasms

A man in his 60s was referred to our institution for the evaluation of a gastric neuroendocrine tumor (G-NET) located in the fornix and that measured 13mm in size. Blood test results revealed hypergastrinemia (up to 3376pg/ml). Additional tests, including esophagogastroduodenoscopy, computed tomography, and intragastric pH monitoring, indicated that hypergastrinemia was not associated with type A autoimmune gastritis or gastrinoma. The patient was positive for the immunoglobulin G antibody against Helicobacter pylori, suggesting type B chronic atrophic gastritis as the cause for the condition. This report describes a rare case of G-NET with hypergastrinemia following type B chronic atrophic gastritis. Evaluation of similar cases is necessary to determine if H. pylori-associated chronic atrophic gastritis is frequently associated with G-NET.

Topics: Chronic Disease; Gastrins; Gastritis, Atrophic; Helicobacter Infections; Helicobacter pylori; Humans; Male; Neuroendocrine Tumors; Stomach Neoplasms

Topics: Aged; Biopsy, Fine-Needle; Carcinoid Tumor; Chromogranins; Duodenal Neoplasms; Duodenoscopy; Duodenum; Endosonography; Gastrinoma; Gastrins; Humans; Immunohistochemistry; Male; Stomach Neoplasms; Synaptophysin

The ABCD screening method was developed for risk stratification of gastric cancer. It is unclear whether the ABCD method can predict the risk of gastric neoplasms, including gastric adenomas, as observed for gastric cancer. We aimed to devise a modified ABCD method for predicting gastric neoplasms.. We reviewed 562 patients who had undergone upper gastrointestinal tract endoscopy and whose serum IgG anti-Helicobacter pylori antibody, gastrin, and pepsinogen (PG) I and PG II data were available. Patients were classified into the following four groups: H. pylori antibody negative and normal PG level (group A), H. pylori antibody positive and normal PG level (group B), H. pylori antibody positive and low PG level (group C), and H. pylori antibody negative and low PG level (group D).. The PG I/PG II ratio was lower in patients with gastric neoplasms than in patients without these lesions (gastric adenoma vs gastric cancer vs no neoplasm, 3.7 ± 2.0 vs 3.8 ± 1.8 vs 4.9 ± 2.1, P < 0.001). The optimal cutoff values of the PG I/PG II ratio for predicting gastric neoplasms were 3.1 for H. pylori antibody negative patients and 4.1 for H. pylori antibody positive patients. A higher group grade was associated with a significantly higher proportion of gastric neoplasms [odds ratio (95 % confidence interval), group A, reference; group B, 1.783 (1.007-3.156); group C, 3.807 (2.382-6.085); and group D, 5.862 (2.427-14.155)].. The modified ABCD method using two different cutoff values according to the H. pylori antibody status was useful for predicting the presence of gastric neoplasms. This method might be a supplementary screening tool for both gastric adenoma and gastric cancer. However, further studies will be required to provide a definitive conclusion.

Topics: Adenoma; Aged; Antibodies, Bacterial; Endoscopy, Gastrointestinal; Female; Gastrins; Helicobacter Infections; Helicobacter pylori; Humans; Immunoglobulin G; Male; Middle Aged; Pepsinogen A; Pepsinogen C; Retrospective Studies; Stomach Neoplasms

Gastrokine 1 (GKN1) acts as a gastric tumor suppressor. Here, we investigated whether GKN1 contributes to the maintenance of gastric mucosal homeostasis by regulating gastrin-induced gastric epithelial cell growth.. We assessed the effects of gastrin and GKN1 on cell proliferation in stable AGS(GKN1) and MKN1(GKN1) gastric cancer cell lines and HFE-145 nonneoplastic epithelial cells. Cell viability and proliferation were analyzed by MTT and BrdU incorporation assays, respectively. Cell cycle and expression of growth factor receptors were examined by flow cytometry and Western blot analyses.. Gastrin treatment stimulated a significant time-dependent increase in cell viability and proliferation in AGS(mock) and MKN1(mock), but not in HFE-145, AGS(GKN1), and MKN1(GKN1), cells, which stably expressed GKN1. Additionally, gastrin markedly increased the S-phase cell population, whereas GKN1 significantly inhibited the effect of gastrin by regulating the expression of G1/S cell-cycle regulators. Furthermore, gastrin induced activation of the NF-kB and β-catenin signaling pathways and increased the expression of CCKBR, EGFR, and c-Met in AGS and MKN1 cells. However, GKN1 completely suppressed these effects of gastrin via downregulation of gastrin/CCKBR/growth factor receptor expression. Moreover, GKN1 reduced gastrin and CCKBR mRNA expression in AGS and MKN1 cells, and there was an inverse correlation between GKN1 and gastrin, as well as between GKN1 and CCKBR mRNA expression in noncancerous gastric mucosae.. These data suggest that GKN1 may contribute to the maintenance of gastric epithelial homeostasis and inhibit gastric carcinogenesis by downregulating the gastrin-CCKBR signaling pathway.

Topics: Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cell Survival; Epithelial Cells; Gastric Mucosa; Gastrins; Gene Expression Regulation; Humans; NF-kappa B; Peptide Hormones; Receptor, Cholecystokinin B; Receptors, Growth Factor; Stomach Neoplasms

Topics: Gastrins; Humans; Proton Pump Inhibitors; Stomach Neoplasms

Green tea catechins (GTCs) have been implicated in various physiological effects, including anti-carcinogenic activities. In the present study, we evaluated the effects of GTCs specifically on the development of gastritis and pre-malignant lesions in insulin-gastrin mice. Nine-week-old male INS-GAS mice (n=38) were supplemented with GTCs for 4 and 28 weeks, and their body weights, serum gastrin levels, histopathology and pro-inflammatory cytokine levels in gastric tissue and mucosal cell proliferation were monitored. Body weights of the GTC-treated mice were significantly lower than those of the untreated controls (P≤0.05). Serum gastrin levels were suppressed at the age of 37-weeks (P≤0.05). The histopathological scores indicated that the extent of dysplasia was significantly diminished (P≤0.05), although GTC supplementation did not affect the inflammation scores. The messenger RNA levels of interferon (IFN)-γ were significantly reduced at the age of 13 weeks (P≤0.05), although the changes did not reach statistical significance at the age of 37 weeks (P=0.056). The labeling index of Ki-67 immunohistochemistry was significantly decreased (P≤0.05). These results demonstrated that GTCs may play a protective role in the development of gastritis and pre-malignant lesions via an IFN-γ, gastrin, and mucosal cell proliferation-dependent mechanism in this rodent model and potentially in humans.

Topics: Animals; Anticarcinogenic Agents; Body Weight; Camellia sinensis; Catechin; Cell Proliferation; Drug Evaluation, Preclinical; Epithelial Cells; Gastric Mucosa; Gastrins; Gastritis; Interferon-gamma; Male; Mice; Stomach Neoplasms

Gastrin-independent gastric neuroendocrine tumors (GNETs) are highly malignant. Radical resections and lymphadenectomy are considered to be the only possible curative treatment for these tumors. However, the prognosis of gastrin-independent GNETs is not well defined. In this study, we identified prognostic factors of locoregional gastrin-independent GNETs.All patients diagnosed with locoregional gastrin-independent GNETs between 2000 and 2014 were included in this retrospective study. Clinical characteristics, blood tests, pathological characteristics, treatments, and follow-up data of the patients were collected and analyzed.Of the 66 patients diagnosed with locoregional gastrin-independent GNETs, 57 (86.4%) received radical resections, 7 (10.6%) with palliative resection, 1 (1.5%) with gastrojejunostomy, and 1 (1.5%) with exploration surgeries. The median survival time for these patients was 19.0 months (interquartile range, 11.0-38.0). The 1-, 3-, and 5-year survival rates were 72%, 34%, and 28%, respectively. Multivariate analysis indicated that carcinoembryonic antigen (CEA) level (P = 0.04), radical resection (P = 0.04), and positive Cluster of Differentiation 56 (CD56) expression (P = 0.016) were significant prognostic factors on overall survival rate. Further univariate and multivariate analysis of 57 patients who received radical resections found that CgA expression (P = 0.35) and CEA level (P = 0.33) are independent prognostic factors.Gastrin-independent GNETs had poor prognosis. Serum CEA level, radical surgery, CD56 and CgA expression are markers to evaluate the survival of patients with locoregional gastrin-independent GNETs.

Topics: Carcinoembryonic Antigen; CD56 Antigen; Chromogranin A; Female; Gastrectomy; Gastrins; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Neuroendocrine Tumors; Prognosis; Proportional Hazards Models; Stomach Neoplasms; Survival Analysis

Connective tissue growth factor (CTGF) has been reported in gastric adenocarcinoma and in carcinoid tumors. The aim of this study was to explore a possible link between CTGF and gastrin in gastric epithelial cells and to study the role of CTGF in gastrin induced migration and invasion of AGS-GR cells. The effects of gastrin were studied using RT-qPCR, Western blot and assays for migration and invasion. We report an association between serum gastrin concentrations and CTGF abundancy in the gastric corpus mucosa of hypergastrinemic subjects and mice. We found a higher expression of CTGF in gastric mucosa tissue adjacent to tumor compared to normal control tissue. We showed that gastrin induced expression of CTGF in gastric epithelial AGS-GR cells via MEK, PKC and PKB/AKT pathways. CTGF inhibited gastrin induced migration and invasion of AGS-GR cells. We conclude that CTGF expression is stimulated by gastrin and involved in remodeling of the gastric epithelium.

Topics: Adenocarcinoma; Animals; Cell Movement; Connective Tissue Growth Factor; Gastric Mucosa; Gastrins; Humans; Mice; Neoplasm Invasiveness; Signal Transduction; Stomach; Stomach Neoplasms

Neuroendocrine tumors in the pancreas and the gastrointestinal tract may secrete hormones which cause specific syndromes. Well-known examples are gastrinomas, glucagonomas, and insulinomas. Cholecystokinin-producing tumors (CCKomas) have been induced experimentally in rats, but a CCKoma syndrome in man has remained unknown until now.. Using a panel of immunoassays for CCK peptides and proCCK as well as for chromogranin A, we have examined plasma samples from 284 fasting patients with gastroenteropancreatic neuroendocrine tumors. In hyperCCKemic samples, plasma CCK was further characterized by chromatography.. One of the patients displayed gross hyperCCKemia. She was a 58-year old woman with a pancreatic endocrine tumor, liver metastases, 500-1000-fold elevated basal CCK concentration in plasma, diarrhea, severe weight loss, recurrent peptic ulcer and bilestone attacks from a contracted gallbladder. The CCK concentrations in plasma were not affected by resection of the pancreatic tumor, but decreased to normal after hemihepatectomy with removal of the metastases.. A CCKoma syndrome with severe hypersecretion of CCK exists in man. The duodenal ulcer disease and diarrhea with permanently low gastrin in plasma suggest that CCKomas may mimic gastrinoma-like symptoms, because CCK peptides are full agonists of the gastrin/CCK-B receptor.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Animals; Child; Cholecystokinin; Denmark; Female; Gastrinoma; Gastrins; Humans; Intestinal Neoplasms; Liver Neoplasms; Male; Middle Aged; Neuroendocrine Tumors; Pancreas; Pancreatic Neoplasms; Rats; Stomach Neoplasms; Young Adult

To review the presentation, treatment and outcome of patients with type 1 gastric carcinoid tumours.. We retrospectively reviewed medical records and re-evaluated histopathological specimens of 26 patients with type 1 gastric carcinoids treated at a single tertiary referral centre from 1993 to 2013, with median time of follow-up 52.5 months (IQR 90.8).. Seven patients (27%) had single tumours and 19 patients (73%) multiple tumours at the time of diagnosis. The median number of tumours and median diameter of largest tumour were 2.5 (IQR 3.2) and 6.0 mm (IQR 9.5) respectively. Median serum gastrin was 321.0 pmol/l (IQR 604.0) and median serum chromogranin A 7.7 nmol/l (IQR 5.3). Three patients had metastatic disease at the time of diagnosis and two developed metastases during follow-up. Patients with metastatic disease had larger primary tumours than the others (20.0 mm (IQR 28.5) vs. 5.0 mm (IQR 5.5), p = 0.04). There was a positive correlation between age and tumour size (r = 0.44, p = 0.03) and between serum chromogranin A and serum gastrin at diagnosis (r = 0.76, p = 0.001). Patients were either treated with surgery (n = 8 (31%)), a long-acting somatostatin analogue and/or gastrin receptor antagonist (n = 10 (39%)) for a period of time, or were observed without treatment (n = 8 (31%) with close endoscopic follow up.. Although gastric carcinoids have an overall good prognosis, a significant proportion develops metastatic disease. As partial and total gastrectomy is associated with major side effects, treatment with long-acting a somatostatin analogue or gastrin antagonist should be considered.

Topics: Aged; Antineoplastic Agents, Hormonal; Carcinoid Tumor; Chromogranin A; Comorbidity; Enterochromaffin-like Cells; Female; Follow-Up Studies; Gastrectomy; Gastric Mucosa; Gastrins; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Neoplasm Metastasis; Norway; Octreotide; Receptor, Cholecystokinin B; Retrospective Studies; Somatostatin; Stomach Neoplasms; Tertiary Care Centers; Tomography, X-Ray Computed; Treatment Outcome

Elevated circulating concentrations of the hormone gastrin contribute to the development of gastric adenocarcinoma and types-1 and 2 gastric neuroendocrine tumors (NETs). MicroRNAs (miRNAs) are small non-coding RNAs that post-transcriptionally regulate proteins which in turn influence various biological processes. We hypothesised that gastrin induces the expression of specific gastric miRNAs within CCK2 receptor (CCK2R) expressing cells and that these mediate functionally important actions of gastrin.. Gastrin increased miR-222 expression in AGSGR cells, with maximum changes observed at 10 nM G17 for 24 h. Signalling occurred via CCK2R and the PKC and PI3K pathways. miR-222 expression was increased in the serum and gastric corpus mucosa of hypergastrinemic INS-GAS mice and hypergastrinemic patients with autoimmune atrophic gastritis and type 1 gastric NETs; it decreased in patients following treatment with the CCK2R antagonist netazepide (YF476). Gastrin-induced miR-222 overexpression resulted in reduced expression and cytoplasmic mislocalisation of p27kip1, which in turn caused actin remodelling and increased migration in AGSGR cells.. miRNA PCR arrays were used to identify changes in miRNA expression following G17 treatment of human gastric adenocarcinoma cells stably transfected with CCK2R (AGSGR). miR-222 was further investigated using primer assays and samples from hypergastrinemic mice and humans. Chemically synthesised mimics and inhibitors were used to assess cellular phenotypical changes associated with miR-222 dysregulation.. These data indicate a novel mechanism contributing to gastrin-associated gastric tumor development. miR-222 may also be a promising biomarker for monitoring gastrin induced premalignant changes in the stomach.

Topics: Adenocarcinoma; Animals; Cyclin-Dependent Kinase Inhibitor p27; Gastrins; Gene Expression Regulation, Neoplastic; Humans; Mice; Mice, Transgenic; MicroRNAs; Neuroendocrine Tumors; Stomach Neoplasms

Gastric cancer is the most common epithelial malignancy and the second leading cause of cancer-related death worldwide; metastasis is a crucial factor in the progression of gastric cancer. The present study applied gastrin-17 amide (G-17) in SGC7901 cells. The results showed that G-17 promoted the cell cycle by accelerating the G0/G1 phase and by increasing the cell proliferation rate by binding to the gastrin receptor. The migratory and invasive abilities of the SGC7901 cells were increased by G-17. The expression levels of matrix metalloproteinase (MMP)-7, MMP-9 and vascular endothelial growth factor (VEGF) were enhanced by G-17 as well. Moreover, G-17 caused the overexpression of β-catenin and TCF-4. G-17 also caused a preferential cytoplasmic and nuclear localization of β-catenin with a high TOP-FLASH activity. Finally, axin reduced the migratory and invasive abilities of the SGC7901 cells, and inhibited the expression of β-catenin, TCF-4, MMP-7, MMP-9 and VEGF; these effects were counteracted by adding G-17. In summary, the present study confirmed the proliferation and metastasis-promoting role of G-17 via binding to the gastrin receptor, and the β-catenin/TCF-4 pathway was found to be essential for mediating G-17-induced metastasis in gastric cancer. These results may provide a novel gene target for the treatment of gastric cancer.

Topics: Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; beta Catenin; Cell Line, Tumor; Cell Movement; Cell Proliferation; G1 Phase; Gastrins; Gene Expression Regulation, Neoplastic; Humans; Matrix Metalloproteinase 7; Matrix Metalloproteinase 9; Neoplasm Invasiveness; Neoplasm Metastasis; Receptor, Cholecystokinin B; Signal Transduction; Stomach Neoplasms; Transcription Factor 4; Transcription Factors; Vascular Endothelial Growth Factor A

By whole exome sequencing, we recently identified a missense mutation (p.R703C) in the human ATP4a gene, which encodes the proton pump responsible for gastric acidification. This mutation causes an aggressive familial type I gastric neuroendocrine tumor in homozygous individuals. Affected individuals show an early onset of the disease, characterized by gastric hypoacidity, hypergastrinemia, iron-deficiency anemia, gastric intestinal metaplasia and, in one case, an associated gastric adenocarcinoma. Total gastrectomy was performed as the definitive treatment in all affected individuals. We now describe the generation and characterization of a knockin mouse model for the ATP4a(R703C) mutation to better understand the tumorigenesis process. Homozygous mice recapitulated most of the phenotypical alterations that were observed in human individuals, strongly suggesting that this mutation is the primary alteration responsible for disease development. Homozygous mice developed premalignant condition with severe hyperplasia, dysplasia and glandular metaplasia in the stomach. Interestingly, gastric acidification in homozygous mice, induced by treatment with 3% HCl acid in the drinking water, prevented (if treated from birth) or partially reverted (if treated during adulthood) the development of glandular metaplasia and dysplasia in the stomach and partially rescued the abnormal biochemical parameters. We therefore suggest that, in this model, achlorhydria contributes to tumorigenesis to a greater extent than hypergastrinemia. Furthermore, our mouse model represents a unique and novel tool for studying the pathologies associated with disturbances in gastric acid secretion.

Topics: Anemia; Animals; Disease Models, Animal; Gastric Acid; Gastrins; Gene Knock-In Techniques; H(+)-K(+)-Exchanging ATPase; Homozygote; Humans; Hydrochloric Acid; Hyperplasia; Mice, Inbred C57BL; Mice, Mutant Strains; Mutation; Neuroendocrine Tumors; Phenotype; Stomach; Stomach Neoplasms

Human anion exchanger 1 and 2 (AE1 and AE2) mediate the exchange of Cl(-)/HCO3 (-) across the plasma membrane and regulate intracellular pH (pHi). AE1 is specifically expressed on the surface of erythrocytes, while AE2 is widely expressed in most tissues, and is particularly abundant in parietal cells. Previous studies showed that an interaction between AE1 and p16 is a key event in gastric cancer (GC) progression, but the importance of AE2 in GC is unclear.. The relationship among AE1, AE2 and p16 in GC cells was characterized by molecular and cellular experiments. AE2 expression and pHi were measured after knockdown or forced expression of AE1 or p16 in GC cells. The effect of AE2 on GC growth and the correlation of AE2 expression with differentiation and prognosis of GC were also evaluated. The effect of gastrin on AE2 expression and GC growth was investigated in cellular experiments and mouse xenograft models.. p16 binds to both AE1 and AE2 simultaneously. AE1 or p16 silencing elevated AE2 expression on the plasma membrane where it plays a role in pHi regulation and GC suppression. AE2 expression was decreased in GC tissue, and these decreased levels were correlated with poor differentiation and prognosis of GC. The low AE2 protein levels are due to rapid ubiquitin-mediated degradation that was facilitated in the presence of p16. Gastrin inhibited the growth of GC cells at least partially through up-regulation of AE2 expression.. AE1/p16 expression promoted AE2 degradation in GC cells. Gastrin is a potential candidate drug for targeted therapies for AE1- and p16-positive GC.

Topics: Animals; Anion Exchange Protein 1, Erythrocyte; Cell Line, Tumor; Chloride-Bicarbonate Antiporters; Cyclin-Dependent Kinase Inhibitor p16; Female; Fluorescent Antibody Technique; Gastrins; Humans; Immunoblotting; Immunoprecipitation; Mice; Mice, Inbred BALB C; Mice, Nude; Stomach Neoplasms; Xenograft Model Antitumor Assays

Effectively managing precancerous lesions is crucial to reducing the gastric cancer (GC) burden. We evaluated associations of temporal changes in multiple serological markers (pepsinogen I [PGI], PGII, PGI/II ratio, gastrin-17 and anti-Helicobacter pylori IgG) with risk for progression of gastric precancerous lesions. From 1997 to 2011, repeated esophagogastroduodenoscopies with gastric mucosal biopsies and blood sample collections were conducted on 2,039 participants (5,070 person-visits) in the Zhuanghe Gastric Diseases Screening Program, Liaoning, China. Serum biomarkers were measured using ELISA, and gastric biopsies were evaluated using standardized histologic criteria. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using generalized estimating equations for correlated binary outcomes. The ORs for progression of gastric conditions comparing those whose serum PGI, PGII, and anti-H. pylori IgG levels increased ≥ 50% relative to those whose decreased ≥ 50% were, respectively 1.67 (CI, 1.22-2.28), 1.80 (CI, 1.40-2.33) and 1.93 (CI, 1.48-2.52). The OR for those whose PGI/II ratio decreased ≥ 50% relative to those whose increased ≥ 50% was 1.40 (CI, 1.08-1.81), and for those whose PGII and anti-H. pylori IgG levels both increased ≥ 50% relative to those whose levels both decreased ≥ 50% the OR was 3.18 (CI, 2.05-4.93). Changes in gastrin-17 were not statistically significantly associated with progression. These findings suggest that temporal changes in serum PGI, PGII, PGI/II ratio, and anti-H. pylori IgG levels (especially PGII and anti-H. pylori IgG combined) may be useful for assessing and managing risk for progression of gastric precancerous lesions.

Topics: Adult; Aged; Biomarkers, Tumor; Disease Progression; Enzyme-Linked Immunosorbent Assay; Female; Follow-Up Studies; Gastrins; Helicobacter Infections; Helicobacter pylori; Humans; Immunoglobulin G; Longitudinal Studies; Male; Middle Aged; Neoplasm Staging; Pepsinogen A; Pepsinogen C; Precancerous Conditions; Prognosis; Stomach Neoplasms

Current histopathologic classification schemes for gastric adenocarcinoma have limited clinical utility and are difficult to apply due to tumor heterogeneity. Elucidation of molecular subtypes of gastric cancer may contribute to our understanding of gastric cancer biology and to the development of new molecular markers that may lead to improved diagnosis, therapy, or prognosis. We previously demonstrated that Epstein-Barr virus (EBV)-infected gastric cancers have a distinct human gene expression profile compared with uninfected cancers. We now examine the histopathologic features characterizing infected (n=14) and uninfected (n=89) cancers; the latter of which are now further divided into 2 major molecular subtypes based on expression patterns of 93 RNAs. One uninfected gastric cancer subtype was distinguished by upregulation of 3 genes with neuroendocrine (NE) function (CHGA, GAST, and REG4 encoding chromogranin, gastrin, and the secreted peptide REG4 involved in epithelial cell regeneration), implicating hormonal factors in the pathogenesis of a major class of gastric adenocarcinomas. Evidence of NE differentiation (molecular, immunohistochemical, or morphologic) was mutually exclusive of EBV infection. EBV-infected tumors tended to have solid-type morphology with lymphoid stroma. This study reveals novel molecular subtypes of gastric cancer and their associated morphologies that demonstrate divergent NE features.

Topics: Adenocarcinoma; Carcinoma, Neuroendocrine; Cell Differentiation; Chromogranin A; Epithelial Cells; Epstein-Barr Virus Infections; Gastric Mucosa; Gastrins; Gene Expression; Genetic Heterogeneity; Herpesvirus 4, Human; Humans; Immunohistochemistry; In Situ Hybridization, Fluorescence; Lectins, C-Type; Pancreatitis-Associated Proteins; Prognosis; Stomach; Stomach Neoplasms

Among neuroendocrine neoplasms, mixed exocrine and endocrine characteristics with at least 30% of each component are classified into mixed adenoneuroendocrine carcinoma (MANEC), according to the 2010 World Health Organization classification. We experienced a rare case of MANEC of the stomach with focal intestinal metaplasia and hypergastrinemia. A 76-year-old Japanese male was diagnosed as having gastric adenocarcinoma and underwent total gastrectomy. The pathologic diagnosis was MANEC of the stomach accompanied by unusual mucosal atrophy without Helicobacter pylori infection, the characteristics of which were different from both type A and type B atrophic gastritis. The patient has a history of long-term use of a proton pump inhibitor. Additional serum chemistry examination using preoperatively obtained plasma from the patient revealed hypergastrinemia. The mechanism of gastric MANEC carcinogenesis is still unclear, but that might be correlated with unusual intestinal metaplasia and hypergastrinemia in this case.

Topics: Adenocarcinoma; Aged; Biomarkers, Tumor; Carcinoma, Neuroendocrine; Gastrins; Humans; Intestines; Male; Metaplasia; Neoplasms, Complex and Mixed; Stomach Neoplasms

Hypergastrinemia causes carcinoids or carcinomas in the gastric corpus in animal models. Helicobacter pylori (HP) infection in patients causes atrophy, hypergastrinemia and promotes gastric carcinogenesis. Many patients with gastric cancer have hypergastrinemia and it has therefore been hypothesized that hypergastrinemia promotes carcinogenesis. We have examined the associations between serum gastrin, the anatomical localization of gastric cancer, histological classification and patient survival. Patients with non-cardia gastric adenocarcinomas were included prospectively (n = 80). Tumour localization, histological classification according to Laurén and disease stage were recorded. Preoperative fasting serum gastrin was analysed by radioimmunoassay and HP serology by ELISA. Patient survival was determined after a median postoperative follow-up of 16.5 years. Hypergastrinemic patients had carcinomas located in the gastric corpus more often compared to normogastrinemic patients (81.8 vs 36.2%, p = 0.002). Patients with disease stage 2-4 and hypergastrinemia had shorter survival than normogastrinemic patients [5.0 (1.1-8.9) vs 10.0 (6.4-13.6) months (p = 0.04)]. There was no significant difference in serum gastrin or survival between patients with intestinal and diffuse type carcinomas. Hypergastrinemia was associated with adenocarcinomas in the gastric corpus and shorter survival. The findings support the hypothesis that hypergastrinemia promotes carcinogenesis and affects biological behaviour.

Topics: Adenocarcinoma; Aged; Chromogranin A; Female; Follow-Up Studies; Gastric Mucosa; Gastrins; Helicobacter Infections; Helicobacter pylori; Humans; Male; Middle Aged; Prospective Studies; Stomach; Stomach Neoplasms; Survival Rate

Reporting on three cases of gastric neuroendocrine tumors (g-NETs) in patients taking long-term proton pump inhibitors (PPIs). These tumors are not classifiable considering current criteria. g-NETs are currently grouped as: types 1 and 2, related to hypergastrinemia due to chronic atrophic gastritis and Zollinger-Ellison syndrome respectively, and type 3, normogastrinemic and more aggressive. Although the g-NETs onset in patients taking PPIs is biologically plausible, only a few cases have been reported so far.. From January 2005 to July 2014, 31 g-NETs were referred to our Unit: 24 (77%), one (3%) and three (10%) resulted types 1, 2 and 3, respectively. Three cases (10%) did not meet the current classification criteria.. The three patients were administered long-term PPIs for gastro-esophageal reflux disease. Patient 1: a 78-year-old man, with a 4-mm well-differentiated g-NET (Ki-67<1%) and marked hypergastrinemia. Patient 2: a 58-year-old man affected by a 6-mm well-differentiated (Ki-67 = 4%) g-NET, with normal gastrin levels. Patients 3: a 67-year-old woman with an 18-mm well-differentiated g-NET (Ki-67 <2%), with mild hypergastrinemia. In the three patients, histology and pertinent blood tests excluded chronic atrophic gastritis, Helicobacter pylori infection or Zollinger-Ellison syndrome. The first two patients underwent endoscopic polypectomy; in the third case total gastrectomy was performed. Further clinical, endoscopic and imaging follow-up did not show any g-NET recurrence.. The present data point to the existence and epidemiological relevance of g-NETs associated with PPIs intake. These neoplasms are not included in the current classification, thus their treatment and follow-up have not been established.

Topics: Aged; Endoscopy; Female; Gastrectomy; Gastrins; Gastroesophageal Reflux; Humans; Male; Middle Aged; Neuroendocrine Tumors; Proton Pump Inhibitors; Stomach Neoplasms

Toll-like receptor 4 is a part of the innate immune system and recognizes Helicobacter pylori lipopolysaccharide. The goal of this study was to analyze the role of Toll-like receptor 4 polymorphisms +896 (rs4986790) and +1196 (rs4986791) in the pathogenesis of Helicobacter pylori related gastroduodenal diseases in relation to gastric secretion and inflammation. Toll-like receptor 4 polymorphisms, serum gastrin-17 and pepsinogen I and II concentrations were determined, and gastroscopies with histopathological analyses were performed to 216 dyspeptic patients. As genotype controls, 179 controls and 61 gastric cancer patients were studied. In our study, the Toll-like receptor 4 +896 and +1196 polymorphisms were in total linkage disequilibrium. The homozygous wild types displayed higher gastrin-17 serum concentrations than the mutants (p = 0.001) and this effect was independent of Helicobacter pylori. The homozygous wild types also displayed an increased risk for peptic ulcers (OR: 4.390). Toll-like receptor 4 genotypes did not show any association with Helicobacter pylori positivity or the features of gastric inflammation. Toll-like receptor 4 expression was seen in gastrin and somatostatin expressing cells of antral mucosa by immunohistochemistry. Our results suggest a role for Toll-like receptor 4 in gastric acid regulation and that the Toll-like receptor 4 +896 and +1196 wild type homozygozity increases peptic ulcer risk via gastrin secretion.

Topics: Adult; Aged; Aged, 80 and over; Female; Gastrins; Gastritis; Gene Frequency; Genetic Predisposition to Disease; Genotype; Helicobacter Infections; Helicobacter pylori; Humans; Immunohistochemistry; Male; Middle Aged; Pepsinogen A; Pepsinogen C; Peptic Ulcer; Polymorphism, Single Nucleotide; Risk Factors; Stomach Neoplasms; Toll-Like Receptor 4; Young Adult

Administration of trastuzumab, a fully humanized monoclonal antibody targeted to the human epidermal growth factor receptor 2 (HER2, p185), has improved outcomes for patients with HER2-positive gastric cancer (GC), but some relevant issues remain to be investigated and will emerge with new anti-GC drugs. Gastrin is a major gastrointestinal hormone proven to have an inhibitory effect on GC in vitro and in vivo.. To explore the sympathetic role of trastuzumab and gastrin on inhibition of GC.. The HER2-positive and HER2-negative GC cell lines were treated with trastuzumab, gastrin, or their combination in vitro and in xenograft model. The synergistical role of trastuzumab and gastrin and related mechanisms were investigated.. We found the synergistic inhibitory effects of trastuzumab and gastrin on HER2-negative GC cells through the gastrin/cholecystokinin B receptor (CCKBR) pathway. Trastuzumab upregulated CCKBR protein levels but could not initiate its signal transduction, whereas gastrin increased the levels and activation of CCKBR. Molecular experiments indicated that trastuzumab and gastrin co-treatment synergistically enhanced the stability of CCKBR. Moreover, their combined treatment synergistically arrested GC cells at G0/G1 phase, down-regulated levels of GC-related proteins, including anion exchanger 1 (AE1), cyclin D1, β-catenin, and cytoplasmic p16, and promoted nuclear translocation of p16. In addition, combination treatment upregulated AE2 levels, which are reduced in GC tissues. The in vivo synergistic anti-GC effect of combined treatment was confirmed in xenograft experiments.. Trastuzumab plus gastrin inhibit growth of Her2-negative GC by targeting cytoplasmic AE1 and p16.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Flow Cytometry; Gastrins; Gene Expression Regulation, Neoplastic; Humans; Hydrogen-Ion Concentration; Immunohistochemistry; Mice; Neoplasms, Experimental; Receptor, Cholecystokinin B; Receptor, ErbB-2; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Stomach Neoplasms; Trastuzumab

Optimal management and treatment of type-1 gastric carcinoids is under debate.. This prospective study evaluates the outcome of patients with recurrent type-1 gastric carcinoids treated with somatostatin analogues.. From 2000 to 2013, among a population of 107 chronic atrophic gastritis patients, 25 (20% males, median age 62 years) developed type-1 gastric carcinoids and underwent regular clinical and endoscopic follow-up (median 77 months, range 6-165) after the initial treatment. Those patients showing recurrent disease were treated with somatostatin analogues until carcinoid disappearance.. 12/25 patients (33% males, median age 65 years) showed recurrent gastric carcinoids and were treated with somatostatin analogues for a median duration of 12 months. Median gastrin and chromogranin A levels, which were 802 pg/mL and 33 U/L, respectively, decreased to 299 pg/mL (p=0.002) and 15.6 U/L (p=0.001) at the end of the treatment. Gastric carcinoids disappeared after a median length of treatment of 12 months. After a median time of 19.5 months from somatostatin analogues discontinuation, 4/12 patients (25% males, median age 56 years) showed a further recurrence. A new cycle of treatment was performed successfully.. This study confirms that type-1 gastric carcinoids are a recurring disease and somatostatin analogues, administered on 12-month cycles, represent an effective treatment.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Autoimmune Diseases; Carcinoid Tumor; Chromogranin A; Cohort Studies; Female; Gastrins; Gastritis, Atrophic; Humans; Male; Middle Aged; Neoplasm Recurrence, Local; Octreotide; Peptides, Cyclic; Prospective Studies; Somatostatin; Stomach Neoplasms; Treatment Outcome

Gastric neuroendocrine neoplasms of type 1 and type 3 are different entities and as such require different therapeutical strategies. The aim of this study was to define and distinguish these two tumour subtypes with clearly different biological properties and patient survival. As shown, serum gastrin is an important diagnostic tool for differentiating the less malignant type 1 "hypergastrinemia non-related" tumor from malignant type 3, along with other parameters of malignant potential such as proliferation index and depth of invasion.. The biological behaviour, tumour marker status, symptomatology, survival and therapeutical strategy were assessed and compared in 18 consecutive patients with type 1 and 7 with type 3 gastric neuroendocrine tumours.. All 18 patients with type 1 gastric carcinoids survived long-term. 17/18 patients were treated with endoscopic tumour removal. The prognosis for patients with generalized type 3 neuroendocrine neoplasms was poor, with short-term survival. No statistically significant differences between the types were found in urine 5-hydroxyindolacetic acid concentration or serum chromogranin A concentration. Significant differences were found in serum gastrin with high levels even in localized type 1 tumors and normal levels in generalized type 3 neoplasm. Further, high neuron-specific enolase levels were found in type 3.. Type 1 tumour should be preferably treated with endoscopic tumour removal. Recently, favourable tumoristatic effects have been reported in somatostatin analogs. Surgery is a treatment option for type 3 neuroendocrine carcinoma with normal gastrinemia. Serum gastrin is suitable for assessment of the biological properties of both neuroendocrine neoplasm types. It serves, among other factors, as a predictor of prognosis and an indicator for the selection of optimal therapeutical strategy.

Topics: Aged; Aged, 80 and over; Biomarkers, Tumor; Czech Republic; Female; Gastrins; Humans; Male; Middle Aged; Neuroendocrine Tumors; Prognosis; Stomach Neoplasms; Survival Rate; Treatment Outcome

The aim of this study was to investigate the prevalence of autoimmune gastritis, enterochromaffin-like cell (ECL-cell) hyperplasia and gastric neuroendocrine neoplasms type 1 (GNEN1) in patients with autoimmune thyroid disease.. Prospective observational study in a single institutional study.. One hundred and twenty patients with autoimmune thyroid disease were consecutively recruited from the Endocrine Unit. Upper gastrointestinal tract endoscopy (UGE) and biochemical parameters for autoimmune thyroid disease and autoimmune gastritis were assessed at recruitment and annually thereafter in patients with a mean follow-up of 37·5 ± 14·4 months. Autoimmune gastritis was defined by the presence of antiparietal cell antibodies (APCA) and histological confirmation after UGE. Serum gastrin and chromogranin Α were also measured.. One hundred and eleven patients had Hashimoto's thyroiditis and nine Graves' disease. Autoimmune gastritis was identified in 40 (38 with Hashimoto's thyroiditis and two with Graves' disease) patients all of whom had increased levels of gastrin and chromogranin Α; Helicobacter pylori infection was histologically identified in 15 of 40 (37·5%) patients. Six patients had isolated nodular ECL-cell hyperplasia and one mixed nodular and linear ECL-cell hyperplasia [7 of 40 (17·5%)]. Only increased gastrin (P = 0·03) levels predicted the presence ECL-cell hyperplasia. A GNEN1 developed in one patient with nodular ECL-cell hyperplasia after 39 months of follow-up.. Concomitant autoimmune gastritis was found in 33·3% of patients with autoimmune thyroid disease, 17·5% of whom had ECL-cell hyperplasia that evolved to GNEN1 in one (2·5%). Larger studies with longer follow-up are needed to define the incidence of GNEN1 in patients with autoimmune thyroid disease and ECL-cell hyperplasia and potential implications.

Topics: Aged; Autoimmune Diseases; Chromogranin A; Endoscopy; Enterochromaffin-like Cells; Female; Gastrins; Gastritis; Hashimoto Disease; Helicobacter Infections; Humans; Male; Middle Aged; Neuroendocrine Tumors; Phenotype; Prevalence; Prospective Studies; Risk; Stomach Neoplasms; Thyroid Diseases

A number of different therapies, including endoscopic resection, have been suggested for the treatment of Type 1 gastric neuroendocrine tumors (NETs). The current study aimed to determine the long-term efficacy of endoscopic resection for Type 1 gastric NETs.. Twenty-two patients (from 1999 to 2012) with Type 1 gastric NETs were included in the study. All patients were treated with endoscopic resection and received regular followed-up appointments at a tertiary referral center.. All patients were initially diagnosed with hypergastrinemia, atrophic gastritis and intestinal metaplasia. Polyps' diameters were >1 cm in 4 patients, and between 0.5 and 1 cm in 18 patients. All detectable lesions were successfully resected. One patient required surgery due to gastric perforation during endoscopic mucosal resection. Recurrence was detected in four patients (18%) and endoscopic resection was performed again. Local or distant metastasis was not observed in any patient during follow-up. Median follow-up time was 7 years, with a maximum of 14 years. Seventeen patients (78%) completed a 5-year follow-up period, and overall disease-free survival rate was 100%.. Long-term follow-ups with 22 patients suggest that endoscopic resection of Type 1 gastric NETs is a safe and effective treatment option with a relatively low recurrence rate.

Topics: Adult; Aged; Chromogranin A; Disease-Free Survival; Female; Follow-Up Studies; Gastric Mucosa; Gastrins; Gastroscopy; Humans; Male; Middle Aged; Neoplasm Recurrence, Local; Neuroendocrine Tumors; Polyps; Prospective Studies; Reoperation; Stomach Neoplasms

Topics: Autoimmune Diseases; Chromogranin A; Female; Gastrectomy; Gastric Mucosa; Gastrin-Secreting Cells; Gastrins; Gastritis, Atrophic; Humans; Hyperplasia; Middle Aged; Mucin-6; Neuroendocrine Tumors; Stomach; Stomach Neoplasms; Synaptophysin

Bone marrow-derived mesenchymal stem cells (MSCs) sustain cancer cells by creating a microenvironment favorable for tumor growth. In particular, MSCs have been implicated in gastric cancer development. There is extensive evidence suggesting that Hedgehog signaling regulates tumor growth. However, very little is known regarding the precise roles of Hedgehog signaling and MSCs in tumor development within the stomach. The current study tests that hypothesis that Sonic Hedgehog (Shh), secreted from MSCs, provides a proliferative stimulus for the gastric epithelium in the presence of inflammation. Red fluorescent protein-expressing MSCs transformed in vitro (stMSCs) were transduced with lentiviral constructs containing a vector control (stMSC(vect)) or short hairpin RNA (shRNA) targeting the Shh gene (stMSC(ShhKO)). Gastric submucosal transplantation of wild-type MSCs (wtMSCs), wild-type MSCs overexpressing Shh (wtMSC(Shh)), stMSC(vect), or stMSC(ShhKO) cells in C57BL/6 control (BL/6) or gastrin-deficient (GKO) mice was performed and mice analyzed 30 and 60 days posttransplantation. Compared with BL/6 mice transplanted with wtMSC(Shh) and stMSC(vect) cells, inflamed GKO mice developed aggressive gastric tumors. Tumor development was not observed in mouse stomachs transplanted with wtMSC or stMSC(ShhKO) cells. Compared with stMSC(ShhKO)-transplanted mice, within the inflamed GKO mouse stomach, Shh-expressing stMSC(vect)- and wtMSC(Shh)-induced proliferation of CD44-positive cells. CD44-positive cells clustered in gland-like structures within the tumor stroma and were positive for Patched (Ptch) expression. We conclude that Shh, secreted from MSCs, provides a proliferative stimulus for the gastric epithelium that is associated with tumor development, a response that is sustained by chronic inflammation.

Topics: Animals; Cell Proliferation; Cell Transformation, Neoplastic; Epithelial Cells; Gastric Mucosa; Gastrins; Gastritis; Hedgehog Proteins; Mesenchymal Stem Cells; Mice; Mice, Inbred C57BL; Signal Transduction; Stomach Neoplasms

To investigate the role of nuclear translocation of calcyclin binding protein, also called Siah-1 interacting protein (CacyBP/SIP), in gastric carcinogenesis.. The expression of CacyBP/SIP protein in gastric cancer cell lines was detected by Western blot. Immunofluorescence experiments were performed on gastric cancer cell lines that had been either unstimulated or stimulated with gastrin. To confirm the immunofluorescence findings, the relative abundance of CacyBP/SIP in nuclear and cytoplasmic compartments was assessed by Western blot. The effect of nuclear translocation of CacyBP/SIP on cell proliferation was examined using MTT assay. The colony formation assay was used to measure clonogenic cell survival. The effect of CacyBP/SIP nuclear translocation on cell cycle progression was investigated. Two CacyBP/SIP-specific siRNA vectors were designed and constructed to inhibit CacyBP/SIP expression in order to reduce the nuclear translocation of CacyBP/SIP, and the expression of CacyBP/SIP in stably transfected cells was determined by Western blot. The effect of inhibiting CacyBP/SIP nuclear translocation on cell proliferation was then assessed.. CacyBP/SIP protein was present in most of gastric cancer cell lines. In unstimulated cells, CacyBP/SIP was distributed throughout the cytoplasm; while in stimulated cells, CacyBP/SIP was found mainly in the perinuclear region. CacyBP/SIP nuclear translocation generated a growth-stimulatory effect on cells. The number of colonies in the CacyBP/SIP nuclear translocation group was significantly higher than that in the control group. The percentage of stimulated cells in G1 phase was significantly lower than that of control cells (69.70% ± 0.46% and 65.80% ± 0.60%, control cells and gastrin-treated SGC7901 cells, P = 0.008; 72.99% ± 0.46% and 69.36% ± 0.51%, control cells and gastrin-treated MKN45 cells, P = 0.022). CacyBP/SIPsi1 effectively down-regulated the expression of CacyBP/SIP, and cells stably transfected by CacyBP/SIPsi1 were then chosen for further cellular assays. In CacyBP/SIPsi1 stably transfected cells, CacyBP/SIP was shown to be distributed throughout the cytoplasm, irregardless of whether they were stimulated or not. After CacyBP/SIP nuclear translocation was reduced, there had no major effect on cell proliferation, as shown by MTT assay. There had no enhanced anchorage-dependent growth upon stimulation, as indicated by colony formation in flat plates. No changes appeared in the percentage of cells in G0-G1 phase in either cell line (71.09% ± 0.16% and 70.86% ± 0.25%, control cells and gastrin-treated SGC7901-CacyBP/SIPsi1 cells, P = 0.101; 74.17% ± 1.04% and 73.07% ± 1.00%, control cells and gastrin-treated MKN45-CacyBP/SIPsi1 cells, P = 0.225).. CacyBP/SIP nuclear translocation promotes the proliferation and cell cycle progression of gastric cancer cells.

Topics: Active Transport, Cell Nucleus; Calcium-Binding Proteins; Cell Cycle; Cell Line, Tumor; Cell Nucleus; Cell Proliferation; Dose-Response Relationship, Drug; Gastrins; Humans; RNA Interference; Stomach Neoplasms; Time Factors; Transfection

Fasting serum gastrin-17 (FsG17) is considered as a noninvasive biomarker reflecting the structure and functional status of gastric mucosa, but its clinical utility remains unclear. This study aimed to evaluate FsG17 comprehensively: establish the ranges and cut-off points of FsG17 levels in different gastric diseases, identify their influencing factors, and investigate the accuracy of FsG17 for identifying diseased stomach.. The study included 4064 participants from Northern China between 2008 and 2013. FsG17 and serum Helicobacter pylori IgG antibody levels were measured by enzyme-linked immunosorbent assay. Diagnostic accuracy was assessed by receiver operator characteristic curves. Multivariate logistic regression analysis was performed to determine the best predictors of gastric histopathological conditions.. Median FsG17 levels in healthy, non-atrophic, atrophic, and cancerous stomachs were 1.8, 4.0, 3.8, and 6.1 pmol/l, respectively. Age, smoking status, alcohol consumption, H. pylori infection, and predominant lesion site were factors that affected FsG17 levels. The optimal cut-off values for FsG17 were 3.0 pmol/l (sensitivity of 59.3% and specificity of 67.3%) for discriminating between healthy stomach and diseased stomach and 10.7 pmol/l (sensitivity of 37% and specificity of 83.7%) for discriminating between cancerous stomach and cancer-free stomach; the screening accuracy was higher (sensitivity of 50.0% and specificity of 83.0%) for gastric cancer in the corpus. Multivariate analysis showed that FsG17, gender, age, and H. pylori infection were independent predictors of cancerous stomach.. With the progression from health stomach to malignancy, FsG17 levels significantly increased and were influenced by other factors. FsG17 combined with age, gender, and H. pylori infection could distinguish between cancerous stomach and cancer-free stomach. The results will enhance our understanding of the potential clinical utility of FsG17.

Topics: Age Factors; Alcohol Drinking; Area Under Curve; Biomarkers; China; Fasting; Female; Gastrins; Gastritis, Atrophic; Helicobacter Infections; Helicobacter pylori; Humans; Immunoglobulin G; Male; Middle Aged; Predictive Value of Tests; ROC Curve; Smoking; Stomach Neoplasms

Gastric cancer (GC) is the second cause of cancer related death in the world. It may develop by progression from its precancerous condition, called gastric atrophy (GA) due to gastritis. The aim of this study was to evaluate the accuracy of serum levels of pepsinogens (Pg) and gastrin-17 (G17) as non-invasive methods to discriminate GA or GC (GA/GC) patients.. Subjects referred to gastrointestinal clinics of Golestan province of Iran during 2010 and 2011 were invited to participate. Serum levels of PgI, PgII and G17 were measured using a GastroPanel kit. Based on the pathological examination of endoscopic biopsy samples, subjects were classified into four groups: normal, non-atrophic gastritis, GA, and GC. Receiver operating curve (ROC) analysis was used to determine cut-off values. Indices of validity were calculated for serum markers.. Study groups were normal individuals (n=74), non-atrophic gastritis (n=90), GA (n=31) and GC patients (n=30). The best cut-off points for PgI, PgI/II ratio, G17 and HP were 80 μg/L, 10, 6 pmol/L, and 20 EIU, respectively. PgI could differentiate GA/GC with high accuracy (AUC=0.83; 95%CI: 0.76-0.89). The accuracy of a combination of PgI and PgI/II ratio for detecting GA/GC was also relatively high (AUC=0.78; 95%CI: 0.70-0.86).. Our findings suggested PgI alone as well as a combination of PgI and PgI/II ratio are valid markers to differentiate GA/GC. Therefore, Pgs may be considered in conducting GC screening programs in high-risk areas.

Topics: Adult; Antibodies, Bacterial; Case-Control Studies; Cross-Sectional Studies; Early Detection of Cancer; Female; Gastrins; Gastritis; Gastritis, Atrophic; Helicobacter Infections; Helicobacter pylori; Humans; Iran; Male; Middle Aged; Pepsinogen A; Pepsinogen C; ROC Curve; Sensitivity and Specificity; Stomach Neoplasms

In Fujian Province, China, gastric cancer is one of the leading causes of mortality among all malignant tumors. Nanjing county and Minqing county are located in inland Fujian and have similar general demographics. However, the adjusted mortality rate of gastric cancer in Minqing was found to be much higher than that in Nanjing. We sought to explore factors associated with this increased risk of gastric cancer between the two counties.. We recruited 231 and 224 residents from Nanjing and Minqing, respectively, and analyzed differences between their dietary habits, Helicobacter pylori infection rates, and concentrations of serum pepsinogen I, pepsinogen II, gastrin-17, and ratio of pepsinogen I:II.. Subjects in Minqing had more first-degree relatives who had been diagnosed with upper gastrointestinal tumor, more unhealthy dietary habits, a higher Helicobacter pylori positive rate, and greater proportion of abnormal serum gastrin-17 than those in Nanjing did.. The factors that differed between these two counties might indicate that residents in Minqing have a higher risk for developing gastric cancer than those in Nanjing do.

Topics: Adult; Aged; China; Feeding Behavior; Female; Gastrins; Helicobacter Infections; Helicobacter pylori; Humans; Male; Middle Aged; Pepsinogen A; Pepsinogen C; Risk Factors; Stomach Neoplasms

The aim of this study was to investigate the value of serum gastric markers to differentiate between patients with precancerous lesions and nonatrophic chronic gastritis.. Serum samples of 128 patients with dyspepsia who were candidates for endoscopic examination were tested for pepsinogen (PG I and PG II), PG I/II ratio, gastrin 17(G-17), anti-Helicobacter pylori (anti-H pylori ) and anti- CagA antibodies. Two sample t-tests, chi-square tests and Pearson's correlation analyses were used for analysis using SPSS (version 20).. PGI, PG I/II ratio values were decreased significantly in the precancerous lesion group (0.05, 0.001 respectively). The frequency of H pylori infection was significantly (p=0.03) different between the two groups ofthe study.. We suggest PGI and the PG I/II ratio as valuable markers for screening of premalignant gastric lesions.

Topics: Aged; Antibodies, Bacterial; Antigens, Bacterial; Bacterial Proteins; Biomarkers; Chronic Disease; Cross-Sectional Studies; Dyspepsia; Female; Follow-Up Studies; Gastrins; Gastritis; Helicobacter Infections; Helicobacter pylori; Humans; Iran; Male; Pepsinogen A; Pepsinogen C; Precancerous Conditions; Prognosis; Stomach Neoplasms

Salt-inducible kinase 1 (SIK1/Snf1lk) belongs to the AMP-activated protein kinase (AMPK) family of kinases, all of which play major roles in regulating metabolism and cell growth. Recent studies have shown that reduced levels of SIK1 are associated with poor outcome in cancers, and that this involves an invasive cellular phenotype with increased metastatic potential. However, the molecular mechanism(s) regulated by SIK1 in cancer cells is not well explored. The peptide hormone gastrin regulates cellular processes involved in oncogenesis, including proliferation, apoptosis, migration and invasion. The aim of this study was to examine the role of SIK1 in gastrin responsive adenocarcinoma cell lines AR42J, AGS-GR and MKN45. We show that gastrin, known to signal through the Gq/G11-coupled CCK2 receptor, induces SIK1 expression in adenocarcinoma cells, and that transcriptional activation of SIK1 is negatively regulated by the Inducible cAMP early repressor (ICER). We demonstrate that gastrin-mediated signalling induces phosphorylation of Liver Kinase 1B (LKB1) Ser-428 and SIK1 Thr-182. Ectopic expression of SIK1 increases gastrin-induced phosphorylation of histone deacetylase 4 (HDAC4) and enhances gastrin-induced transcription of c-fos and CRE-, SRE-, AP1- and NF-κB-driven luciferase reporter plasmids. We also show that gastrin induces phosphorylation and nuclear export of HDACs. Next we find that siRNA mediated knockdown of SIK1 increases migration of the gastric adenocarcinoma cell line AGS-GR. Evidence provided here demonstrates that SIK1 is regulated by gastrin and influences gastrin elicited signalling in gastric adenocarcinoma cells. The results from the present study are relevant for the understanding of molecular mechanisms involved in gastric adenocarcinomas.

Topics: Adenocarcinoma; Animals; Cell Line, Tumor; Cell Movement; Cyclic AMP Response Element Modulator; Gastrins; Hormones; Humans; Phosphorylation; Protein Serine-Threonine Kinases; Rats; Signal Transduction; Stomach Neoplasms

Elevated levels of serum gastrin (SG) have been associated with tumorigenic effects in a number of gastrointestinal cancers. We decided to investigate the relationship between SG and gastric epithelial lesions.. A total of 90 patients with gastric epithelial lesions (hyperplastic polyp, 12; adenoma, 41; early gastric cancer, 29; advanced gastric cancer, 8) were enrolled as the case group and 79 patients without epithelial lesions were enrolled as the control group.. Serum gastrin levels were significantly different between the case and control groups (p<0.001). A high SG level (>80 pg/mL), intestinal metaplasia, and a pepsinogen I/II ratio <3 were independently associated with an increased risk of epithelial lesions (odds ratio: 14.6, 9.4, and 4.1, respectively, p<0.05). SG levels in case subjects showed a unimodal distribution pattern as the disease progressed. The mean SG level was highest in those with hyperplastic polyps and then decreased significantly to the control level in the gastric cancer group. Higher SG levels in each disease category were not associated with increased tumor size, synchronicity, invasiveness, presence of lymph node metastasis, or a higher cellular proliferation index (p>0.05).. An increased SG level was an independent and potent risk factor for gastric epithelial lesions. However, it does not seem to relate with distal gastric tumor growth. Serial decreases in SG levels should be considered a warning sign in index hypergastrinemic patients with no prior Helicobacter pylori eradication.

Topics: Case-Control Studies; Cell Proliferation; Female; Gastrins; Humans; Male; Middle Aged; Neoplasm Staging; Precancerous Conditions; Predictive Value of Tests; Retrospective Studies; Stomach Neoplasms

The stomach is innervated by the vagal nerve. Several studies have demonstrated that the vagal nerve has a trophic effect on the rat oxyntic mucosa and that the trophic effect of hypergastrinemia is dependent on intact vagal innervation. The effect of vagal denervation on gastric carcinogenesis has been examined in Mastomys natalensis and hypergastrinemic transgenic INS-GAS mice, with no effect of unilateral vagotomy in Mastomys but an anti-carcinogenic effect in INS-GAS mice. A proportion of female Japanese cotton rats develop spontaneous hypergastrinemia and ECL cell derived gastric carcinomas. In the current study we have examined the effects of unilateral anterior subdiaphragmatic vagotomy on gastric carcinogenesis. Female Japanese cotton rats were operated with unilateral anterior vagotomy or sham-operation at age 2 months and were terminated at age 10 months. Ten of fifteen animals operated by anterior vagotomy and 11 of 16 sham-operated developed hypergastrinemia. Vagotomy did not affect intragastric pH or serum gastrin. When comparing the anterior and posterior sides of the stomachs, vagotomy did not affect the occurrence of dysplasia or carcinoma development in the oxyntic mucosa. However, vagotomy resulted in lower stomach weight and reduced oxyntic mucosal thickness on the anterior side. Vagotomy also resulted in a reduction in volume density of chromogranin A positive cells in the oxyntic mucosa. In conclusion, vagotomy reduced the trophic effects of hypergastrinemia on the ECL cell and oxyntic mucosa, but did not prevent gastric carcinogenesis in female Japanese cotton rats. The effects of vagotomy on gastric carcinogenesis in animal models are conflicting and further studies in patients should be done to clarify the clinically significant effects of vagotomy.

Topics: Animals; Carcinogenesis; Chromogranin A; Disease Models, Animal; Enterochromaffin-like Cells; Female; Gastric Mucosa; Gastrins; Hydrogen-Ion Concentration; Sigmodontinae; Stomach Neoplasms; Vagotomy, Truncal

Gastric cancer is increasingly recognized in Zambia. Although nutritional factors contribute to gastric cancer risk, their effect in Zambia is unknown.. The objective was to investigate the association between intake of dietary antioxidants, urinary 8-iso prostaglandin F2α (8-iso PGF2α) as a marker of oxidative stress, and gastric cancer.. This was a case-control study at the University Teaching Hospital in Zambia. Gastric cancer cases were compared with age- and sex-matched controls. Urine 8-iso PGF2α was measured primarily by ELISA, and by gas chromatography-mass spectrometry in a subset, expressed as a ratio to creatinine. Blood was collected for Helicobacter pylori, HIV serology, gastrin-17, and pepsinogen 1 and 2 concentrations. Clinical and dietary data were collected by using questionnaires. Food items were broadly classified into 7 major categories (fruit, vegetables, fish, meat, insects, cereals, and starches).. Fifty cases with gastric cancer (mean age: 61 y; n = 31 males) and 90 controls (mean age: 54 y; n = 41 males) were enrolled. Median urinary 8-iso PGF2α excretion was higher in cases (0.014; IQR: 0.008-0.021) than in controls (0.011; IQR: 0.006-0.018; P = 0.039). On univariate analysis, habitual fruit intake was lower in cases than in controls during the dry season (P = 0.02). On multivariate analysis, smoking (OR: 7.22; IQR: 1.38-37.9) and gastric atrophy (OR: 2.43; IQR: 1.12-5.13) were independently associated with cancer, and higher fruit intake was protective (OR: 0.44; IQR: 0.20-0.95). Isoprostane excretion was inversely correlated with total fruit intake (ρ = -0.23; n = 140; P = 0.006).. Urinary 8-iso PGF2α excretion was associated with the risk of gastric cancer, as were smoking and gastric atrophy, but increased fruit intake conferred protection. This trial was registered at www.pactr.org as ISRCTN52971746.

Topics: Adult; Antioxidants; Biomarkers; Case-Control Studies; Creatinine; Dinoprost; Energy Intake; Feeding Behavior; Female; Fruit; Gas Chromatography-Mass Spectrometry; Gastrins; Helicobacter pylori; HIV; Humans; Isoprostanes; Logistic Models; Male; Middle Aged; Multivariate Analysis; Nutritional Status; Oxidative Stress; Pepsinogen A; Pepsinogen C; Prospective Studies; Risk Factors; Smoking; Stomach Neoplasms; Surveys and Questionnaires; Vegetables; Zambia

The gastrin and the gastrin/CCK-B receptor genes are co-expressed in several carcinomas. The primary translational product, progastrin, however, is processed to several peptides of which only those that are α-amidated at their C-terminus are receptor ligands. So far, characterization of the progastrin-derived peptides in gastric cancer has not been reported. The authors therefore examined the molecular nature of gastrin and its receptor in human gastric carcinomas.. Twenty patients with adenocarcinoma underwent partial or total gastrectomy. In samples from each carcinoma, gastrin peptides were characterized, using a library of sequence-specific immunoassays. Expression was also demonstrated by immunohistochemistry. In addition, the gastrin and gastrin/CCK-B receptor gene expression was quantitated using real-time PCR, and the receptor protein demonstrated by western blotting.. α-Amidated gastrins were detectable in 16 of 20 carcinomas (median concentration 2.1 pmol/g tissue; range 0-386 pmol/g tissue). The tissue concentrations correlated closely to the gastrin mRNA contents (r = 0.75, p < 0.0001). Moreover, progastrin and non-amidated processing intermediates, including glycine-extended gastrins, were detected in 19 carcinomas. Immunohistochemistry corroborated gastrin expression in carcinoma cells. Chromatography revealed extensive progastrin processing with α-amidated gastrin-34 and -17 (tyrosyl-sulfated as well as non-sulfated) as major products. Finally, gastrin/CCK-B receptor mRNA and protein were detected in all tumors.. The results show that the elements for a local loop of α-amidated gastrins and their receptor are detectable in 80% of human gastric adenocarcinomas. Therefore, the results support the contention that locally expressed gastrin may be involved in the tumorigenesis of gastric adenocarcinomas.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Female; Gastrins; Gene Expression; Humans; Male; Middle Aged; Protein Precursors; Receptor, Cholecystokinin B; RNA, Messenger; Stomach Neoplasms

Iran is a country with very high incidences of stomach cancer, especially in Northern parts. Here we assessed prognostic value of serum screening biomarkers among people >50 years old for early detection of precancerous lesions in a hot spot for gastric carcinoma in Guilan Province, North Iran.. A cross- sectional population-based survey was conducted on 1,390 residents of Lashtenasha city with the mean age (SD) of 61.8 (9.02) years old (50.8% females) to assess the association of gastrin and the pepsinogen (PG) I/II ratio with premalignant gastric lesions. Blood samples were taken for CBC, blood group, and serologic exams (PGI, PGII, and gastrin 17) from each subject. Expert gastroenterologists performed upper GI endoscopy and ROC curves were generated to determine appropriate cutoff points.. Mean values of PGI, PGII, PGI/PGII and gastrin were significantly different between patients with and without atrophy or metaplasia (P<0.05). To diagnose atrophy and intestinal metaplasia, a significantly higher AUC was observed for the PGI/PGII ratio (70 and 72%, respectively) compared to the PGI (56, 55%), PGII (63, 64%) and gastrin (59, 61%) (all p<0.001).. Biomarker tests such as the PGI/II ratio can be used in the screening and diagnosis of subjects at high gastric cancer risk in our region.

Topics: Aged; Aged, 80 and over; Biomarkers; Biomarkers, Tumor; Cross-Sectional Studies; Female; Follow-Up Studies; Gastric Mucosa; Gastrins; Gastritis, Atrophic; Humans; Iran; Male; Metaplasia; Middle Aged; Neoplasm Staging; Pepsinogen A; Pepsinogen C; Precancerous Conditions; Prognosis; ROC Curve; Stomach Neoplasms

The peptide hormone gastrin is known to play a role in differentiation, growth and apoptosis of cells in the gastric mucosa. In this study we demonstrate that gastrin induces Nuclear Receptor 4A2 (NR4A2) expression in the adenocarcinoma cell lines AR42J and AGS-GR, which both possess the gastrin/CCK2 receptor. In vivo, NR4A2 is strongly expressed in the gastrin responsive neuroendocrine ECL cells in normal mucosa, whereas gastric adenocarcinoma tissue reveals a more diffuse and variable expression in tumor cells. We show that NR4A2 is a primary early transient gastrin induced gene in adenocarcinoma cell lines, and that NR4A2 expression is negatively regulated by inducible cAMP early repressor (ICER) and zinc finger protein 36, C3H1 type-like 1 (Zfp36l1), suggesting that these gastrin regulated proteins exert a negative feedback control of NR4A2 activated responses. FRAP analyses indicate that gastrin also modifies the nucleus-cytosol shuttling of NR4A2, with more NR4A2 localized to cytoplasm upon gastrin treatment. Knock-down experiments with siRNA targeting NR4A2 increase migration of gastrin treated adenocarcinoma AGS-GR cells, while ectopically expressed NR4A2 increases apoptosis and hampers gastrin induced invasion, indicating a tumor suppressor function of NR4A2. Collectively, our results uncover a role of NR4A2 in gastric adenocarcinoma cells, and suggest that both the level and the localization of NR4A2 protein are of importance regarding the cellular responses of these cells.

Topics: Active Transport, Cell Nucleus; Adenocarcinoma; Blotting, Western; Butyrate Response Factor 1; Cell Line, Tumor; Feedback, Physiological; Flow Cytometry; Fluorescence Recovery After Photobleaching; Gastrins; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Humans; Immunohistochemistry; Nuclear Receptor Subfamily 4, Group A, Member 2; Real-Time Polymerase Chain Reaction; RNA, Small Interfering; Stomach Neoplasms

Gastric cancer remains a significant medical and social problem. Familial, hereditary, social, and demographic factors increase the susceptibility of subjects to cancer development, especially those infected with Helicobacter pylori (H. pylori). Apart from genetic studies, there are ongoing biochemical studies of possible practical value in assessment of the risk of gastric cancer development. The GastroPanelBiohit test, that include determination of the levels of gastrin (G-17), pepsinogen I (PGI), pepsinogen II (PGII) and antibodies IgG/IgA against H. pylori in serum, allowed us to determine whether there are any abnormal changes in the gastric mucosa. The aim of the study was to determine whether GastroPanel parameters, identified in patients with dyspeptic symptoms (with or without history of gastric cancer in first degree relatives) before and after successful eradication of H. pylori, have any clinical value, especially in gastric cancer development.. The study comprised 61 patients aged 18-56 years with symptoms of dyspepsia. In all patients, the preliminary urea breath test (UBT) for the presence of H. pylori was performed and the positive result qualified for further study. For final analysis, 42 patients were approved, who were divided into two groups: group I (a control group) - 22 patients with negative family history of gastric cancer among the relatives of first degree, group II - 20 patients with positive history of gastric cancer among the relatives of first degree. All the patients had the gastroscopy with the biopsy of gastric mucosa for the histopathological evaluation. Additionally, the GastroPanel test was performed.. In the blood serum of the patients with H. pylori infection, the concentrations of gastrin (G-17), pepsinogen I (PGI) and pepsinogen II (PGII) did not depend on family history of gastric cancer (p > 0.05). Successful eradication of H. pylori decreases the levels of G-17, PGI and PGII (statistical significance p < 0.05), and this correlates with the histopathological changes of gastric mucosa. The patients with positive family history of gastric cancer had more intense H. pylori colonization of gastric mucosa (IV degree of insensitivity of infection in UBT; group I - 22% vs group II - 69%) as compared to the control group. After effective eradication of H. pylori, statistically significant decreases of IgG H. pylori antibodies and of the level of gastrin (p < 0.05) in blood serum were seen (in a 3 months follow up) only in the control group.. Independently of the history of familial gastric cancer, the GastroPanelBiohit test provides important clinical data useful for diagnosis, for assessment of effectiveness of H. pylori eradication therapy and in evaluation of the degree of the inflammatory changes in gastric mucosa.

Topics: Adolescent; Adult; Biopsy; Breath Tests; Dyspepsia; Female; Gastric Mucosa; Gastrins; Gastroscopy; Helicobacter Infections; Helicobacter pylori; Humans; Immunoglobulin A; Immunoglobulin G; Male; Medical History Taking; Middle Aged; Pepsinogen A; Pepsinogen C; Stomach Neoplasms; Urea; Young Adult

To describe disease characteristics and treatment modalities in a group of rare patients with metastatic gastric carcinoid type 1 (GCA1).. Information on clinical, biochemical, radiological, histopathological findings, the extent of the disease, as well as the use of different therapeutic modalities and the long-term outcome were recorded. Patients' data were assessed at presentation, and thereafter at 6 to 12 monthly intervals both clinically and biochemically, but also endoscopically and histopathologically. Patients were evaluated for the presence of specific symptoms; the presence of autoimmune disorders and the presence of other gastrointestinal malignancies in other family members were also recorded. The evaluation of response to treatment was defined using established WHO criteria.. We studied twenty consecutive patients with a mean age of 55.1 years. The mean follow-up period was 83 mo. Twelve patients had regional lymph node metastases and 8 patients had liver metastases. The primary tumor mean diameter was 20.13 ± 10.83 mm (mean ± SD). The mean Ki-67 index was 6.8% ± 11.2%. All but one patient underwent endoscopic or surgical excision of the tumor. The disease was stable in all but 3 patients who had progressive liver disease. All patients remained alive during the follow-up period.. Metastatic GCA1 carries a good overall prognosis, being related to a tumor size of ≥ 1 cm, an elevated Ki-67 index and high serum gastrin levels.

Topics: Adult; Aged; Carcinoid Tumor; Chemotherapy, Adjuvant; Disease Progression; Europe; Female; Gastrectomy; Gastric Bypass; Gastrins; Gastroscopy; Humans; Israel; Ki-67 Antigen; Liver Neoplasms; Lymph Node Excision; Lymphatic Metastasis; Male; Middle Aged; Multimodal Imaging; Positron-Emission Tomography; Retrospective Studies; Stomach Neoplasms; Time Factors; Tomography, X-Ray Computed; Treatment Outcome; Tumor Burden

The gastric hormone ghrelin is known as an important factor for energy homeostasis, appetite regulation and control of body weight. So far, ghrelin has mainly been examined as a serological marker for gastrointestinal diseases, and only a few publications have highlighted its role in local effects like mucus secretion. Ghrelin can be regarded as a gastroprotective factor, but little is known about the distribution and activity of ghrelin cells in pathologically modified tissues. We aimed to examine the morphological changes in ghrelin expression under several inflammatory, metaplastic and carcinogenic conditions of the upper gastrointestinal tract. In particular, autoimmune gastritis showed interesting remodeling effects in terms of ghrelin expression within neuroendocrine cell hyperplasia by immunohistochemistry. Using confocal laser microscopy, the gastrin/cholecystokinin receptor (CCKB) could be detected on normal ghrelin cells as well as in autoimmune gastritis. Functionally, we found evidence for a physiological interaction between gastrin and ghrelin in a primary rodent cell culture model. Additionally, we gathered serological data from patients with different basic gastrin levels due to long-term autoimmune gastritis or short-term proton pump inhibitor treatment with slightly reactive plasma gastrin elevations. Total ghrelin plasma levels showed a significantly inverse correlation with gastrin under long-term conditions. Autoimmune gastritis as a relevant condition within gastric carcinogenesis therefore has two effects on ghrelin-positive cells due to hypergastrinemia. On the one hand, gastrin stimulates the proliferation of ghrelinpositive cells as integral part of neuroendocrine cell hyperplasia, while on the other hand, plasma ghrelin is reduced by gastrin and lost in pseudopyloric and intestinal metaplastic areas. Ghrelin is necessary for the maintenance of the mucosal barrier and might play a role in gastric carcinogenesis, if altered under these pre neoplastic conditions.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Animals; Autoimmune Diseases; Child; Child, Preschool; Down-Regulation; Duodenum; Esophagus; Female; Gastric Mucosa; Gastrins; Gastritis, Atrophic; Ghrelin; Humans; Infant; Male; Middle Aged; Rats; Rats, Wistar; Receptor, Cholecystokinin B; Stomach Neoplasms; Young Adult

The thyrogastric autoimmune syndrome (TAS) was described in patients in whom the serum cross-reacted both with gastric parietal cells antigens and thyroid antigens. We report two cases illustrating the spectrum of pathogical features of TAS. The first case associates Hashimoto's thyroiditis and anemia perniciosa,and develops a gastric neuroendocrine tumor during follow up. The second case presents with a Graves' disease and an autoimmune reversible gastritis, secondary to Helicobacter pylori. Whereas type III autoimmune polyendocrinopathy is rare, TAS is frequent in our experience. Some 13% (32/240) of patients that we have prospectively followed affected with thyroiditis have also autoimmune gastritis. Helicobacter pylori is clearly implicated in 16% of autoimmune gastritis cases. Infection, malabsorption and gastritis are potentially reversible after bacterial eradication treatment. In the other 84% of gastritis patients, no histological or serological proof of Helicobacter pylori is found. Gastric autoimmunity is then irreversible, leading to gastric severe atrophy, hypochlorhydria and hypergastrinemia. Hypergastrinemia stimulates enterochromaffin cell hyperplasia, possibly progressing to neuroendocrine tumors. We propose a diagnostic approach to improve the characterization of TAS. We review the literature on the subject and discuss some interesting animal models of infectious gastric autoimmunity.

Topics: Enterochromaffin-like Cells; Gastrins; Gastritis; Humans; Hyperplasia; Neuroendocrine Tumors; Stomach Neoplasms; Thyroiditis, Autoimmune

Gastrin is a growth factor for the gastric epithelial cells. However, it is unknown how gastric receptor (GR) expression is regulated in the gastric mucosa. We studied GR expression using a newly raised antibody and investigated the relationship between GR expression and gastritis.. Gastric receptor expression in 63 human gastric mucosa was studied. Helicobacter pylori infection and histological gastritis status were evaluated in gastric biopsy samples. In gastric ulcer cases, additional biopsy specimens were taken from injured mucosa. Fasting sera were collected and serum gastrin level evaluated. MKN-28 cells were cultured at various pH conditions, and the change in GR expression was determined.. Gastric receptor expression was detected in the foveolar epithelium of the gastric mucosa, and its expression was stronger in patients infected with H. pylori. In particular, higher expression was detected in regenerating injured mucosa. There was no association between gastritis score/serum gastrin level and GR expression in H. pylori-positive cases. In MKN-28 cells, GR protein expression was lower in neutral conditions than in acidic or alkaline conditions.. Gastric mucosal injury with H. pylori infection destroys the pH barrier on the foveolar epithelium and may induce GR expression through pH changes.

Topics: Adenocarcinoma; Aged; Biopsy; Cell Line, Tumor; Female; Gastric Mucosa; Gastrins; Gastritis; Gene Expression Regulation; Helicobacter Infections; Helicobacter pylori; Humans; Hydrogen-Ion Concentration; Male; Middle Aged; Receptor, Cholecystokinin B; Stomach Neoplasms

The essential anion exchanger (AE) involved in bicarbonate secretion is AE2/SLC4A2, a membrane protein recognized to be relevant for the regulation of the intracellular pH in several cell types. Here we report that gastrin, a major gastrointestinal hormone, upregulates the expression of AE2 mRNA and protein in a cholecystokinin B receptor dependent manner in gastric cancer cells. The upregulated species of AE2 mRNA originates from the classical upstream promoter of the AE2 gene (here referred to as AE2a1) which provides the binding site for transcription factors early growth response 1 (EGR1) and SP1. EGR1 upregulated the AE2 expression that can be competitively inhibited by SP1 in co-transfection experiments. This competitive inhibition was avoided in cells because the SP1 expression was time-staggered to EGR1 in response to gastrin. Overexpression or knockdown of EGR1 consistently increased or decreased the expression of AE2. Our data linked a novel signal pathway involved in gastrin-stimulated AE2 expression.

Topics: Anion Transport Proteins; Antiporters; Base Sequence; Binding Sites; Cell Line, Tumor; Chloride-Bicarbonate Antiporters; Early Growth Response Protein 1; Gastrins; Gene Expression; Gene Expression Regulation, Neoplastic; Humans; Hydrogen-Ion Concentration; Promoter Regions, Genetic; Protein Isoforms; Receptor, Cholecystokinin B; Signal Transduction; SLC4A Proteins; Sp1 Transcription Factor; Stomach Neoplasms; Up-Regulation

To study the clinical presentation, diagnostic approach, response to treatment, and the presence of other pathologies in patients with gastric carcinoid type 1 (GC 1) tumors.. Retrospective analysis of 111 patients from four institutions and a mean follow-up of 76 months.. The main indications for gastroscopy were upper gastrointestinal tract symptoms. The mean number of lesions, maximum tumoral diameter, and percentage of cells expressing Ki-67 labeling index were 3.6±3.8, 8±12.1 mm and 1.9±2.4% respectively. Serum gastrin and chromogranin A (CgA) levels were elevated in 100/101 and 85/90 patients respectively. Conventional imaging studies demonstrated pathology in 9/111 patients. Scintigraphy with radiolabeled octreotide was positive in 6/60 without revealing any additional lesions. From the 59 patients who had been followed-up without any intervention, five developed tumor progression. Thirty-two patients were treated with long-acting somatostatin analogs (SSAs), leading to a significant reduction of gastrin and CgA levels, number of visible tumors, and CgA immune-reactive tumor cells in 28, 19, 27, and 23 treated patients respectively. Antrectomy and/or gastrectomy were initially performed in 20 patients and a complete response was achieved in 13 patients. The most common comorbidities were vitamin B12 deficiency, thyroiditis, and parathyroid adenomas.. Most GCs1 are grade 1 (82.7%) tumors presenting with stage I (73.9%) disease with no mortality after prolonged follow-up. Ocreoscan did not provide further information compared with conventional imaging techniques. Treatment with SSAs proved to be effective for the duration of administration.

Topics: Antineoplastic Agents, Hormonal; Biomarkers, Tumor; Carcinoid Tumor; Chromogranin A; Female; Follow-Up Studies; Gastrins; Humans; Male; Octreotide; Prognosis; Retrospective Studies; Stomach Neoplasms; Treatment Outcome

The aim of this study was to investigate the association between serum pepsinogens, serum gastrin, serum vascular endothelial growth factor, serum interleukin-1 Beta, serum toll-like receptor-4 levels and Helicobacter pylori Cag A status in patients with various gastric precancerous lesions.. One hundred and sixty two consecutive patients with various gastric lesions [38 (23.5%) H. pylori positive chronic non-atrophic gastritis, 45 (27.8%) autoimmune gastritis, 42 intestinal metaplasia and 37 dysplasia] were enrolled into the study. Serum pepsinogen I and II, gastrin 17, vascular endothelial growth factor, interleukin-1 Beta, toll-like receptor-4 levels, H. pylori Cag A status were evaluated.. H. pylori was positive in 98 (60.5%) patients and 38 of these patients were Cag A positive. Serum pepsinogen level was significantly lower in patients with autoimmune atrophic gastritis compared to the patients with non-atrophic chronic gastritis (p<0.001), intestinal metaplasia (P<0.001) and dysplasia (P=0.002). Mean serum gastrin was 1209.6±268.48 pg/mL in patients with autoimmune atrophic gastritis and 234.95±184.018 pg/mL in patients with chronic non-atrophic gastritis. Mean toll-like receptor-4 level was 0.56±0.098 ng/mL in patient with dysplasia, and this value was higher compared to patients with chronic non-atrophic gastritis (P=0.007), autoimmune atrophic gastritis (P=0.003) and intestinal metaplasia (P=0.006). Interleukin-1 Beta level was significantly lower in patients with dysplasia compared to patients with chronic non-atrophic gastritis (P=0.034).. Serum pepsinogens, serum gastrin and H. pylori Cag A status are important tests in detecting gastric precancerous lesions. However, toll-like receptor-4 may be a sensitive test to differentiate the patients with dysplasia from the other precancerous gastric lesions. Non-invasive tests are sensitive in the diagnosis of gastric precancerous lesions.

Topics: Adult; Aged; Antigens, Bacterial; Bacterial Proteins; Biomarkers; Female; Gastrins; Gastritis; Helicobacter pylori; Humans; Interleukin-1beta; Male; Metaplasia; Middle Aged; Pepsinogen A; Pepsinogen C; Precancerous Conditions; Sensitivity and Specificity; Stomach; Stomach Neoplasms; Toll-Like Receptor 4; Vascular Endothelial Growth Factor A

Type-1 gastric neuroendocrine tumours (NETs) arise in some patients with chronic hypergastrinaemia secondary to autoimmune atrophic gastritis. Patients with small tumours are usually managed conservatively, because their prognosis is very good. However, larger tumours may require surgical intervention. Many type-1 gastric NETs regress following antrectomy because this removes the source of hypergastrinaemia. However, some tumours do not regress following antrectomy and additional surgery may be required. An octreotide suppression test has been previously suggested as a means to assess whether type-1 gastric NETs are likely to regress following antrectomy.. To prospectively examine the role of a short-term intravenous octreotide suppression test in predicting type-1 gastric NET regression in five patients who subsequently underwent antrectomy.. Serum gastrin concentrations and gastric corpus and tumour histidine decarboxylase mRNA abundances were assessed in patients with type-1 gastric NETs before and 72 h after the administration of 25 µg/h intravenous octreotide. Gastric tumour response was assessed endoscopically following subsequent antrectomy.. All patients showed significant decreases in serum gastrin concentrations as well as corpus and tumour biopsy histidine decarboxylase mRNA abundance following octreotide infusion. All patients also showed resolution of hypergastrinaemia following subsequent antrectomy. However, tumour regression was only observed in four of the five patients. One patient had a persistent tumour 3 years after antrectomy and required additional surgical resection.. A positive octreotide suppression test result does not always predict response to antrectomy in patients with type-1 gastric NETs. Assessment of gastric mucosal responses to a gastrin/CCK-2 receptor antagonist may therefore also be helpful.

Topics: Adult; Aged; Antineoplastic Agents, Hormonal; Female; Gastrectomy; Gastrins; Gastroscopy; Histidine Decarboxylase; Humans; Infusions, Intravenous; Male; Neuroendocrine Tumors; Octreotide; Patient Selection; Prognosis; Prospective Studies; Pyloric Antrum; RNA, Messenger; Stomach Neoplasms; Treatment Outcome

Gastrin/cholecystokinin subtype 2 receptor (CCK2R) is overexpressed in several types of tumors. Gastrin-17 (G17) peptide has a high affinity with CCK2R. These characters suggest that G17 may be useful for target cancer therapy.. Construct a new immunotoxin (IT) targeting of CCK2R overexpressed gastric cancer.. Two ITs were generated using forward and reverse G17 peptides fused with PE38. To get a high yield, codon optimized gene and optimized fermentation parameters were used in large-scale protein expression. An immunoaffinity technique was introduced into pseudomonas exotoxin (PE)-derived IT purification procedure. G17 competition, GST pull-down and indirect immunoflourescence assays were carried out to confirm the interaction between rG17 and CCK2R. Then, several cytotoxic assays were carried out on 18 cell lines, and an in vivo antitumor activity experiment was tested in nude mice.. The rG17PE38 showed specific cytotoxicity on three gastric cancer cells, while G17PE38 did not. After optimization, the expression level reached about 40% in medium deprived of NaCl. Next, 15-27.5 mg of pure rG17PE38 per 1 L of cultures was obtained. Results of G17 competition, GST pull-down and indirect immunoflourescence assays demonstrated that rG17 have a specific interact with CCK2R. Purified rG17PE38 showed high cytotoxicity on gastric cancer cell lines with the IC50 value of 0.6-4 ng·mL(-1). Treatment of nude mice inoculated with BGC-823 tumor xenografts with rG17PE38 efficiently inhibited tumor size.. The present study demonstrates that reversed G17 could be used as target moiety of PE-derived IT and the rG17PE38 could be developed as a new immunotherapy agent. Codon optimized gene could increase the rG17PE38 expression level in E. coli and furthermore NaCl inhibits the rG17PE38 expression in large scale. Meanwhile, our present study inducts an immunoaffinity method in the IT purification procedure, which could purify the PE-derived ITs in native form.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Codon; Female; Gastrins; HeLa Cells; Hep G2 Cells; Humans; Immunotoxins; K562 Cells; MCF-7 Cells; Mice; Mice, Inbred BALB C; Mice, Nude; Receptor, Cholecystokinin B; Sodium Chloride; Stomach Neoplasms

Gastrin, cholecystokinin2 receptor (CCK2R), and cyclooxygenase-2 (COX-2) have been implicated in the carcinogenesis and progression of gastric cancer. Our study demonstrated that antagonist or siRNA against CCK2R blocked amidated gastrin (G17)-induced activation of STAT3 and Akt in gastric cancer cell lines. G17-increased COX-2 expression and cell proliferation were effectively blocked by CCK2R antagonist and inhibitors of JAK2 and PI3K. In addition, knockdown of STAT3 expression significantly attenuated G17-induced PI3K/Akt activation, COX-2 expression, and cell proliferation. These results suggest that CCK2R-mediated COX-2 up-regulation via JAK2/STAT3/PI3K/Akt pathway is involved in the proliferative effect of G17 on human gastric cancer cells.

Topics: Cell Line, Tumor; Cell Proliferation; Cyclooxygenase 2; Gastrins; Humans; Janus Kinase 2; Phosphatidylinositol 3-Kinase; Phosphoinositide-3 Kinase Inhibitors; Phosphorylation; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Receptor, Cholecystokinin B; RNA Interference; RNA, Messenger; Signal Transduction; STAT3 Transcription Factor; Stomach Neoplasms; Time Factors; Transfection; Up-Regulation

Autophagy has dual roles in tumorigenesis: tumor-promoting or tumor-suppressing. The aim of the present study was to examine autophagy-related markers by immunohistochemistry in gastric carcinoids and adenocarcinomas in rodent models and patients.. Gastric carcinoids in Mastomys were induced by loxtidine treatment. Spontaneously developed gastric adenocarcinomas in Japanese cotton rats and INS-GAS transgenic mice were included. Patient tissue samples of gastric carcinoids or adenocarcinomas were collected. Immunohistochemistry was performed against autophagy-related gene protein-6 (ATG-6, also called beclin-1), ATG-5 and ATG-16.. In tumor-free Mastomys, ATG-5, ATG-16 and beclin-1 were immunepositive in the gastric mucosa. In tumor-bearing Mastomys, ATG-5 and ATG-16 were negative in the tumors, whereas beclin-1 was positive in four of five animals. In carcinoid patients, ATG-5 was negative in six of ten, ATG-16 negative in nine of ten, and beclin-1 negative in three of ten patients. In cotton rats, ATG-5 and ATG-16 were negative in all tumors. Beclin-1 was negative in three of five rats. In INS-GAS mice, ATG-5 and beclin-1 were positive in the tumor area, but the numbers of immunopositive cells per gland were reduced by about 50% in comparison with wild-type mice. In adenocarcinoma patients, ATG-5 and ATG-16 were negative in eight of ten, and beclin-1 positive in all ten patients.. An impaired autophagy took place at the stage of formation of ATG-5-ATG-12-ATG-16 complex in both gastric carcinoids and adenocarcinoma of both rodent models and patients. ATG-5 and ATG-16 might be better markers than beclin-1 in assessing autophagy in these lesions.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Animals; Apoptosis Regulatory Proteins; Autophagy; Autophagy-Related Protein 5; Beclin-1; Biomarkers, Tumor; Carcinoid Tumor; Female; Gastric Mucosa; Gastrins; Humans; Immunohistochemistry; Insulin; Male; Membrane Proteins; Mice; Mice, Transgenic; Microtubule-Associated Proteins; Middle Aged; Murinae; Promoter Regions, Genetic; Sigmodontinae; Stomach Neoplasms; Triazoles

In a prospective study the risk of subsequent gastric cancer (GC) was assessed in persons aged 45-69 over 5 years after the initial testing with a set of serological tests (pepsinogen I, pepsinogen II, gastrin-17, antibodies to Helicobacter pylori). The presence of gastric atrophy markers was a significant predictor of GC in the forthcoming years. Non-invasive techniques may be used in the formation of high-risk groups, followed by GC active surveillance.

Topics: Aged; Antibodies, Bacterial; Biomarkers; Cohort Studies; Female; Gastrins; Gastritis, Atrophic; Helicobacter Infections; Helicobacter pylori; Humans; Male; Middle Aged; Pepsinogen A; Pepsinogen C; Pepsinogens; Retrospective Studies; Serologic Tests; Stomach Neoplasms

We show that the gastric hormone gastrin induces the expression of the prosurvival secretory clusterin (sCLU) in rat adenocarcinoma cells. Clusterin mRNA was still upregulated in the presence of the protein synthesis inhibitor cycloheximide, although at a lower level. This indicates that gastrin induces clusterin transcription independently of de novo protein synthesis but requires de novo protein synthesis of signal transduction pathway components to achieve maximal expression level. Luciferase reporter assay indicates that the AP-1 transcription factor complex is involved in gastrin-mediated activation of the clusterin promoter. Gastrin-induced clusterin expression and subsequent secretion is dependent on sustained treatment, because removal of gastrin after 1-2 h abolished the response. Neutralization of secreted clusterin by a specific antibody abolished the antiapoptotic effect of gastrin on serum starvation-induced apoptosis, suggesting that extracellular clusterin is involved in gastrin-mediated inhibition of apoptosis. The clusterin response to gastrin was validated in vivo in hypergastrinemic rats, showing increased clusterin expression in the oxyntic mucosa, as well as higher levels of clusterin in plasma. In normal rat oxyntic mucosa, clusterin protein was strongly expressed in chromogranin A-immunoreactive neuroendocrine cells, of which the main cell type was the histidine decarboxylase-immunoreactive enterochromaffin-like (ECL) cell. The association of clusterin with neuroendocrine differentiation was further confirmed in human gastric ECL carcinoids. Interestingly, in hypergastrinemic rats, clusterin-immunoreactive cells formed distinct groups of diverse cells at the base of many glands. Our results suggest that clusterin may contribute to gastrin's growth-promoting effect on the oxyntic mucosa.

Topics: Adenocarcinoma; Animals; Apoptosis; Carcinoid Tumor; Cell Line, Tumor; Chromogranin A; Clusterin; Enterochromaffin Cells; Female; Gastrins; Histidine Decarboxylase; Humans; Neuroendocrine Cells; Pancreatic Neoplasms; Parietal Cells, Gastric; Promoter Regions, Genetic; Rats; Rats, Sprague-Dawley; Stomach Neoplasms; Transcription Factor AP-1; Up-Regulation

We present a case of a gastric neuroendocrine carcinoma in a patient with a history of long-term proton pump inhibitor (PPI) use. A 49-year-old man using PPI for the last 15 years due to gastroesophageal reflux disease developed progressive dysphagia, dyspepsia and weight loss. Upper gastrointestinal endoscopy, endoscopic ultrasonography and abdominal CT diagnosed a malignant tumor localized to a hiatal hernia. Fasting serum chromogranin A and gastrin concentrations were elevated (32 nmol/l and 159 pmol/l, respectively). Helicobacter pylori PCR analysis of antral biopsies was negative. Biopsies from endoscopically normal oxyntic mucosa showed enterochromaffin-like (ECL) cell hyperplasia. Tumor biopsies revealed a poorly differentiated neuroendocrine carcinoma. Sevier-Munger staining, immunohistochemistry and electron microscopy indicated ECL cell as origin of the tumor cells. Concerns have previously been raised about the safety of long-term PPI use due to a possible increased risk of cancer. This case illustrates a patient with a poorly differentiated neuroendocrine carcinoma with ECL cell characteristics probably induced by hypergastrinemia secondary to long-term PPI use.

Topics: 2-Pyridinylmethylsulfinylbenzimidazoles; Carcinoma, Neuroendocrine; Chromogranin A; Gastrins; Gastroesophageal Reflux; Humans; Lansoprazole; Male; Middle Aged; Proton Pump Inhibitors; Stomach Neoplasms; Time Factors

Previous studies have suggested that dietary folic acid (FA) can protect against certain types of cancers. However, the findings have varied, and the mechanisms by which FA exerts chemopreventive effects remain to be clarified. We examined the effects of FA supplementation on DNA methylation, gene expression, and gastric dysplasia in a transgenic mouse model that is etiologically and histologically well matched with human gastric cancers.. Hypergastrinemic mice infected with Helicobacter felis were studied at multiple stages of gastric dysplasia and early cancer with FA supplementation initiated both at weaning and later in life. Global DNA methylation was assessed by a methylation sensitive cytosine incorporation assay, bisulfite pyrosequencing of B1 repetitive elements, and immunohistochemistry with anti-5-methylcytosine. We also profiled gene expression in the same tissues.. We found a decrease in global DNA methylation and tissue folate and an increase in serum homocysteine with progression of gastric dysplasia. FA supplementation prevented this loss of global DNA methylation and markedly reduced gastric dysplasia and mucosal inflammation. FA protected against the loss of global DNA methylation both in the dysplastic gastric epithelial cells and in gastric stromal myofibroblasts. In addition, FA supplementation had an anti-inflammatory effect, as indicated by expression profiling and immunohistochemistry for lymphocyte markers.. We conclude that FA supplementation is chemopreventive in this model of Helicobacter-associated gastric cancer. The beneficial effect of FA is likely due to its ability to prevent global loss of methylation and suppress inflammation.

Topics: Animals; Anti-Inflammatory Agents; Anticarcinogenic Agents; Disease Models, Animal; DNA Methylation; Folic Acid; Gastric Mucosa; Gastrins; Gastritis; Gene Expression Profiling; Gene Expression Regulation; Helicobacter felis; Helicobacter Infections; Homocysteine; Immunohistochemistry; Lymphocytes; Male; Mice; Mice, Transgenic; Myofibroblasts; Stomach; Stomach Neoplasms; Stromal Cells; Up-Regulation

One of the most important hormones in the human stomach is the peptide gastrin. It is mainly required for the regulation of gastric pH but is also involved in growth and differentiation of gastric epithelial cells. In Helicobacter pylori infected patients, gastrin secretion can be upregulated by the pathogen, resulting in hypergastrinaemia. H pylori induced hypergastrinaemia is described as being a major risk factor for the development of gastric adenocarcinoma.. In this study, the upstream receptor complex and bacterial factors involved in H pylori induced gastrin gene expression were investigated, utilising gastric epithelial cells which were stably transfected with a human gastrin promoter luciferase reporter construct.. Integrin linked kinase (ILK) and integrin β5, but not integrin β1, played an important role in gastrin promoter activation. Interestingly, a novel CagL/integrin β5/ILK signalling complex was characterised as being important for H pylori induced gastrin expression. On interaction of H pylori with αvβ(5)-integrin and ILK, the epidermal growth factor receptor (EGFR)→Raf→mitogen activated protein kinase kinase (MEK)→extracellular signal regulated kinase (Erk) downstream signalling cascade was identified which plays a central role in H pylori gastrin induction.. The newly discovered recognition receptor complex could be a useful target in treating precancerous conditions triggered by H pylori induced hypergastrinaemia.

Topics: Animals; Bacterial Proteins; Epithelial Cells; Gastric Mucosa; Gastrins; Gene Expression; Gerbillinae; Helicobacter Infections; Helicobacter pylori; Humans; Immunoblotting; Mitogen-Activated Protein Kinases; Protein Serine-Threonine Kinases; Real-Time Polymerase Chain Reaction; Signal Transduction; Stomach Neoplasms

Non-invasive tools for gastric cancer screening and diagnosis are lacking. Serological testing with the detection of pepsinogen 1 (PG1), pepsinogen 2 (PG2) and gastrin 17 (G17) offers the possibility to detect preneoplastic gastric mucosal conditions. Aim of this study was to assess the performance of these serological tests in the presence of gastric neoplasia.. Histological and serological samples of 118 patients with gastric cancer have been assessed for tumor specific characteristics (Laurén type, localisation), degree of mucosal abnormalities (intestinal metaplasia, atrophy) and serological parameters (PG1, PG2, PG1/2-ratio, G17, H. pylori IgG, CagA status). Association of the general factors to the different serological values have been statistically analyzed.. Patients with intestinal type gastric cancer had lower PG1 levels and a lower PG1/2-ratio compared to those with diffuse type cancer (p = 0.003). The serum levels of PG2 itself and G17 were not significantly altered. H. pylori infection in general had no influence on the levels of PG1, PG2 and G17 in the serum of gastric cancer patients. There was a trend towards lower PG1 levels in case of positive CagA-status (p = 0.058). The degree of both intestinal metaplasia and atrophy correlated inversely with serum levels for PG1 and the PG1/2-ratio (p < 0.01). Laurén-specific analysis revealed that this is only true for intestinal type tumors. Univariate ANOVA revealed atrophy and CagA-status as the only independent factors for low PG1 and a low PG1/2-ratio.. Glandular atrophy and a positive CagA status are determinant factors for decreased pepsinogen 1 levels in the serum of patients with gastric cancer. The serological assessment of gastric atrophy by analysis of serum pepsinogen is only adequate for patients with intestinal type cancer.

Topics: Adenocarcinoma; Aged; Antibodies, Bacterial; Antigens, Bacterial; Atrophy; Bacterial Proteins; Biomarkers, Tumor; Female; Gastric Mucosa; Gastrins; Helicobacter Infections; Helicobacter pylori; Humans; Male; Middle Aged; Pepsinogen A; Precancerous Conditions; Retrospective Studies; Stomach Neoplasms

Topics: Animals; Bacterial Proteins; Epithelial Cells; Gastric Mucosa; Gastrins; Helicobacter Infections; Helicobacter pylori; Humans; Mitogen-Activated Protein Kinases; Protein Serine-Threonine Kinases; Stomach Neoplasms

Huntingtin interacting protein 1 related (Hip1r) is an F-actin- and clathrin-binding protein involved in vesicular trafficking that is crucial for parietal cell function and epithelial cell homeostasis in the stomach. Gastric parietal cells in Hip1r-deficient mice are lost by apoptotic cell death, which leads to a progressive epithelial cell derangement, including glandular hypertrophy, zymogenic cell loss and expansion of a metaplastic mucous cell lineage known as spasmolytic polypeptide-expressing metaplasia (SPEM). The epithelial cell changes are associated with infiltration of inflammatory cells. As inflammatory mediators, such as IFNγ, have been shown to contribute to the development of the gastric epithelial cell metaplasia after Helicobacter infection, we tested whether IFNγ played a role in the spontaneous progressive epithelial metaplasia observed in Hip1r-deficient mice. Hip1r-deficient mice were crossed with IFNγ-deficient mice and single- and double-mutant mice were analyzed at 3 and 12 months of age. Histopathology scoring showed that loss of IFNγ tempered the spontaneous development of metaplastic lesions in Hip1r-deficient mice. Loss of IFNγ was observed to abrogate the glandular hypertrophy evident in Hip1r mutant stomach, although increased epithelial cell proliferation and elevated gastrin levels were not affected by the presence or absence of this pro-inflammatory cytokine. An analysis of cell lineage markers in the double-mutant mice demonstrated that IFNγ specifically affected the development of metaplastic mucous cells in the neck region, whereas the parietal cell, surface mucous cell and zymogenic cell alterations remained similar to the histopathology in the Hip1r mutant. Morphometric analysis showed that IFNγ was required for the mucous cell hypertrophy and hyperplasia observed in Hip1r-deficient mice. Together, these findings demonstrate that IFNγ is critical for the development of the gastric epithelial cell metaplasia that results from parietal cell atrophy in the Hip1r-deficient mice.

Topics: Adaptor Proteins, Signal Transducing; Animals; Cell Proliferation; DNA-Binding Proteins; Female; Gastric Mucosa; Gastrins; Hypertrophy; Interferon gamma Receptor; Interferon-gamma; Male; Metaplasia; Mice; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Knockout; Microfilament Proteins; Receptors, Interferon; Stomach Neoplasms

We present a case-report of a woman with persisting gastric ulcers, who had elevated gastrin blood levels. First of all, a rare cause of hypergastrinaemia was excluded - a gastrinoma. It was not found despite of extensive investigation. Ulcers were repetitively biopted and transition of high grade dysplasia to adenocarcinoma was detected. Gastrin levels normalised after surgical antrectomia. Afterwards pernicious anaemia was diagnosed as the underlining cause of hypergastrinaemia.

Topics: Adenocarcinoma; Anemia, Pernicious; Diagnosis, Differential; Female; Gastrinoma; Gastrins; Humans; Middle Aged; Pancreatic Neoplasms; Stomach Neoplasms

Helicobacter pylori (HP) has been associated with neuroendocrine tumors of the stomach and duodenum. Gastric enterochromaffin-like (ECL) cell tumors and duodenal gastrinomas have also been associated with HP gastritis in separate series but have not been reported together. With other possible causes excluded, we present a patient with HP-associated atrophy of the oxyntic mucosa that ultimately resulted in stimulation and reactive hyperplasia of gastrin-producing cells in both the antrum and proximal duodenum, the latter progressing to formation of a gastrin-producing cell nodule (gastrinoma). Both of these sources of gastrin resulted in ECL hyperplasia in the atrophied oxyntic mucosa with progression to microcarcinoids and well-differentiated neuroendocrine tumors, along with hypertrophy of residual proximal gastric parietal cells. As atrophy tends to spread from the antrum proximally, residual oxyntic mucosa was still infected with HP and offers 1 explanation for the apparent paradox of atrophic gastritis with ECL hyperplasia and neoplasia in the distal oxyntic mucosa, with proximal oxyntic mucosa showing mild hypertrophic changes in a background of typical HP gastritis.

Topics: Aged; Atrophy; Chronic Disease; Duodenal Neoplasms; Gastrectomy; Gastrinoma; Gastrins; Gastritis; Helicobacter Infections; Humans; Intestinal Mucosa; Male; Neoplasms, Multiple Primary; Neuroendocrine Tumors; Stomach Neoplasms

Topics: Adenocarcinoma; Anemia, Pernicious; Female; Gastrinoma; Gastrins; Humans; Pancreatic Neoplasms; Stomach Neoplasms

Autoimmune gastritis (AIG) may predispose to gastric carcinoid tumors or adenocarcinomas and may also cause unexplained iron and/or vitamin B(12) deficiency. The aims of this study were to explore clinical manifestations, endoscopic findings and laboratory features of patients with AIG.. 109 patients with AIG were enrolled into the study. In addition to demographic and clinical data, gastric lesions, serum gastrin, vitamin B(12), antiparietal cell antibody (APA), current Helicobacter pylori status, and anti-H. pylori IgG were also investigated.. The mean age of the patients was 53.06 ± 12.7 years (range 24-81; 72 (66.1%) women). The most common main presenting symptom was abdominal symptoms in 51 patients, consultation for iron and/or vitamin B(12) deficiency in 36, and non-specific symptoms including intermittent diarrhea in 15 patients. Endoscopic lesions were detected in 17 patients, hyperplastic polyps in 8, gastric carcinoid tumor in 4, fundic gland polyps in 3, and adenomatous polyps in 2 patients. H. pylori was negative in all patients in biopsy specimens; however, anti-H. pylori IgG was positive in 30 (27.5%) patients. 91 patients (83.4%) were positive for APA.. In patients with AIG, the main symptoms prompted for clinical investigation were: abdominal symptoms, iron/B(12) deficiency and non-specific symptoms. 20% of patients with AIG had various gastric lesions including type I gastric carcinoids. None of the patients were positive for H. pylori by means of invasive tests; however, anti-H. pylori IgG was found in 27.5% of patients. Patients referring with non-specific abdominal symptoms such as bloating, diarrhea and iron/B(12) deficiency should be investigated for the presence of AIG.

Topics: Adenomatous Polyps; Adult; Age Factors; Aged; Aged, 80 and over; Antibodies, Bacterial; Autoimmune Diseases; Carcinoid Tumor; Diarrhea; Female; Gastrins; Gastritis; Gastroscopy; Helicobacter Infections; Helicobacter pylori; Humans; Immunoglobulin G; Iron; Iron Deficiencies; Male; Middle Aged; Parietal Cells, Gastric; Polyps; Sex Factors; Stomach Neoplasms; Vitamin B 12 Deficiency; Young Adult

The aim of the study was to assess the accuracy of some specific biochemical indicators in discriminating between Helicobacter pylori-associated gastritis and H. pylori-associated stomach cancer (serum gastrin level, serum soluble E-cadherin and tissue COX-2 activity, as well as serodiagnostic markers for H. pylori infection) in order to find a simple diagnostic test that can reasonably predict the development of gastric cancer. The study participants comprised 20 patients with gastric carcinoma, 20 patients with positive H. pylori-associated gastritis and 20 individuals as the control group. Standard procedures and quality control measures were followed. Using cut-off values and ROC analysis to assess the diagnostic abilities of the biochemical indicators, E-cadherin showed the highest sensitivity (100%). We suggest that close follow-up together with periodic endoscopic examination for all patients with persistent H. pylori infection and serum soluble E-cadherin level above 5 microg/mL is essential.

Topics: Biomarkers, Tumor; Cadherins; Case-Control Studies; Cyclooxygenase 2; Diagnosis, Differential; Early Diagnosis; Egypt; Female; Gastrins; Gastritis; Helicobacter Infections; Helicobacter pylori; Humans; Male; Middle Aged; Risk Assessment; Sensitivity and Specificity; Stomach Neoplasms

The cholecystokinin 2 receptor (CCK2R/CCKBR) is expressed in gastrointestinal stromal tumours (GISTs). We sought to investigate the role of CCK2R in GIST pathogenesis. Molecular characterization of CCK2R was performed on a heterogeneous cohort of 50 GISTs. In addition, CCK2R expression was evaluated by immunohistochemistry (IHC), using tissue microarray (TMA) containing 292 GISTs, two cases of hyperplasia of interstitial Cajal's cells (ICC) and six gastric microscopic GISTs. Mono-allelic loss of the CCK2R/11p15 allele was identified in 13.7% of GISTs, having no impact on the level of CCK2R transcript expression. No CCK2R mutations were found. The CCK2Ri4sv, CCK2R splice variant with retention of intron 4 was detected in six of 20 tumours analysed. Wild-type CCK2R transcripts were commonly expressed (57.1% of cases) and this expression was highly correlated with gastric primary site of GISTs (p < 0.001). At the protein level, expression of CCK2R in incidental ICC hyperplasia and early stages of gastric GIST development was documented, and its gastric association was confirmed on GIST-TMA by IHC. To explore the in vivo effect of CCK2R activation on tumour growth, gastrin versus placebo was administered intraperitoneally in nude mice carrying human GIST xenografts. The tumour volume was followed for 10 weeks. The effect of this stimulation on tumour cell proliferation/apoptosis was assessed by IHC and KIT/PKC-θ signalling was evaluated by western blotting (WB). In vivo experiments showed a two-fold increase in the volume of tumours which were exposed to gastrin in comparison with non-exposed controls (p = 0.03), with a significant increase in mitotic activity (p = 0.04) and Ki-67 proliferation index (p = 0.008). By WB, gastrin stimulation resulted in hyper-activation of KIT and PKC-θ kinases, and in evident PI3K-AKT pathway over-activation. Our results indicate a promoting role of CCK2R on GIST tumourigenesis, particularly in tumours of gastric origin.

Topics: Adult; Aged; Aged, 80 and over; Cell Proliferation; Female; Gastrins; Gastrointestinal Neoplasms; Gastrointestinal Stromal Tumors; Gene Expression Regulation, Neoplastic; Humans; Male; Middle Aged; Polymerase Chain Reaction; Protein Kinase C; Proto-Oncogene Proteins c-kit; Receptor, Cholecystokinin B; Signal Transduction; Stomach Neoplasms

Gastric neuroendocrine neoplasms of the stomach can be divided into the usually well-differentiated, hypergastrinemia-dependent type I and II lesions and the more aggressively behaving gastrin-independent type III lesions. Mainly due to better diagnostics and awareness of this tumor, the observed incidence has increased more than tenfold over the last 30 years. Small (<15-20 mm) localized type I and II lesions that are slowly proliferating (Ki67<2%) can usually be managed conservatively with endoscopic surveillance. Reducing hypergastrinemia by surgical removal of an underlying gastrinoma is important in inhibiting growth and induce reduction of type II lesions, while the specific gastrin receptor antagonist YF476 or gastrin antibodies may become useful for both type I and II lesions. Infiltrating and metastasized tumors and type III lesions require a more aggressive approach with surgical resection and consideration of modalities such as somatostatin analogs, cytotoxics, and peptide receptor targeted treatment.

Topics: Carcinoid Tumor; Gastrinoma; Gastrins; Humans; Neuroendocrine Tumors; Stomach Neoplasms

Gastric cancer is one of the most common malignant tumors causing death in Fujian Province, China. However, the mortality of gastric cancer is greatly varied in different areas in Fujian; for example, the mortality in Changle City is 7.4 times higher than that in Fuan City. In this study, we compared the differences in serological parameters, pepsinogen (PG) I, PG II, gastrin-17 (G-17), and Helicobacter pylori (H. pylori) antibody, between the two cities. It has been reported that low serum PG I is correlated with atrophic gastritis, a high-risk condition for developing gastric cancer, while high serum G-17 has been used for serological detection of atrophic corpus gastritis. We recruited 224 healthy subjects in Changle and 229 healthy subjects in Fuan, matched in age and sex. The serum levels of PG II and G-17 were significantly higher in Changle than those in Fuan. Importantly, the frequency of the subjects with low serum PG I (< 25 μg/L) was significantly higher in Changle than in Fuan, although the serum PG I levels were similar between the two cities. Moreover, the percentage of the subjects with high serum G-17 (≥ 2 pmol/L) and the positive rate of serum IgG antibody against H. pylori were significantly higher in Changle than those in Fuan. The detected differences in these serological parameters are consistent with the notion that the prevalence of atrophic gastritis may be higher in Changle than in Fuan, which results in a higher risk condition for developing gastric cancer in Changle.

Topics: Adult; Aged; Antibodies, Bacterial; China; Cities; Female; Gastrins; Geography; Helicobacter Infections; Helicobacter pylori; Humans; Immunoglobulin G; Male; Middle Aged; Pepsinogen A; Pepsinogen C; Pepsinogens; Residence Characteristics; Stomach Neoplasms

We investigated whether corpus atrophic gastritis worsens in Mongolian gerbils (MGs) after long-term administration of proton pump inhibitor (PPI). MGs are an excellent model for studying Helicobacter pylori-related gastritis and adenocarcinoma.. MGs were separated into four groups (n =15/group); H pylori (ATCC43504) was inoculated into the OPZ(omeprazole)+Hp (H pylori) and Hp groups, a PPI (OPZ) was administered to the OPZ+Hp and OPZ groups and the control group received no treatment. MGs had access to food containing omeprazole (100 mg/kg body weight/day) for 6 months, after which their stomachs were removed and cut into nine sections (six sections in the fundus and three sections in the antrum). Corpus atrophy was evaluated by the absence of parietal cells in the six sections in the fundus. First, we calculated a percentage of the area devoid of parietal cells in each haematoxylin and eosin-stained section, and then we scored the degree of atrophy by adding the percentages of the six sections. A full score was 600.. Neutrophilic and lymphoid infiltrates were greater in the OPZ+Hp group than in the other groups. The corpus atrophy score in the OPZ+Hp group was significantly higher than that in the Hp group (p < 0.0048, Student t test). Significantly more adenocarcinomas were found in the OPZ+Hp (60%) than in the Hp (7%) group animals.. Long-term PPI administration promotes development of adenocarcinoma, which is associated with the progression of atrophic corpus gastritis in MGs infected with H pylori.

Topics: Adenocarcinoma; Animals; Body Weight; Cocarcinogenesis; Disease Models, Animal; Disease Progression; Drug Administration Schedule; Gastrins; Gastritis, Atrophic; Gerbillinae; Helicobacter Infections; Helicobacter pylori; Male; Metaplasia; Proton Pump Inhibitors; Stomach; Stomach Neoplasms

Epigenetic alterations have been correlated with field cancerization in human patients, but evidence from experimental models that specific epigenetic changes can initiate cancer has been lacking. Although hormones have been associated with cancer risk, the mechanisms have not been determined. The peptide hormone gastrin exerts a suppressive effect on antral gastric carcinogenesis.. N-methyl-N-nitrosourea (MNU)-dependent gastric cancer was investigated in hypergastrinemic (INS-GAS), gastrin-deficient (GAS(-/-)), Tff1-deficient (Tff1(+/-)), and wild-type (WT) mice. Epigenetic alterations of the trefoil factor 1 (TFF1) tumor suppressor gene were evaluated in vitro and in vivo.. Human intestinal-type gastric cancers in the antrum exhibited progressive TFF1 repression and promoter hypermethylation. Mice treated with MNU exhibited a field defect characterized by widespread Tff1 repression associated with histone H3 lysine 9 methylation and H3 deacetylation at the Tff1 promoter in epithelial cells. In MNU-induced advanced cancers, DNA methylation at the Tff1 promoter was observed. Tumor induction and Tff1 repression were increased in MNU-treated mice by Helicobacter infection. Hypergastrinemia suppressed MNU-dependent tumor initiation and progression in a manner that correlated with gene silencing and epigenetic alterations of Tff1. In contrast, homozygous gastrin-deficient and heterozygous Tff1-deficient mice showed enhanced MNU-dependent field defects and cancer initiation compared with WT mice. In gastric cancer cells, gastrin stimulation partially reversed the epigenetic silencing in the TFF1 promoter.. Initiation of antral gastric cancer is associated with progressive epigenetic silencing of TFF1, which can be suppressed by the hormone gastrin.

Topics: Adult; Aged; Aged, 80 and over; Animals; Apoptosis; Cell Line, Tumor; Cell Proliferation; Cell Transformation, Neoplastic; Chromatin Assembly and Disassembly; Disease Models, Animal; DNA Methylation; Female; Gastrins; Gene Expression Regulation, Neoplastic; Gene Silencing; Helicobacter felis; Helicobacter Infections; Histones; Humans; Male; Methylnitrosourea; Mice; Mice, Knockout; Middle Aged; Neoplastic Stem Cells; Peptides; Promoter Regions, Genetic; RNA, Messenger; Stomach Neoplasms; Time Factors; Transfection; Trefoil Factor-1; Tumor Suppressor Proteins

Gastric carcinoids type 1 (GC1) are neuroendocrine tumors (NETs) arising from the enterochromaffin-like (ECL) cells in patients with chronic atrophic gastritis (CAG). The treatment of GC1 has been endoscopic polypectomy or surgical tumor excision and antrectomy. One year treatment with somatostatin analogs (SSAs) diminished tumor load and ECL cell density. The effect persisted 1 year after treatment was discontinued. However, the optimal SSA dose and treatment duration are unknown.. The aim of the present work was to study macroscopic and histopathological changes in the stomach and serum markers gastrin and chromogranin A (CgA) in GC1 patients 5 years after 1 year of octreotide long-acting release (LAR) treatment.. Five patients with GC1 were included 5 years after the initial year of octreotide LAR treatment. All patients underwent upper gastrointestinal endoscopy including tumor and mucosal biopsies from oxyntic mucosa, chest and abdominal computer tomography and octreotide scintigraphy. Fasting serum gastrin and CgA were also measured.. At 5 years, one patient had a highly malignant gastric tumor, one patient had an increased number of GCs, regional and distant metastases and three patients had an increased number of GCs. Serum gastrin and CgA increased to pre-treatment levels after 1 year of follow-up and were unchanged at the 5-year follow-up.. The disease had progressed in all five GCs patients treated with octreotide for 12 months at 5 years of follow-up. This suggests that, if started, octreotide treatment should not be discontinued in these patients.

Topics: Aged; Antineoplastic Agents, Hormonal; Biopsy; Carcinoid Tumor; Chromogranin A; Disease Progression; Enterochromaffin-like Cells; Female; Follow-Up Studies; Gastric Mucosa; Gastrins; Gastritis, Atrophic; Gastroscopy; Humans; Male; Middle Aged; Octreotide; Stomach Neoplasms; Tomography, X-Ray Computed; Tumor Burden

Atrophic gastritis (AG) is a well-recognized high-risk condition for developing gastric cancer (GC). Gastrin 17 (G17), a hormone secreted from antral G cells, regulates gastric acid secretion, and its serum level is a possible indicator of antral atrophy. Serum pepsinogen is well established as the indicator of AG involving the corpus. Here we investigated whether serum PG and G17 levels would be useful for determining the topographic pattern of AG and estimating the risk of GC. Enrolled were 122 Japanese patients with early GC (114 well- to moderate-differentiated cancers and 8 poorly-differentiated cancers). In addition, 178 subjects without GC were recruited as control from those undergoing endoscopic examination (non-GC group). All subjects were histologically assigned to the following four groups: non-AG, antrum-predominant AG, corpus-predominant AG, and multifocal AG, affecting the antrum and corpus. Serum concentrations of pepsinogen and G17 were determined using ELISA. Multifocal AG was more frequent in the GC group than in the adjusted non-GC group, and had the highest risk of GC (OR 25.1). Serum G17 was significantly decreased with the exacerbation of antral atrophy in the coexistence of corpus atrophy. Serum biomarker profiles showed that the low levels of pepsinogen and G17 could discriminate between multifocal AG and other types of AG, but not with pepsinogen level alone. Serologically defined multifocal AG had the highest cancer risk among other serologically defined AG groups (OR 26.9). In conclusion, the low serum levels of pepsinogen and G17 are predictive of extensive gastric atrophy with high-risk of early GC.

Topics: Adult; Age of Onset; Aged; Aged, 80 and over; Asian People; Atrophy; Biomarkers, Tumor; Case-Control Studies; Demography; Female; Gastrins; Helicobacter pylori; Hematologic Tests; Humans; Japan; Male; Middle Aged; Pepsinogen A; Risk Assessment; Risk Factors; Stomach Neoplasms

To investigate plasma ghrelin, gastrin and growth hormone secretagogue receptor (GHS-R) expression in advanced gastric cancer (GC) before and after resection.. Seventy subjects in whom endoscopy of the upper gastrointestinal tract was performed in the Department of General Surgery at Cracow University during the past decade: (1) 25 patients with GC associated with Helicobacter pylori (H. pylori) infection; (2) 10 patients with GC 4-5 years after (total or subtotal) gastrectomy; (3) 25 healthy H. pylori-negative controls, matched by age and BMI to the above two groups; and (4) 10 GC patients 4-5 years after total gastrectomy. Ghrelin and gastrin plasma concentrations were measured by specific radioimmunoassay under fasting conditions and postprandially at 60 and 90 min after ingestion of a mixed meal. GHS-R expression was examined in biopsy samples from intact healthy mucosa and GC tissue using semi-quantitative reverse transcription-polymerase chain reaction.. In healthy controls, fasting plasma ghrelin levels were significantly elevated and declined markedly at 60 and 90 min after a mixed meal. The concomitant enhanced ghrelin, GHS-R and gastrin expression in GC tissue over that recorded in intact mucosa, and the marked rise in plasma gastrin in these subjects under fasting conditions indicate the role of these hormonal factors in GC formation. Fasting plasma levels and postprandial response of ghrelin and gastrin appear to be inversely correlated in healthy subjects. Feeding in the controls resulted in a significant fall in plasma ghrelin with a subsequent rise in plasma gastrin, but in H. pylori-positive GC patients submitted to total or distal gastrectomy, feeding failed to affect significantly the fall in plasma ghrelin that was recorded in these patients before surgery. Fasting ghrelin concentrations were significantly lower in patients 4-5 years after total gastrectomy compared to those in healthy controls and to these in GC patients before surgery.. Elevated plasma gastrin and suppression of fasting ghrelin in patients with GC suggest the existence of a close relationship between these two hormones in gastric carcinogenesis.

Topics: Adult; Aged; Aged, 80 and over; Fasting; Female; Gastrectomy; Gastrins; Ghrelin; Helicobacter Infections; Humans; Male; Middle Aged; Postprandial Period; Radioimmunoassay; Receptors, Ghrelin; Stomach Neoplasms

Gastric cancer is the fourth most common cancer in the world and the second most prevalent cause of cancer related death. The development of gastric cancer is mainly associated with H. Pylori infection leading to a focus in pathology studies on bacterial and environmental factors, and to a lesser extent on the mechanistic development of the tumour. MicroRNAs are small non-coding RNA molecules involved in post-transcriptional gene regulation. They are found to regulate genes involved in diverse biological functions and alterations in microRNA expression have been linked to the pathogenesis of many malignancies. The current study is focused on identifying microRNAs involved in gastric carcinogenesis and to explore their mechanistic relevance by characterizing their targets.. Invitrogen NCode miRNA microarrays identified miR-449 to be decreased in 1-year-old Gastrin KO mice and in H. Pylori infected gastric tissues compared to tissues from wild type animals. Growth rate of gastric cell lines over-expressing miR-449 was inhibited by 60% compared to controls. FACS cell cycle analysis of miR-449 over-expressing cells showed a significant increase in the sub-G1 fraction indicative of apoptosis. ß-Gal assays indicated a senescent phenotype of gastric cell lines over-expressing miR-449. Affymetrix 133v2 arrays identified GMNN, MET, CCNE2, SIRT1 and CDK6 as miR-449 targets. Luciferase assays were used to confirm GMNN, MET, CCNE2 and SIRT1 as direct targets. We also show that miR-449 over-expression activated p53 and its downstream target p21 as well as the apoptosis markers cleaved CASP3 and PARP. Importantly, qPCR analyses showed a loss of miR-449 expression in human clinical gastric tumours compared to normal tissues.. In this study, we document a diminished expression of miR-449 in Gastrin KO mice and further confirmed its loss in human gastric tumours. We investigated the function of miR-449 by identifying its direct targets. Furthermore we show that miR-449 induces senescence and apoptosis by activating the p53 pathway.

Topics: Adenoma; Animals; Base Sequence; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cellular Senescence; Down-Regulation; Gastrins; Gene Expression Regulation, Neoplastic; Helicobacter Infections; Helicobacter pylori; Humans; Mice; Mice, Knockout; MicroRNAs; Molecular Sequence Data; Pyloric Antrum; Signal Transduction; Stomach Neoplasms; Tumor Suppressor Protein p53

Helicobacter pylori-cytotoxin-associated protein A (CagA) and gastrin are believed to play an important role in gastric carcinogenesis, but their interaction has been incompletely clear.. We constructed a eukaryotic expression vector pcDNA3.1/cagA and a luciferase reporter vector pGL/gastrin promoter, and then co-transfected them into gastric cancer AGS and SGC-7901 cells. The two kinds of gastric cancer cells were, respectively, infected with cagA-positive H. pylori NCTC11637, and then the gastrin promoter activity and gastrin mRNA level were detected with a Dual-Luciferase reporter assay system and quantitative reverse transcription polymerase chain reaction (RT-PCR), respectively. Next, after the MEK/ERK and JAK2-signaling pathway inhibitors, U0126 and AG490, were used to treat the two cell lines, or the ERK1 and JAK2 genes were knocked down by siRNAs (small interference RNAs) in the two cell lines, the gastrin promoter activity and gastrin mRNA level were observed again.. The results indicated that CagA could activate the gastrin promoter and up-regulate gastrin mRNA expression in AGS and SGC-7901 cells, but these effects could be inhibited by the inhibitors U0126 and AG490, and the CagA-induced gastrin mRNA expression was down-regulated in the cells whose ERK1 or JAK2 gene was knocked down.. Gastrin promoter may be the transcriptional target of CagA, and CagA activates the gastrin promoter to up-regulate gastrin mRNA expression through the MEK/ERK and JAK1-signaling pathway in gastric cancer cells.

Topics: Antigens, Bacterial; Bacterial Proteins; Binding Sites; Butadienes; Enzyme Inhibitors; Gastrins; Gene Expression Regulation, Neoplastic; Helicobacter pylori; Humans; Janus Kinase 2; MAP Kinase Signaling System; Mitogen-Activated Protein Kinase 3; Nitriles; Promoter Regions, Genetic; RNA, Messenger; RNA, Small Interfering; Signal Transduction; Stomach Neoplasms; Tumor Cells, Cultured; Tyrphostins; Up-Regulation

Gastric type I carcinoid is a rare neoplasm, deriving from enterochromaffin-like cells (ECL), mainly affecting women with autoimmune gastritis. The approach to treatment, either endoscopic, medical or surgical, is not well defined, particularly in multifocal tumours or carcinoids with rapid growth/frequent recurrence.. To determine whether an anti-G17 vaccination might interfere on the natural history of gastric type I carcinoid.. Padua teaching Hospital, outpatient clinic.. Three patients with type I gastric carcinoid in autoimmune gastritis were administered, after informed consent and ethic committee approval, with a vaccine against gastrin 17 (G17), a synthetic peptide that stimulates specific and high-affinity anti-G17 antibodies, and followed up endoscopically and clinically for a mean of 36 months.. Gastric histology and specifically carcinoid growth/recurrence and trend in time in gastrin, G17, pepsinogens, chromogranin A and clinical parameters.. Following vaccination, carcinoid regression was observed in 2/3 patients and, in one of the patients, even the disappearance of ECL hyperplasia, with a reduced ECL cells stimulation, confirmed by a significant reduction in chromogranin A levels. Regression was observed in the two patients that showed a more clear local response to the vaccine. Increased autoantibody titre was observed, but no appearance of new autoimmune diseases.. Anti-G17 vaccination induced regression of type I gastric carcinoid and could be considered for the treatment of this tumour, when endoscopic removal is not indicated.

Topics: Aged; Cancer Vaccines; Carcinoid Tumor; Female; Gastrins; Gastritis, Atrophic; Humans; Immunoenzyme Techniques; Male; Pilot Projects; Prognosis; Stomach Neoplasms; Survival Rate; Tumor Microenvironment; Vaccination

Topics: Carcinoid Tumor; Female; Gastrins; Humans; Middle Aged; Prognosis; Stomach Neoplasms

Proton pump inhibitors (PPIs) are routinely used for control of upper gastrointestinal disorders, often with long-term application. However, there has been some concern about the long-term safety and the possibility of cancer induction and development of neuroendocrine tumors (NET) in the stomach. We therefore analyzed the influence of PPI use on tumor development histologically, immunohistochemically, and serologically in the glandular stomachs of Helicobacter pylori (Hp)-infected and uninfected Mongolian gerbils (MGs). 53 MGs were divided into 6 groups: Hp+25PPI, Hp+5PPI, Hp, 25PPI, 5PPI, and controls. The high-dose Hp+25PPI and 25PPI groups received the PPI (lansoprazole) at 25mg/kg/day, and the low-dose Hp+5PPI and 5PPI groups were given 5mg/kg/day. After 50 or 100 weeks, animals were sacrificed humanely, and the glandular stomach samples were evaluated histologically and phenotypically, using antibodies against chromogranin A (CgA), gastrin and gastric inhibitory polypeptide (GIP). Serum gastrin levels were also examined. NETs occurred in the Hp+25PPI, Hp+5PPI, Hp, and 25PPI groups, but there was no synergistic effect between Hp-infection and high-dose PPI administration. Serum gastrin was increased statistically by Hp infection and high-dose PPI administration, but not influenced by the low-dose. The NETs featured expression of CgA, but not gastrin or GIP. In conclusions, PPI at low dose had no influence on development of carcinomas and NETs in the Hp-infected and uninfected glandular MG stomach, suggesting clinical safety. However, PPI at high dose increased NET development and serum gastrin in the MG model.

Topics: 2-Pyridinylmethylsulfinylbenzimidazoles; Animals; Carcinoma; Cell Transformation, Neoplastic; Chromogranin A; Gastric Inhibitory Polypeptide; Gastrins; Gerbillinae; Helicobacter Infections; Helicobacter pylori; Lansoprazole; Male; Neoplasms, Glandular and Epithelial; Neuroendocrine Tumors; Proton Pump Inhibitors; Stomach Neoplasms

Histamine-containing enterochromaffin-like (ECL) cells are numerous in the gastric mucosa. They operate under the control of gastrin. ECL-cell tumors (gastric carcinoids) may arise as a consequence of sustained hypergastrinemia. For reasons unknown, such tumors have a female preponderance both in laboratory animals and humans. The present study consisted of four experiments exploring the possibility that gender-related factors might affect rat ECL cells. 1) A gender difference in terms of serum gastrin concentration and oxyntic mucosal histidine decarboxylase (HDC) activity appeared in Sprague-Dawley but not Wistar rats. Ultrastructural appearance of the ECL cells did not differ between genders. 2) During the different phases of the estrous cycle, the serum gastrin concentration, HDC activity and histamine concentration did not change. 3) During pregnancy, the serum gastrin concentration was suppressed, while it was increased during lactation. The HDC activity and the histamine concentration of the oxyntic mucosa were correlated with the levels of circulating gastrin. 4) Twelve-month treatment with estrogen-like agents, dieldrin and/or toxaphene (alone or in combination) was without any effect on the ECL cells neither in male nor in female rats. In conclusion, the ECL cells are under the control of gastrin, but probably not hormones that involve in the estrous cycle and pregnancy and lactation in rats. Possible gender-related factors behind the female preponderance of ECL-cell tumors remain unknown.

Topics: Animals; Dieldrin; Enterochromaffin-like Cells; Estrogens; Estrous Cycle; Female; Gastric Mucosa; Gastrins; Histamine; Histidine Decarboxylase; Lactation; Male; Parietal Cells, Gastric; Pregnancy; Rats; Rats, Sprague-Dawley; Rats, Wistar; Stomach Neoplasms; Time Factors; Toxaphene

Carcinoid tumors are the most common neuroendocrine tumors. Gastric carcinoids represent 2% of all carcinoids and 1% of all gastric masses. Due to the widespread use of Esophagogastroduodenoscopy for evaluating a variety of upper gastrointestinal symptoms, the detection of early gastric carcinoids has increased. We highlight an alternative management of a young patient with recurrent type 1 gastric carcinoids with greater than 5 lesions, as well as lesions intermittently greater than 1 cm. Gastric carcinoids have a variable presentation and clinical course that is highly dependent on type. Type 1 gastric carcinoids are usually indolent and have a metastasis rate of less than 2%, even with tumors larger than 2 cm. There are a number of experts as well as organizations that recommend endoscopic resection for all type 1 gastric carcinoid lesions less than 1 cm, with a follow-up every 6-12 mo. They also recommend antrectomy for type 1 gastric carcinoids with greater than 5 lesions, lesions 1 cm or greater, or refractory anemia. However, the American Society of Gastrointestinal Endoscopy guidelines state that type 1 gastric carcinoid surveillance is controversial based on the evidence and could not make an evidence-based position statement on the best treatment modality. Our report illustrates a rare cause of iron deficiency anemia in a young male (without any medical history) due to multiple recurrent gastric carcinoid type 1 lesions in the setting of atrophic gastritis causing hypergastrinemia, and in the absence of a vitamin B12 deficiency. Gastric carcinoid type 1 can present in young males without an autoimmune history, despite the known predilection for women aged 50 to 70 years. Type 1 gastric carcinoids can be managed by endoscopic resection in patients with greater than 5 lesions, even with lesions larger than 1 cm. This course of treatment enabled the avoidance of early antrectomy in our patient, who expressed a preference against more invasive measures at his young age.

Topics: Adult; Anemia, Iron-Deficiency; Carcinoid Tumor; Endoscopy, Gastrointestinal; Female; Gastrectomy; Gastrins; Humans; India; Male; Neoplasm Recurrence, Local; Stomach Neoplasms

RegI (Regenerating islet derived-1) was originally characterized as a growth factor involved in pancreatic islet cell regeneration. It is also considered a gastrointestinal mitogen as its expression is increased during pathologies involving aberrant cell proliferation that can lead to neoplasia. However, the absolute requirement for RegI to directly stimulate gastric mucosal cell proliferation in vivo requires further investigation. We used RegI-deficient mice to determine the requirement for RegI in normal gastric mucosal development, wound healing, hyperplasia and tumourigenesis. We found that epithelial repair of acetic acid ulcers in compound mutant RegI/gastrin-deficient mice was significantly reduced compared to wild type, RegI-deficient or gastrin-deficient mice. In contrast, RegI was dispensable for normal gastric mucosal development, hyperplasia in HKbeta-deficient mice and tumourigenesis in gp130(F/F) mice. Although RegI was not required for proliferation in these pathological models, expression of multiple Reg family members were increased during gp130(F/F) tumourigenesis. Interestingly, loss of RegI in gp130(F/F) mice resulted in decreased expression of other Reg family members. Our results indicate that RegI and gastrin may synergistically regulate gastric mucosal proliferation during certain pathological settings like wound healing while gastric epithelial proliferation in other pathologies may require coordinated expression of multiple Reg genes.

Topics: Animals; Base Sequence; Cell Proliferation; Gastric Mucosa; Gastrins; Hyperplasia; Immunoblotting; Lithostathine; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Molecular Sequence Data; Sequence Alignment; Stomach Neoplasms; Stomach Ulcer; Wound Healing

There are limited data on response and long-term follow-up of octreotide therapy in type-I gastric neuroendocrine tumors. The objective of the present study was to assess the response of type-I gastric neuroendocrine tumors to octreotide-long acting, repeatable (LAR) therapy and evaluate long-term follow up of such patients after therapy.. Three patients with documented type-I gastric neuroendocrine tumors from a tertiary gastroenterology centre were studied. Octreotide-LAR therapy 20 mg intramuscularly every 28 days was administered for one year. Serum gastrin and chromogranin levels, gastroscopies and biopsies from tumor nodules at 6 months and one year on therapy and every 6 months after completion of drug therapy were taken. Follow-up after completion of therapy extended for 3 years in two and 2.5 years in one patient.. During octreotide therapy there was normalization of serum gastrin levels and serum chromogranin levels. Tumors in all three patients had regressed at 6 months of treatment. Following cessation of therapy, there was progressive rise of serum gastrin to pre-treatment levels. Serum chromogranin levels remained within normal limits. Gastroscopic and histologic examination of gastric biopsies did not reveal recurrence of tumors in any patients. All patients tolerated therapy well and became asymptomatic soon after drug therapy.. Octreotide-LAR therapy causes regression of type-I gastric neuroendocrine tumors. After completion of drug therapy there was no recurrence of tumors even with continued hypergastrinemia. Octreotide therapy should be considered as one of the treatment options in such patients.

Topics: Adult; Antineoplastic Agents, Hormonal; Biomarkers, Tumor; Carcinoid Tumor; Chromogranins; Female; Follow-Up Studies; Gastrins; Humans; Injections, Intramuscular; Male; Middle Aged; Octreotide; Stomach Neoplasms; Treatment Outcome

Gastrin is a gastrointestinal peptide hormone, secreted by the gastric G cells and can exist as a fully processed amidated form (G17) or as unprocessed forms. All forms of gastrin possess trophic properties towards the gastrointestinal mucosa. An understanding of the signaling pathways involved is important to design therapeutic approaches to target gastrin-mediated cellular events. The studies described here were designed to identify the signaling pathways by which amidated gastrin (G17) mediates cancer cell migration. These studies indicated a time- and dose-dependent increase in gastric cancer cell migration after G17 stimulation, involving cholecystokinin 2 receptor. G17-induced migration was preceded by activation of MAPK pathways and was antagonized after pretreatment with SP600125, a pharmacological inhibitor of c-Jun-NH(2)-terminal kinase (JNK) pathway. Knockdown of endogenous JNK1 expression via small interference RNA (JNK1-siRNA) inhibited G17-induced phosphorylation of c-Jun and migration, and overexpression of wild-type JNK1 or constitutive active JNK1 promoted G17-induced migration. Studies designed to identify the MAPK kinase kinase member mediating JNK activation indicated the involvement of mixed lineage kinase-3 (MLK3), which was transiently activated upon G17 treatment. Inhibition of MLK3 pathway via a pan-MLK inhibitor or knockdown of MLK3 expression by MLK3-siRNA antagonized G17-induced migration. Incubation with G17 also resulted in an induction of matrix metalloproteinase 7 promoter activity, which is known to mediate migration and invasion pathways in cancer cells. Modulation of MLK3, JNK1, and c-Jun pathways modulated G17-induced matrix metalloproteinase 7 promoter activation. These studies indicate that the MLK3/JNK1 axis mediates G17-induced gastric cancer cell migration, which can be targeted for designing novel therapeutic strategies for treating gastric malignancies.

Topics: Anthracenes; Blotting, Western; Cell Line, Tumor; Cell Movement; Enzyme Activation; Gastrins; Humans; JNK Mitogen-Activated Protein Kinases; MAP Kinase Kinase Kinases; Matrix Metalloproteinase 7; Mitogen-Activated Protein Kinase 8; Mitogen-Activated Protein Kinase Kinase Kinase 11; Phosphorylation; RNA, Small Interfering; Stomach Neoplasms

Physiology of gastric acid secretion is one of the earliest subjects in medical research and education. Gastric acid secretion has been sometimes inadequately expressed as pH value rather than amount of gastric H(+) secreted per unit time. Gastric acid secretion is regulated by endocrine, paracrine and neurocrine signals via at least three messenger pathways: gastrin-histamine, CCK-somatostatin, and neural network. These pathways have been largely validated and further characterized by phenotyping a series of knockout mouse models. The complexity of gastric acid secretion is illustrated by both expected and unexpected phenotypes of altered acid secretion. For examples, in comparison with wild-type mice, gastrin and CCK double knockout and SSTR(2) knockout mice displayed a shift in the regulation of ECL cells from somatostatin-SSTR(2) pathway to galanin-Gal1 receptor pathway; a shift in the regulation of parietal cells from gastrin-histamine pathway to vagal pathway; and a shift in the CCK(2) receptors on parietal cells from functional silence to activation. The biological function of glycine-extended gastrin in synergizing gastrin-17 has been revealed in gastrin knockout mice. The roles of gastric acid secretion in tumorigenesis and ulceration have not been fully understood. Transgenic hypergastrinemic INS-GAS mice developed a spontaneous gastric cancer, which was associated with an impaired acid secretion. Gastrin knockout mice were still able to produce acid in response to vagal stimulation, especially after H. pylori infection. Taken together, phenotyping of a series of genetically engineered mouse models reveals a high degree of complexity of gastric acid secretion in both physiological and pathophysiological conditions.

Topics: Animals; Cholecystokinin; Gastric Acid; Gastrins; Gene Targeting; Helicobacter Infections; Helicobacter pylori; Humans; Mice; Mice, Knockout; Paracrine Communication; Peptic Ulcer; Receptors, Somatostatin; Stomach Neoplasms

We report the case of a patient demonstrating multiple gastric carcinoids with hypergastrinemia. A 50-year-old Japanese woman was admitted to our hospital for the further examination of multiple carcinoids of the stomach with hypergastrinemia, although she was asymptomatic. However, based on our clinical examination, this case seemed to be neither type I nor II carcinoid. We performed a total gastrectomy with D1 lymph node dissection. A pathological examination showed numerous endocrine micronests, hyperplasia of the parietal cells extending to the foveolar neck region, and numerous dilated oxyntic glands filled with eosinophilic secretions. Many parietal cells exhibited vacuolated cytoplasms and apical snouts. Furthermore, the dilated glands at the base of the mucosa had hyperchromatic nuclei and ciliated surfaces. The postoperative serum gastrin level was soon normalized to 47 pg/ml. This is only the third reported case of multiple gastric carcinoids with hypergastrinemia due to an intrinsic abnormality in the acid secretion of the parietal cells.

Topics: Carcinoid Tumor; Female; Gastrectomy; Gastric Acid; Gastrins; Humans; Lymph Node Excision; Middle Aged; Parietal Cells, Gastric; Stomach Neoplasms

We previously reported that Reg IV is associated with neuroendocrine (NE) differentiation in gastric cancers. The aim was to examine which NE hormone products are related to Reg IV-positive NE cells and their roles in gastric cancers. In the present study, we performed immunohistochemical analysis in a tissue microarray (TMA) of a consecutive series of 630 cases with ten different antibodies, including chromogranin A, synaptophysin and neural cell adhesion molecule (NCAM) as NE differentiation markers, and gastrin, serotonin, calcitonin, gastrin-releasing peptide (GRP), pancreatic polypeptide (PP), somatostatin and glucagon as NE hormones. In 630 cases, we identified 205 (33%) with NE differentiation and 147 (23%) positive for Reg IV. Reg IV-positive cases showed NE differentiation more frequently than Reg IV-negative cases (P < 0.0001). In 205 cases with NE differentiation, Reg IV-positive cases expressed serotonin (P= 0.0032) and somatostatin (P= 0.036) more frequently than Reg IV-negative cases. Double immunofluorescence staining revealed co-expression of Reg IV with gastrin, serotonin and PP. These results indicate that Reg IV might be a mediating factor of several NE hormones.

Topics: Calcitonin; Chromogranin A; Gastrins; Humans; Immunohistochemistry; Lectins, C-Type; Neurosecretory Systems; Pancreatic Polypeptide; Pancreatitis-Associated Proteins; Serotonin; Somatostatin; Stomach Neoplasms; Synaptophysin; Tissue Array Analysis

While the optimal treatment for type I gastric carcinoid tumors remains controversial, there is evidence to suggest that in multifocal disease, antrectomy may not only control local disease but also may lead to enterochromaffin-like cell (ECL) hyperplasia regression compared to medical and endoscopic treatments.. A single institution retrospective review of eight consecutive patients with multifocal type I gastric carcinoid tumor patients with no evidence of metastatic disease was performed from 2005 to 2006. All of these patients underwent laparoscopic antrectomy with Billroth II reconstruction. Patients' preoperative gastrin, chromogranin A levels, and biopsy and surgical specimen slides were compared with postoperative laboratory and biopsy slides. Pathology slides were reanalyzed by a blinded pathologist from our institution for evidence of tumor and ECL hyperplasia regression.. All patients tolerated the procedure well with no reoperations or mortalities. Six of eight patient complained of mild reflux which was treated medically. One of eight had a mild wound infection which resolved with a course of cephalexin. Gastrin levels significantly decreased (98.9%) in all patients (P = 0.001). Furthermore, chromogranin A levels also significantly decreased (81.4%). Eight of eight patients showed no evidence of carcinoid tumor after surgery at mean biopsy follow-up of 17 mo (range 2-35 mo), however there was ECL hyperplasia after resection. Four of eight patients (50%) showed regression of ECL hyperplasia on postop biopsy, while the remaining four of eight showed no evidence of regression.. This is the largest case series to investigate the surgical, clinical, and histologic outcomes of laparoscopic antrectomy in type I gastric carcinoid. Our data suggest that laparoscopic antrectomy is a safe and minimally invasive approach to treat nonmetastatic type I gastric carcinoid. All patients had no evidence of gross or microscopic disease at follow-up biopsy and almost half had regression of ECL hyperplasia at follow-up suggesting that antrectomy may be sufficient to prevent tumor recurrence. However, continued regular endoscopic surveillance and medical follow-up of patients with ECL hyperplasia are recommended.

Topics: Adult; Aged; Carcinoid Tumor; Enterochromaffin-like Cells; Female; Gastrins; Humans; Hyperplasia; Laparoscopy; Male; Middle Aged; Pyloric Antrum; Retrospective Studies; Stomach Neoplasms

Helicobacter pylori (H pylori) infection is a major risk factor in the development of distal gastric adenocarcinoma. Development of the invasive phenotype is associated with the phenomenon of epithelial:mesenchymal transition (EMT). Soluble heparin-binding epidermal growth factor (HB-EGF) has been implicated in this process. A study was undertaken to investigate the possibility that matrix metalloproteinase (MMP)-7 is upregulated in H pylori infection as a result of hypergastrinaemia, which may enhance shedding of HB-EGF and contribute towards EMT in gastric adenocarcinoma cell lines.. Three gastric epithelial cell lines (AGS, MGLVA1 and ST16) were co-cultured with the pathogenic H pylori strain 60190 and non-pathogenic strain Tx30a in an in vitro infection model. Gene expression was quantified by real-time PCR, HB-EGF shedding by ELISA and protein expression by immunofluorescence or immunohistochemistry. The INS-GAS mouse, a transgenic mouse model of gastric carcinogenesis which overexpresses amidated gastrin, was used to investigate the in vivo relationship between HB-EGF, MMP-7, gastrin and EMT.. The pathogenic strain of H pylori significantly upregulated EMT-associated genes Snail, Slug and vimentin in all three gastric cell lines to a greater degree than the non-pathogenic strain. Pathogenic H pylori also upregulated HB-EGF shedding, a factor implicated in EMT, which was partially dependent on both gastrin and MMP-7 expression. Gastrin and MMP-7 siRNAs and MMP-7 neutralising antibody significantly reduced upregulation of HB-EGF shedding in H pylori infected gastric cell lines and reduced EMT gene expression. The effect of H pylori on EMT was also reversed by gastrin siRNA. Neutralisation of gastrin in the INS-GAS mouse model reduced expression of MMP-7, HB-EGF and key EMT proteins.. The upregulation of MMP-7 by pathogenic H pylori is partially dependent on gastrin and may have a role in the development of gastric cancer, potentially through EMT, by indirectly increasing levels of soluble HB-EGF.

Topics: Animals; Cell Transformation, Neoplastic; Coculture Techniques; Disease Models, Animal; Epithelial Cells; Gastrins; Gene Expression Regulation, Neoplastic; Helicobacter Infections; Helicobacter pylori; Heparin-binding EGF-like Growth Factor; Humans; Intercellular Signaling Peptides and Proteins; Matrix Metalloproteinase 7; Mesenchymal Stem Cells; Mice; Mice, Transgenic; Neoplasm Proteins; Reverse Transcriptase Polymerase Chain Reaction; RNA, Small Interfering; Stomach Neoplasms; Tumor Cells, Cultured; Up-Regulation; Virulence

Autoimmune metaplastic atrophic gastritis (AMAG) is an early manifestation of pernicious anemia that precedes the hematologic changes by years to decades. It is associated with metaplastic changes and neoplasms, including pyloric gland adenomas (PGAs). We investigated the frequency of PGAs and other lesions in all nonconsultation gastric biopsies and resections (1988 to 2008) diagnosed as AMAG. We further selected cases confirmed as AMAG by immunohistochemical identification of the gastric body (negative gastrin) and linear and nodular enterochromaffin-like cell hyperplasia (chromogranin). From this subset, all polyps and neoplasms were reviewed. We identified a total of 41,245 patients with gastric biopsies or resections from 46.7% males and 53.3% females comprising patients self-identified as 67.0% white, 23.6% African-American, 1.4% Asian, 0.8% non-White Hispanic, and 7.2% other or unknown. AMAG was diagnosed in 461 patients (1.1%), and had the following percentages based on race: 1.1% White, 1.3% African-American, 1.4% Asian, and 2.7% non-White Hispanic. The female:male ratio was 2:1 with an overall median age at presentation of 67.0 years. Of the 461 patients with AMAG, 143 had endoscopically identifiable lesions. These lesions (n=240) consisted of 179 polyps (138 hyperplastic polyps, 20 oxyntic mucosa pseudopolyps, 18 intestinal-type gastric adenomas, and 3 PGAs), 46 well-differentiated neuroendocrine neoplasms (carcinoid), 1 gastrointestinal stromal tumor, 3 lymphomas, and 11 adenocarcinomas. In summary, AMAG occurred with similar frequency across all racial groups. Although PGAs are associated with AMAG, they remain rare in the setting of AMAG.

Topics: Adenoma; Aged; Autoimmune Diseases; Baltimore; Biopsy; Chromogranins; Female; Gastrectomy; Gastric Mucosa; Gastrins; Gastritis, Atrophic; Humans; Immunohistochemistry; Male; Metaplasia; Middle Aged; Polyps; Precancerous Conditions; Stomach; Stomach Neoplasms

To study the regulatory effect of Helicobacter pylori CagA protein on gastrin promoter and the related signaling pathways as to further elucidate the mechanism of the development and progression of human gastric carcinoma.. After pcDNA3.1ZEO(-)/CagAand PGL/GP were identified by double restriction enzyme digestion, PCR and sequencing, the gastric cancer cell lines AGS and SGC-7901 cells were co-transfected with pcDNA3.1ZEO(-)/CagA and PGL/GP for 48 h. Alternatively, AGS and SGC-7901 cells were transfected by PGL/GP for 36 h later, and infected with Helicobacter pylori for additional 12 h. Meanwhile, the transfected and infected cells were treated using the JAK2 signaling pathway inhibitor AG490 and the ERK signaling pathway inhibitor U0126. The untreated cells and empty-vector-transfected cells were used as the control. Finally, luciferase activity was detected using the luciferase reporter assay system in transfected and infected cells. The levels of gastrin mRNA was determined by TaqMan® real-time quantitative PCR.. After co-transfection with pcDNA3.1ZEO(-)/CagA and PGL/GP, the activities of luciferase were increased by 251.3, 106.1 and 2.4 times in AGS cells and 35.8, 22.7 and 13.4 times in SGC-7901 cells, respectively, as compared with that of the control, pcDNA3.1 ZEO(-)/CagA + PGL3/Basic and pcDNA3.1 ZEO(-) + PGL/GP groups. The activities of luciferase in PGL/GP transfection and HP infection group were also increased by 1673.2, 33.5, 1.4 times in AGS cells and 1180.2, 72.2 and 1.5 times in SGC-7901 cells, respectively, as compared with that of the control, PGL3/Basic + HP and PGL/GP groups. There were statistically significant differences between them (P < 0.05), which suggested that the transcription activity of gastrin promoter increased significantly. But after adding the inhibitor AG490 and U0126, respectively, the activities of luciferase were significantly decreased by 95.7% (U0126) and 33.0% (AG490) in co-transfected AGS cells and 94.8% (U0126) and 86.2% (AG490) in co-transfected SGC-7901 cells with pcDNA3.1ZEO(-)/CagA and PGL/GP (P < 0.05). In the PGL/GP transfection and HP infection group, the activities of luciferase were significantly decreased by 24.6% (U0126) and 25.8% (AG490) in AGS cells and 57.3% (U0126) and 14.1% (AG490) after adding the inhibitor AG490 and U0126, respectively (P < 0.05). The results showed that the gastrin promoter activities were significantly inhibited. The gastrin mRNA levels were 3.0 and 4.5 times higher in HP-infected AGS and SGC-7901 cells, respectively, than that in the control groups. In the cells transfected with pcDNA3.1ZEO(-)/CagA, the gastrin mRNA levels were raised 10.8 and 2.3 times (AGS cells) and 10.9 and 16.2 times (SGC-7901 cells), respectively, as compared with that of control and pcDNA3.1ZEO(-) groups. All of the differences were statistically significant (P < 0.05).. These results suggest that CagA may activate the gastrin promoter and up-regulate the expression of gastrin gene, and CagA is one of the important proteins in regulating gastrin gene expression. The ERK/MAPK and JAK/STAT signaling pathways may be involved in the controlling of gastrin gene expression by CagA.

Topics: Antigens, Bacterial; Antineoplastic Agents; Bacterial Proteins; Butadienes; Cell Line, Tumor; Enzyme Inhibitors; Gastrins; Gene Expression Regulation, Neoplastic; Genetic Vectors; Helicobacter Infections; Helicobacter pylori; Humans; Nitriles; Promoter Regions, Genetic; RNA, Messenger; Stomach Neoplasms; Transfection; Tyrphostins; Up-Regulation

To investigate the effect of a high-protein diet on corpus atrophic gastritis in Helicobacter pylori-infected Mongolian gerbils, H. pylori was administered orally to 5-wk-old Mongolian gerbils; and the animals were then fed a control diet (Group C); a high-fat diet (Group F: 40% fat); a high-protein diet (Group P: 32% protein); or a high-fat, high-protein diet (Group FP: 40% fat, 32% protein) for 50 wk beginning at 7 wk of age. In uninfected animals, the mucosal thickness of the corpus was significantly greater in Group P and Group FP than in Group C (P < 0.05). In infected animals, the serum gastrin level was significantly decreased in Group FP and marginally significantly decreased in Group P (P = 0.057) in comparison to Group C. The mucosal thickness of the corpus was significantly greater in Group P and Group FP than in Group C (P < 0.05). Mean inflammation and atrophy scores in the corpus were significantly lower in the high-protein groups (Groups P and FP) than in the control groups (Groups C and F; both inflammation and atrophy: P < 0.05). In conclusion, long-term administration of a high-protein diet suppresses corpus atrophic gastritis in H. pylori-infected Mongolian gerbils.

Topics: Animals; Antibodies, Bacterial; Body Weight; Caseins; Dietary Fats; Dietary Proteins; Gastric Fundus; Gastric Mucosa; Gastrins; Gastritis, Atrophic; Gerbillinae; Helicobacter Infections; Helicobacter pylori; Male; Metaplasia; Organ Size; Severity of Illness Index; Specific Pathogen-Free Organisms; Stomach; Stomach Neoplasms

Carcinoid is a rare gastrointestinal tumor, with an incidence varying from 1 to 2.5 per 100,000 in the general population. In this article, we report an elevated incidence of carcinoid tumor in an obese population, showing the importance of performing an endoscopic procedure before bariatric surgery.

Topics: Adult; Bariatric Surgery; Carcinoid Tumor; Duodenal Neoplasms; Endoscopy, Digestive System; Female; Gastrectomy; Gastrins; Hepatectomy; Humans; Hysterectomy; Incidental Findings; Liver Neoplasms; Male; Middle Aged; Obesity, Morbid; Preoperative Care; Stomach Neoplasms; Uterine Neoplasms; White People

Female Japanese cotton rats become hypoacidic and hypergastrinaemic from age 2 months and later develop gastric carcinomas in the oxyntic mucosa. Previous studies have demonstrated that carcinogenesis can be halted by a gastrin receptor antagonist and that carcinomas can be induced by a histamine-2 receptor antagonist or partial corpectomy, both of which induce hypergastrinaemia. The aim of the present study was to examine the effect of antrectomy in female cotton rats.. The animals were either antrectomized (Group 1) or sham-operated (Group 2) 2 months after detection of hypergastrinaemia and terminated 4 months after operation. A third group was antrectomized at age 2 months while still normo-acidic (Group 3) and terminated 6 months after operation.. Antrectomy after 2 months of hypergastrinaemia prevented the development of carcinoma compared with in sham-operated animals, whereas some of the animals that were antrectomized at 2 months of age also developed carcinomas. In Groups 1 and 2 as well as in animals developing carcinomas in Group 3, there was marked hyperplasia of neuroendocrine cells in the oxyntic mucosa expressing chromogranin A, vesicular monoamine transporter (VMAT)-2, ghrelin and somatostatin. Gastrin-positive cells were found adjacent to neoplastic areas in the oxyntic mucosa.. The removal of antral gastrin by antrectomy halts carcinogenesis in cotton rats, but other mechanisms may also play a role.

Topics: Animals; Carcinoma; Disease Models, Animal; Female; Gastrectomy; Gastrins; Hormones; Pyloric Antrum; Sigmodontinae; Stomach Neoplasms

To study the value of serum biomarker tests to differentiate between patients with healthy or diseased stomach mucosa: i.e. those with Helicobacter pylori (H pylori) gastritis or atrophic gastritis, who have a high risk of gastric cancer or peptic ulcer diseases.. Among 162 Japanese outpatients, pepsinogen I (Pg I) and II (Pg II) were measured using a conventional Japanese technique, and the European GastroPanel examination (Pg I and Pg II, gastrin-17 and H pylori antibodies). Gastroscopy with gastric biopsies was performed to classify the patients into those with healthy stomach mucosa, H pylori non-atrophic gastritis or atrophic gastritis.. Pg I and Pg II assays with the GastroPanel and the Japanese method showed a highly significant correlation. For methodological reasons, however, serum Pg I, but not Pg II, was twice as high with the GastroPanel test as with the Japanese test. The biomarker assays revealed that 5% of subjects had advanced atrophic corpus gastritis which was also verified by endoscopic biopsies. GastroPanel examination revealed an additional seven patients who had either advanced atrophic gastritis limited to the antrum or antrum-predominant H pylori gastritis. When compared to the endoscopic biopsy findings, the GastroPanel examination classified the patients into groups with "healthy" or "diseased" stomach mucosa with 94% accuracy, 95% sensitivity and 93% specificity.. Serum biomarker tests can be used to differentiate between subjects with healthy and diseased gastric mucosa with high accuracy.

Topics: Adult; Aged; Biopsy; Diagnosis, Differential; Gastrins; Gastritis; Gastritis, Atrophic; Helicobacter Infections; Helicobacter pylori; Humans; Japan; Middle Aged; Outpatients; Pepsinogen A; Pepsinogen C; Peptic Ulcer; Prevalence; Reference Values; Risk Factors; Stomach; Stomach Neoplasms; Young Adult

Surveillance of intestinal metaplasia (IM) of the gastric mucosa should be limited to patients at high risk of gastric cancer. Patients with extensive IM are at increased cancer risk; however, the intragastric extent of IM is usually unknown at the time of the initial diagnosis.. To assess the predictive value of clinical, histologic, and serologic parameters for the intragastric extent of IM.. Prospective, multicenter study.. Eighty-eight patients with a previous diagnosis of IM of the gastric mucosa.. Surveillance gastroscopy with extensive random biopsy sampling.. Biopsy specimens were evaluated according to the Sydney classification system. In addition, serologic testing of Helicobacter pylori and cagA status, pepsinogens I and II, gastrin, and intrinsic factor antibodies was performed. The association between the available parameters and extensive IM was evaluated with logistic regression analysis.. In 51 patients (58%), IM was present in the biopsy specimens from at least 2 intragastric locations. The most important predictors of extensive IM were a family history of gastric cancer, alcohol use > or = 1 unit/d (1 glass, approximately 10 mL or 8 g ethanol), moderate or marked IM of the index biopsy specimen, and a pepsinogen I to II ratio < 3.0. A simple risk score based on these factors could identify extensive IM in 24 of 25 patients (sensitivity 96%).. A prospective cohort study should confirm the proposed risk stratification.. A risk score of clinical, histologic, and serologic parameters can predict extensive intragastric IM and may serve as a practical tool to select patients for surveillance endoscopy in routine clinical practice.

Topics: Adult; Aged; Antibodies, Bacterial; Antigens, Bacterial; Bacterial Proteins; Biopsy; Endoscopy, Gastrointestinal; Enzyme-Linked Immunosorbent Assay; Female; Follow-Up Studies; Gastric Mucosa; Gastrins; Helicobacter pylori; Humans; Intrinsic Factor; Male; Metaplasia; Middle Aged; Pepsinogen A; Pepsinogen C; Precancerous Conditions; Prognosis; Prospective Studies; Risk Factors; Stomach Neoplasms; Surveys and Questionnaires; Time Factors; Young Adult

Infection with Helicobacter pylori, carrying a functional cag type IV secretion system (cag-T4SS) to inject the Cytotoxin associated antigen (CagA) into gastric cells, is associated with an increased risk for severe gastric diseases in humans. Here we studied the pathomechanism of H. pylori and the role of the cag-pathogenicity island (cag-PAI) for the induction of gastric ulcer and precancerous conditions over time (2-64 weeks) using the Mongolian gerbil model. Animals were challenged with H. pylori B128 (WT), or an isogenic B128DeltacagY mutant-strain that produces CagA, but is unable to translocate it into gastric cells. H. pylori colonization density was quantified in antrum and corpus mucosa separately. Paraffin sections were graded for inflammation and histological changes verified by immunohistochemistry. Physiological and inflammatory markers were quantitated by RIA and RT-PCR, respectively. An early cag-T4SS-dependent inflammation of the corpus mucosa (4-8 weeks) occurred only in WT-infected animals, resulting in a severe active and chronic gastritis with a significant increase of proinflammatory cytokines, mucous gland metaplasia, and atrophy of the parietal cells. At late time points only WT-infected animals developed hypochlorhydria and hypergastrinemia in parallel to gastric ulcers, gastritis cystica profunda, and focal dysplasia. The early cag-PAI-dependent immunological response triggers later physiological and histopathological alterations towards gastric malignancies.

Topics: Achlorhydria; Animals; Antigens, Bacterial; Bacterial Proteins; Cytokines; Gastrins; Gastritis; Genomic Islands; Gerbillinae; Helicobacter Infections; Helicobacter pylori; Hypertrophy; Immunoenzyme Techniques; Precancerous Conditions; Radioimmunoassay; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Somatostatin; Stomach Neoplasms; Stomach Ulcer

We have previously described a synergistic interaction between hypergastrinemia and Helicobacter felis infection on gastric corpus carcinogenesis in FVB/N mice housed under specific-pathogen-free conditions. However, gastrin-deficient (GAS-KO) mice on a mixed C57BL/6/129Sv genetic background maintained in conventional housing were reported to develop spontaneous gastric antral tumors. Therefore, we investigated the role of gastrin in Helicobacter-associated gastric carcinogenesis in H. felis-infected mice on a uniform C57BL/6 background housed in specific-pathogen-free conditions. Hypergastrinemic transgenic (INS-GAS) mice, GAS-KO mice, and C57BL/6 wild-type mice were infected with H. felis for either 12 or 18 months. At 12 months postinfection, INS-GAS mice had mild corpus dysplasia, while B6 wild-type mice had either severe gastritis or metaplasia, and GAS-KO mice had only mild to moderate gastritis. At 18 months postinfection, both INS-GAS and B6 wild-type mice had both severe atrophic gastritis and corpus dysplasia, while GAS-KO mice had severe gastritis with mild gastric atrophy, but no corpus dysplasia. In contrast, both GAS-KO and B6 wild-type mice had mild to moderate antral dysplasia, while INS-GAS mice did not. H. felis antral colonization remained stable over time among the three groups of mice. These results point to a distinct effect of gastrin on carcinogenesis of both the gastric corpus and antrum, suggesting that gastrin is an essential cofactor for gastric corpus carcinogenesis in C57BL/6 mice.

Topics: Animals; Cytokines; Female; Gastrins; Gastritis; Helicobacter felis; Helicobacter Infections; Immunohistochemistry; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Precancerous Conditions; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Stomach Neoplasms; T-Lymphocytes, Helper-Inducer

Gastric carcinoid tumors are rare but increasing in incidence. Current recommendations suggest endoscopic resection for type I carcinoids found in the stomach, however reports of incomplete resection have led to difficulty planning future management. Our purpose was to describe the application of the endoscopic multi-band mucosectomy (MBM) device to achieve en-bloc resection of multiple gastric carcinoid tumors.. Over a 30-month period (June 2006-January 2009) eight patients attending for endoscopic assessment of gastric carcinoid tumors were identified at two tertiary referral centers. Patients underwent endoscopic resection of the carcinoids with an MBM device. En-bloc specimens underwent histological evaluation for identification and tumor resection margins. Patients with type I carcinoids were subsequently enrolled in an endoscopic follow-up program.. A total of 34 gastric carcinoid tumors were removed from eight patients. On histological analyses seven out of eight patients were diagnosed with type I tumors. In the remaining patient a single, sporadic (type III) gastric carcinoid was diagnosed. No complications of severe bleeding or perforation occurred. All specimens were shown to have clear deep and peripheral histological resection margins.. Complete 'en-bloc' endoscopic resection of multiple 'type I' gastric carcinoid tumors can be safely and easily performed with an MBM technique.

Topics: Adult; Aged; Australia; Biomarkers; Biopsy; Carcinoid Tumor; Female; Gastric Mucosa; Gastrins; Gastroscopy; Humans; Male; Middle Aged; Neoplasms, Multiple Primary; Stomach Neoplasms; Treatment Outcome; Vitamin B 12

We describe a 30-year-old man in whom upper endoscopy revealed multiple gastric carcinoids. The peripheral blood gastrin level was 2400 ng/ml (normal range, <200 ng/ml). Mucosal biopsy of the gastric body and fundus showed no atrophy; typical type A chronic atrophic gastritis was thus unlikely. Neither abdominal computed tomography nor selective angiography showed any evidence of tumor in the pancreas or at its periphery. However, the possibility of microgastrinoma could not be ruled out. We performed radioguided surgery with a somatostatin analog, diethylenetriamine pentaacetic acid-D-Phe1-octreotide labeled with (111)In (Octreo Scan). The location of the carcinoids was confirmed. Gastrinoma was ruled out. Total gastrectomy was performed, and the gastrin level decreased to the normal range. Macroscopically, 20 carcinoid tumors, measuring 30 mm in maximum diameter, were confirmed. Microscopic examination showed large numbers of endocrine cell micronests. Hyperplasia of parietal cells was observed, suggesting early-stage type A chronic atrophic gastritis. The antrum contained increased numbers of gastrin-positive cells, which probably caused the preoperative hypergastrinemia.

Topics: Adult; Carcinoid Tumor; Gastrectomy; Gastrins; Gastritis, Atrophic; Humans; Hyperplasia; Male; Parietal Cells, Gastric; Radiopharmaceuticals; Somatostatin; Stomach Neoplasms; Surgery, Computer-Assisted

To study the change of the serum gastrin (GAS) and plasma motilin (MTL) levels as well as the gastric motility in gastric cancer patients after subtotal gastrectomy.. We used radioimmunoassay method to detect the levels of serum GAS and plasma MTL in 39 healthy volunteers (control group) and 39 gastric cancer patients before and after gastrectomy (gastric cancer group). Electrogastrography (EGG) was measured at the same time points.. The levels of serum GAS and plasma MTL in gastric cancer group before operation were significantly higher than those in control group (P = 0.000), and the levels of serum GAS and plasma MTL in gastric cancer stage II patients were also significantly higher than those in stage III patients (P <0.05). The levels of serum GAS and plasma MTL in gastric cancer group significantly decreased on the first post-operative day (P = 0.000), but returned to the pre-operative levels on the seventh post-operative day. The incidence of the abnormity of gastric motility in gastric cancer group on the seventh post-operative day was significantly higher than the pre-operation incidence (89.7% vs. 43.6%; chi2 = 18.692, P <0.01).. The levels of serum GAS and plasma MTL transiently decreased in gastric cancer patients. Subtotal gastrectomy could affect the gastric motility in gastric cancer patients.

Topics: Adult; Aged; Female; Gastrectomy; Gastrins; Gastrointestinal Motility; Humans; Male; Middle Aged; Motilin; Radioimmunoassay; Stomach Neoplasms; Treatment Outcome

Elevated serum concentrations of the hormone gastrin are associated with the development of gastric carcinoid tumors, but the mechanisms of tumor development are not fully understood. We hypothesized that the antiapoptotic effects of gastrin may be implicated and have therefore investigated the role of antiapoptotic members of the bcl-2 family of proteins. AGS-G(R) human gastric carcinoma cells stably transfected with the CCK-2 receptor were used to assess changes in the expression of bcl-2 family members following gastrin treatment and the function of mcl-1 during apoptosis was investigated by use of small-interfering RNA (siRNA). Treatment of AGS-G(R) cells with 10 nM gastrin for 6 h caused maximally increased mcl-1 protein abundance. Gastrin-induced mcl-1 expression was inhibited by the transcription inhibitor actinomycin D and by the protein synthesis inhibitor cycloheximide. Downstream signaling of mcl-1 expression occurred via the CCK-2 receptor, protein kinase C, and MAP kinase pathways, but not via PI 3-kinase. Transfection with mcl-1 siRNA significantly suppressed mcl-1 protein expression and abolished the antiapoptotic effects of gastrin on serum starvation-induced apoptosis. Mcl-1 protein expression was also specifically increased in the type I enterochromaffin-like cell carcinoid tumors of 10 patients with autoimmune atrophic gastritis and hypergastrinemia. Gastrin therefore signals via the CCK-2 receptor, protein kinase C, and MAP kinase to induce expression of antiapoptotic mcl-1 in AGS-G(R) cells, and mcl-1 expression is also increased in human hypergastrinemia-associated type I gastric carcinoid tumors. Gastrin-induced mcl-1 expression may therefore be an important mechanism contributing toward type I gastric carcinoid development.

Topics: Adult; Aged; Aged, 80 and over; Blotting, Western; Carcinoid Tumor; Cell Line, Tumor; Female; Gastrins; Humans; Immunohistochemistry; Male; Middle Aged; Myeloid Cell Leukemia Sequence 1 Protein; Proto-Oncogene Proteins c-bcl-2; Receptor, Cholecystokinin B; Stomach Neoplasms

We previously showed that antral gastric tumors develop in gastrin-deficient (Gas(-/-)) mice. Therefore Gas(-/-) mice were studied sequentially over 12 months to identify molecular mechanisms underlying gastric transformation. Fundic atrophy developed by 9 months in Gas(-/-) mice. Antral mucosal hyperplasia developed coincident with the focal loss of TFF1 and Muc5AC. Microarray analysis of 12 month Gas(-/-) tumors revealed an increase in follistatin, an activin/BMP antagonist. We found that elevated follistatin expression occurred in the proliferative neck zone of hyperplastic antrums, in antral tumors of Gas(-/-) mice, and also in human gastric cancers. Follistatin induced cyclin D1 and the trefoil factors TFF1 and TFF2 in a gastric cancer cell line. We concluded that antral hyperplasia in Gas(-/-) mice involves amplification of mucous cell lineages due to follistatin, suggesting its role in the development of antral gastric tumors.

Topics: Animals; Cell Line, Tumor; Cell Transformation, Neoplastic; Cyclin D1; Follistatin; Gastric Mucosa; Gastrins; Hyperplasia; Mice; Mice, Knockout; Mucins; Muscle Proteins; Peptides; Pyloric Antrum; Stomach Neoplasms; Trefoil Factor-1; Trefoil Factor-2

Gastrointestinal stromal tumor is the most common mesenchymal tumor in the gastrointestinal tract. It may coexist with other type of cancers, and if so, the tumors usually involve the stomach. The most common associated cancers are gastrointestinal carcinomas. We report a 65-year-old woman with a history of gastric gastrointestinal stromal tumor who had undergone subtotal segmental gastrectomy. New polypoid lesions were detected on a follow-up gastroscopy one year later. The lesions were biopsied and found to be carcinoid tumors. There was serum hypergastrinemia, and type 1 gastric carcinoid tumor was diagnosed. A total gastrectomy was performed. Pathologic examination revealed both carcinoid tumors and a recurrent gastrointestinal stromal tumor.

Topics: Aged; Biopsy; Carcinoid Tumor; Female; Gastrectomy; Gastrins; Gastrointestinal Stromal Tumors; Gastroscopy; Humans; Lymph Node Excision; Lymphatic Metastasis; Neoplasm Recurrence, Local; Neoplasms, Second Primary; Reoperation; Stomach Neoplasms; Up-Regulation

Gastrin is one of the most important gut hormones. However, the role of the gastrin-gastrin receptor (GR) system in the growth of gastric tumors is still unclear.. We examined serum gastrin levels in 957 patients with early gastric carcinoma. Next, we raised antibody against the GR and examined GR expression in 5 gastric carcinoma cell lines and 48 human gastric tumor tissues. In 28 cases, Helicobacter pylori eradication therapy was performed and morphological tumor changes were examined.. Serum gastrin levels were significantly higher in patients with elevated tumors than in patients with depressed tumors (p = 0.02). All gastric carcinoma cell lines expressed GR. Thirty-one of 48 (65%) gastric tumors expressed GR, and its expression was prominent in elevated-type tumor with an intestinal histologic feature. Of 28 patients who underwent eradication therapy, 9 showed gastric tumors that became flat or depressed. In these 9 cases, GR expression was detected in all tumors, and the decrease in gastrin levels was more prominent than in those without morphological change (p = 0.01).. The gastrin-GR system plays an important role in the elevated morphology of gastric tumors.

Topics: Aged; Female; Gastrins; Humans; Male; Receptor, Cholecystokinin B; Stomach Neoplasms

Topics: Adult; Biopsy; Carcinoid Tumor; Chronic Disease; Female; Follow-Up Studies; Gastrectomy; Gastrins; Gastritis, Atrophic; Humans; Lymph Node Excision; Neoplasms, Multiple Primary; Radiography, Abdominal; Stomach; Stomach Neoplasms; Time Factors; Tomography, X-Ray Computed; Treatment Outcome

Cancer of stomach is currently regarded as the final result of a staged multifactor process during which the microenvironment affects cells and causes their changes. One of the main triggering factors is Hp infection. Adenocarcinoma of stomach develops via stages of gastritis, precancerous changes, and cancer. The possibility to prevent cancer ensues from the potential irreversibility of premalignant processes in gastric mucosa, in the first place its atrophy; hence, the importance of its early diagnosis. The state of the endoscopic service in this country is inadequate for mass screening of patients with symptoms of dyspepsia. "GastroPanel", a new serological test for the diagnosis of gastric pathology provides information about histological and functional characteristics of gastric mucosa in the antral and fundal regions of the stomach. The method determines serum gastrin-17, pepsinogen-1, and IgG expressed in response to Hp infection. Our results demonstrate high diagnostic efficiency of "GastroPanel" as a screening technique for atrophic gastritis and assessment of stomach cancer risk.

Topics: Adolescent; Adult; Aged; Female; Gastrins; Gastritis, Atrophic; Helicobacter Infections; Helicobacter pylori; Humans; Male; Mass Screening; Middle Aged; Neoplasm Staging; Pepsinogen A; Peptide Fragments; Stomach Neoplasms; Young Adult

Topics: Carcinoid Tumor; Female; Gastrins; Gastritis, Atrophic; Humans; Kidney Failure, Chronic; Kidney Transplantation; Middle Aged; Remission Induction; Stomach; Stomach Neoplasms

Our previous work revealed that gastrin regulates chromogranin A (CgA) transcription through enhanced binding of Sp1, CREB and Egr-1 to a proximal gastrin-responsive promoter element (Gas-RE). Here, we provide a detailed characterization of the signalling pathways transmitting the effect of gastrin on the CgA promoter. Gastrin treatment of gastric AGS-B cells potently stimulated MEK-1 as well as MAP kinases ERK-1/-2, JNK and p38 in a time-dependent manner. Interruption of ERK-1/-2/MEK-1 pathways abolished the transactivating effect of gastrin, whereas blockade of JNK or p38 activity was without effect. Functional promoter analysis revealed that the minimal element CgA-85/-64 was sufficient and necessary to confer MEK-1/ERK responsiveness. Analysis of proximal signalling pathways showed that activation of the MEK-1/ERK-1/2 module by gastrin does not require Ras, PI3-kinase or intracellular calcium signals, but depends on activation of kinases of the PKC family. This report demonstrates that a pathway comprising PKCs>Raf-1>MEK-1>ERK-1/-2 mediates the effect of gastrin on the CgA promoter, and strongly suggests that enhanced phosphorylation of Sp1 and CREB is crucial for CgA transactivation through the G protein-coupled CCK-B/gastrin receptor.

Topics: Adenocarcinoma; Calcium; Cell Line, Tumor; Chromogranin A; CREB-Binding Protein; Extracellular Signal-Regulated MAP Kinases; Gastrins; Gene Expression Regulation; Humans; MAP Kinase Kinase 1; Phosphatidylinositol 3-Kinases; Phosphorylation; Protein Kinase C; Receptor, Cholecystokinin B; Signal Transduction; Sp1 Transcription Factor; Stomach Neoplasms

Plasma concentrations of the hormone gastrin are elevated by Helicobacter pylori infection and by gastric atrophy. It has previously been proposed that gastrin acts as a cofactor during gastric carcinogenesis and hypergastrinemic transgenic INS-GAS mice are prone to developing gastric adenocarcinoma, particularly following H. pylori infection. We hypothesised that the increased risk of carcinogenesis in these animals may partly result from altered susceptibility of gastric epithelial cells to undergo apoptosis. Gastric corpus apoptosis was significantly increased 48 h after 12Gy gamma-radiation in mice rendered hypergastrinemic by transgenic (INS-GAS) or pharmacological (omeprazole treatment of FVB/N mice) methods and in both cases the effects were inhibited by the CCK-2 receptor antagonist YM022. However, no alteration in susceptibility to gamma-radiation-induced gastric epithelial apoptosis was observed in mice overexpressing progastrin or glycine-extended gastrin. Apoptosis was also significantly increased in gastric corpus biopsies obtained from H. pylori-infected humans with moderate degrees of hypergastrinemia. We conclude that hypergastrinemia specifically renders cells within the gastric corpus epithelium more susceptible to induction of apoptosis by radiation or H. pylori. Altered susceptibility to apoptosis may therefore be one factor predisposing to gastric carcinogenesis in INS-GAS mice and similar mechanisms may also be involved in humans.

Topics: Animals; Anti-Ulcer Agents; Apoptosis; Benzodiazepines; Cells, Cultured; Disease Susceptibility; Gamma Rays; Gastric Mucosa; Gastrins; Helicobacter pylori; Humans; Mice; Mice, Transgenic; Omeprazole; Receptor, Cholecystokinin B; Stomach Neoplasms

Oxidative stress is linked to gastric carcinogenesis because of its ability to damage DNA. Here we examined antioxidative and anti-inflammatory effects of 4-vinyl-2,6-dimethoxyphenol (canolol), a recently identified potent antioxidative compound obtained from crude canola oil, on Helicobacter (H.) pylori-induced gastritis and gastric carcinogenesis using a Mongolian gerbil model. The animals were allocated to H. pylori-infection alone (12 weeks) or H.pylori + N-methyl-N-nitrosourea (MNU) administration (52 weeks). After oral inoculation of H. pylori, they were fed for 10 and 44 weeks with or without 0.1% canolol. H. pylori-induced gastritis, 5'-bromo-2'-deoxyuridine (BrdU) labeling and scores for cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) immunohistochemistry were attenuated in the canolol-treated groups. Expression of interleukin-1 beta (IL-1 beta), tumor necrosis factor-alpha (TNF-alpha), COX-2 and iNOS mRNA in the gastric mucosa, and serum 8-hydroxy-2'-deoxyguanosine (8-OHdG), anti-H. pylori IgG and gastrin levels were also significantly lower in canolol-treated groups. Furthermore, the incidence of gastric adenocarcinomas was markedly reduced in the H. pylori + MNU + canolol-treated group [15.0% (6/40)] compared to the control group [39.4% (13/33)] (p < 0.05). These data indicate canolol to be effective for suppressing inflammation, gastric epithelial cell proliferation and gastric carcinogenesis in H. pylori-infected Mongolian gerbils. Interestingly, the viable H. pylori count was not changed by the canolol containing diet. Thus, the data point to the level of inflammation because of H. pylori rather than the existence of the bacteria as the determining factor. Importantly, canolol appears to suppress induction of mRNAs for inflammatory cytokines.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Anti-Inflammatory Agents; Antibodies, Bacterial; Antioxidants; Biomarkers; Cell Proliferation; Cell Transformation, Neoplastic; Cyclooxygenase 2; Deoxyguanosine; Disease Models, Animal; Gastric Mucosa; Gastrins; Gastritis; Gerbillinae; Helicobacter Infections; Helicobacter pylori; Immunoglobulin G; Immunohistochemistry; Interleukin-1beta; Nitric Oxide Synthase Type II; Oxidative Stress; Phenols; Polymerase Chain Reaction; RNA, Messenger; Stomach Neoplasms; Tumor Necrosis Factor-alpha; Vinyl Compounds

Gastrin contributes to the growth and proliferation of gastric cancer cells and it is related to the effect of tyrosine kinase. This study was to investigate the effect of gastrin on tyrosine phosphorylation of focal adhesion kinase (FAK) in human gastric cancer cell line SGC7901.. The vector pCR3.1/GR, that expresses human gastrin receptor (GR) stably, was transfected into SGC7901 cells (SGC7901-GR). The expression of GR was tested by reverse transcription-polymerase chain reaction (RT-PCR). SGC7901-GR and SGC7901 cells were treated with L-365260, an antagonist of GR, and stimulated with gastrin at different concentrations for different time. The tyrosine phosphorylation level of FAK was detected by immunoprecipitation and Western blot.. When treated with different concentrations of gastrin for 1 min, the tyrosine phosphorylation levels of FAK were significantly higher in SGC7901-GR cells than in SGC7901 cells (0.64+/-0.06 vs. 0.40+/-0.05 at 0.1 nmol/L, 0.91+/-0.10 vs. 0.52+/-0.07 at 1 nmol/L, and 1.00+/-0.10 vs. 0.62+/-0.06 at 10 nmol/L, P<0.01). When treated with 10 nmol/L gastrin for different time, the tyrosine phosphorylation levels of FAK were also significantly higher in SGC7901-GR cells than in SGC7901 cells (0.72+/-0.08 vs. 0.59+/-0.05 at 1 min, 0.83+/-0.05 vs. 0.65+/-0.07 at 5 min, 0.88+/-0.06 vs. 0.58+/-0.03 at 10 min, and 1.00+/-0.08 vs. 0.47+/-0.10 at 20 min, P<0.05). L-365260 decreased the tyrosine phosphorylation levels of FAK from 1.00+/-0.07 to 0.72+/-0.07 in SGC7901-GR cells (P<0.01), and from 0.62+/-0.06 to 0.45+/-0.05 in SGC7901 cells (P<0.01). The protein levels of FAK in different cells remained unchanged during these experiments (P>0.05).. FAK is a pivotal signal transducer in downstream of gastrin with GR. Tyrosine phosphorylation is the symbol of FAK activation.

Topics: Benzodiazepinones; Cell Line, Tumor; Focal Adhesion Kinase 1; Gastrins; Genetic Vectors; Humans; Phenylurea Compounds; Phosphorylation; Receptor, Cholecystokinin B; Signal Transduction; Stomach Neoplasms; Transfection

First-degree relatives of gastric cancer patients are at risk for developing precancerous conditions. The aim of this study was to investigate the potential of biomarkers pepsinogen I (PGI), pepsinogen II (PGII), their ratio (PG I:II), as well as gastrin 17 for screening of precancerous conditions and corpus predominant gastritis.. First-degree relatives of gastric cancer patients underwent endoscopy. Three biopsy specimens from the antrum and 3 from the corpus were evaluated according to the Sydney classification. Serum was taken for the measurement of fasting PGI, PGII, and gastrin 17 by enzyme-linked immunosorbent assay kits.. A total of 481 patients were examined (age, 47.8 +/- 6.7 y). With the extension of gastritis, PGII was increased up to 2.5 times (6.6 +/- 2.8 microg/mL in normal mucosa, 9.5 +/- 6.7 microg/mL in antral gastritis, and 16.9 +/- 12.4 microg/mL in corpus-predominant gastritis; P < .01), PGI increased slightly (88.3 +/- 29.4 microg/mL in normal mucosa and 111.2 +/- 71.4 microg/mL in corpus-predominant gastritis), and gastrin 17 was increased substantially in corpus-predominant gastritis (15.3 +/- 19.5 pmol/mL vs 3.8 +/- 5.7 pmol/mL in normal mucosa). By using a cut-off value of 7.5 microg/mL for PGII, any type of gastritis from normal mucosa can be diagnosed with a sensitivity and specificity of 80%. The sensitivity and specificity of the PG I:II ratio (< or =3) and gastrin 17 (>17 pmol/mL) together were 9.4% and 99% for screening corpus-predominant gastritis and 14.8% and 97.8%, respectively, for screening intestinal metaplasia in the corpus.. PGII is a suitable marker for screening any gastritis from normal mucosa, but neither PGI, the PG I:II ratio, gastrin 17, nor their combination were able to select those with precancerous conditions and corpus-predominant gastritis among the first-degree relatives of gastric cancer patients.

Topics: Adult; Biomarkers; Biopsy; Enzyme-Linked Immunosorbent Assay; Family; Female; Gastric Mucosa; Gastrins; Gastritis; Gastroscopy; Humans; Male; Middle Aged; Pepsinogen A; Pepsinogen C; Sensitivity and Specificity; Serum; Stomach Neoplasms

Loss of gastric parietal cells is a critical precursor to gastric metaplasia and neoplasia. However, the origin of metaplasia remains obscure. Acute parietal cell loss in gastrin-deficient mice treated with DMP-777 leads to the rapid emergence of spasmolytic polypeptide/trefoil factor family 2 (TFF2)-expressing metaplasia (SPEM) from the bases of fundic glands. We now sought to characterize more definitively the pathway for emergence of SPEM.. Emerging SPEM lineages in gastrin-deficient mice treated with DMP-777 were examined for immunolocalization of TFF2, intrinsic factor, and Mist1, and morphologically with electron microscopy. Emerging SPEM was isolated with laser-capture microdissection and RNA was analyzed using gene microarrays. Immunohistochemistry in mouse and human samples was used to confirm up-regulated transcripts.. DMP-777-induced SPEM was immunoreactive for TFF2 and the differentiated chief cell markers, Mist1 and intrinsic factor, suggesting that SPEM derived from transdifferentiation of chief cells. Microarray analysis of microdissected SPEM lineages induced by DMP-777 showed up-regulation of transcripts associated with G1/S cell-cycle transition including minichromosome maintenance deficient proteins, as well as a number of secreted factors, including human epididymis 4 (HE4). HE4, which was absent in the normal stomach, was expressed in SPEM of human and mouse and in intestinal metaplasia and gastric cancer in human beings.. Although traditionally metaplasia was thought to originate from normal mucosal progenitor cells, these studies indicate that SPEM evolves through either transdifferentiation of chief cells or activation of a basal cryptic progenitor. In addition, induction of metaplasia elicits the expression of secreted factors, such as HE4, relevant to gastric preneoplasia.

Topics: Animals; Atrophy; Basic Helix-Loop-Helix Transcription Factors; beta-Defensins; Carrier Proteins; Cell Cycle Proteins; Cell Transformation, Neoplastic; Chief Cells, Gastric; DNA-Binding Proteins; Epididymal Secretory Proteins; Fetal Proteins; Gastric Fundus; Gastric Mucosa; Gastrins; Humans; Intercellular Signaling Peptides and Proteins; Intrinsic Factor; Metaplasia; Mice; Mice, Inbred C57BL; Mice, Knockout; Microtubule-Associated Proteins; Minichromosome Maintenance Complex Component 3; Mucins; Muscle Proteins; Nuclear Proteins; Parietal Cells, Gastric; Peptides; Precancerous Conditions; Stomach Neoplasms; Trefoil Factor-2

Gastrin and cyclooxygenase-2 (COX-2) play important roles in the carcinogenesis and progression of gastric cancer. However, it remains unknown whether the combination of cholecystokinin-2 (CCK-2) receptor antagonist plus COX-2 inhibitor exerts synergistic anti-tumor effects on human gastric cancer. Here, we demonstrated that the combination of AG-041R (a CCK-2 receptor antagonist) plus NS-398 (a selective COX-2 inhibitor) treatment had synergistic effects on proliferation inhibition, apoptosis induction, down-regulation of Bcl-2 and up-regulation of Bax expression in MKN-45 cells. These results indicate that simultaneous targeting of CCK-2 receptor and COX-2 may inhibit gastric cancer development more effectively than targeting either molecule alone.

Topics: Apoptosis; Cell Line, Tumor; Cell Proliferation; Cyclooxygenase 2 Inhibitors; Gastrins; Humans; Receptor, Cholecystokinin B; Stomach Neoplasms

Multiple endocrine neoplasia type 1 (MEN1) patients frequently develop Zollinger-Ellison syndrome (ZES). These patients can develop proliferative changes of gastric enterochromaffin-like (ECL) cells and gastric carcinoids (ECL-cell tumors). ECL-cell changes have been extensively studied in sporadic ZES patients and can be precursor lesions of gastric carcinoids, but little is known about factors influencing their severity or development of carcinoids in MEN1/ZES patients.. Our objective was to prospectively analyze ECL-cell changes and gastric carcinoids (ECL-cell tumors) in a large series of MEN1/ZES patients to detect risk factors and deduct clinical guidelines.. Fifty-seven consecutive MEN1/ZES patients participated in this prospective study at two tertiary-care research centers.. Assessment of MEN1, gastric hypersecretion, and gastroscopy with multiple biopsies was done according to a fixed protocol and tumor status. ECL-cell changes and alpha-human chorionic gonadotropin staining were assessed in each biopsy and correlated with clinical, laboratory, and MEN1 features.. ECL-cell proliferative changes were universally present, advanced changes in 53% and carcinoids in 23%. Gastric nodules are common and are frequently associated with carcinoids. Patients with high fasting serum gastrin levels, long disease duration, or a strong alpha-human chorionic gonadotropin staining in a biopsy are at higher risk for an advanced ECL-cell lesion and/or gastric carcinoid.. Gastric carcinoids and/or advanced ECL-cell changes are frequent in MEN1/ZES patients, and therefore, regular surveillance gastroscopy with multiple routine biopsies and biopsies of all mucosal lesions are essential. Clinical/laboratory data and biopsy results can be used to identify a subgroup of MEN1/ZES patients with a significantly increased risk for developing gastric carcinoids, allowing development of better surveillance strategies.

Topics: Adolescent; Adult; Aged; Carcinoid Tumor; Enterochromaffin-like Cells; Female; Gastrins; Humans; Male; Middle Aged; Multiple Endocrine Neoplasia Type 1; Prospective Studies; Risk Factors; Stomach Neoplasms; Zollinger-Ellison Syndrome

Gastric endocrine tumors associated with autoimmune chronic atrophic gastritis (gastric carcinoid type I) are almost exclusively benign lesions with little risk of deep invasion of the gastric parietal wall. For this reason, the role of octreotide in the treatment of these neoplastic lesions is controversial. Nine patients with more than five type I gastric endocrine tumors each <1 cm in size, without invasion of the muscularis propria and with Ki-67 index lower than 3%, were treated with long-acting somatostatin analogs for 12 months. After 6 months and again after 12 months, all the patients underwent upper gastrointestinal (GI) endoscopy with multiple biopsies. The plasma chromogranin A (CgA) levels and the gastrin levels in the serum were also determined. In all patients, the gastric neoplastic lesions disappeared after 12 months of somatostatin analog therapy. We also observed a significant reduction of CgA and gastrin levels at 6 and at 12 months of therapy as compared with the baseline values. We demonstrate that somatostatin analog treatment provokes the pathological regression of type I gastric carcinoids. This therapeutic approach should be considered as a valid option in selected patients with multiple type I gastric endocrine tumors.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Carcinoid Tumor; Chromogranin A; Chronic Disease; Endosonography; Female; Gastrins; Gastritis, Atrophic; Humans; Immunoenzyme Techniques; Male; Middle Aged; Octreotide; Parietal Cells, Gastric; Stomach Neoplasms; Treatment Outcome

This study was performed to determine whether serum pepsinogen (PG) and gastrin testing can be used to detect gastric cancer in Korea.. Serum levels of PG I (sPGI) and sPGII, PG I/II ratios, and gastrin levels were measured in 1006 patients with gastroduodenal diseases including cancer. Follow-up tests were performed 1 year after Helicobacter pylori eradication.. sPGI and sPGII levels increased and PG I/II ratios decreased in line with the severity of activity, chronic inflammation, and the presence of H. pylori (p < .01). In contrast, sPGI levels and PG I/II ratios decreased in proportion with the severity of atrophic gastritis (AG)/intestinal metaplasia (p < .01). Gastrin levels were found to be correlated with chronic inflammation negatively in the antrum but positively in the corpus. H. pylori eradication reduced sPGI, sPGII, and gastrin levels, and increased PG I/II ratios to the levels of H. pylori-negative patients, and was found to be correlated with reductions in activity and chronic inflammation of gastritis. The sensitivity and specificity of a PG I/II ratio of < or = 3.0 for the detection of dysplasia or cancer were 55.8-62.3% and 61%, respectively. In addition, sPGI and sPGII levels of intestinal-type cancer were significantly lower than those of the diffuse type, respectively (p = .008 and p = .05, respectively). Gastric cancer risk was highest in the H. pylori-positive, low PGI/II ratio (< or = 3.0) group with an odds ratio of 5.52 (confidence interval: 2.83-10.77).. PG I/II ratio (< or = 3.0) was found to be a reliable marker for the detection of dysplasia or gastric cancer, especially of the intestinal type. This detection power of PG I/II ratio (< or = 3.0) significantly increased in the presence of H. pylori, and thus, provides a means of selecting those at high risk of developing gastric cancer in Korea.

Topics: Antigens, Bacterial; Biomarkers; Gastrins; Helicobacter Infections; Helicobacter pylori; Humans; Korea; Pepsinogens; Sensitivity and Specificity; Stomach Neoplasms

Gastrin induces the expression of cyclooxygenase (COX)-2 and interleukin (IL)-8; however, the mechanism(s), especially in gastric epithelial cells, is not well understood. Here, we have determined the intracellular mechanisms mediating gastrin-dependent gene expression.. AGS-E human gastric cancer cell line stably expressing cholecystokinin-2 receptor was treated with amidated gastrin-17. Real-time polymerase chain reaction, Western blot, and enzyme-linked immunosorbent assay were performed to determine COX-2 and IL-8 expression and Akt, Erk, and p38 phosphorylation. Gene promoter activity was determined by luciferase assay. Electrophoretic mobility shift assay analysis was performed for nuclear factor kappaB (NF-kappaB) and activator protein-1 activity. RNA stability was determined after actinomycin D treatment. HuR localization was determined by immunocytochemistry.. Gastrin induced COX-2 and IL-8 expression in AGS-E cells, which was inhibited by phosphatidylinositol 3' kinase (PI3K) and p38 inhibitors. Gastrin-mediated Akt activation was observed to be downstream of p38. IL-8 expression was dependent on COX-2-mediated prostaglandin E(2) synthesis. In the presence of an NF-kappaB inhibitor MG132, IL-8 transcription was inhibited, but not that of COX-2. This was confirmed after knockdown of the p65 RelA subunit of NF-kappaB. Further studies showed that COX-2 gene transcription is regulated by activator protein-1. Gastrin increased the stability of both COX-2 and IL-8 messenger RNA (mRNA) in a p38-dependent manner, the half-life increasing from 31 minutes to 8 hours and approximately 4 hours, respectively. Gastrin, through p38 activity, also enhanced HuR expression, nucleocytoplasmic translocation, and enhanced COX-2 mRNA binding.. Gastrin differentially induces COX-2 and IL-8 expression at the transcriptional and posttranscriptional levels by PI3K and p38 mitogen-activated protein kinase pathways, respectively.

Topics: Adenocarcinoma; Blotting, Western; Cell Line, Tumor; Cyclooxygenase 2; Dinoprostone; Electrophoretic Mobility Shift Assay; Enzyme-Linked Immunosorbent Assay; Gastric Mucosa; Gastrins; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; Immunoprecipitation; Interleukin-8; Oncogene Protein v-akt; p38 Mitogen-Activated Protein Kinases; RNA Stability; RNA, Neoplasm; Stomach Neoplasms; Transcription, Genetic

Helicobacter pylori infects over half the population worldwide and is a leading cause of chronic gastritis and gastric cancer. However, the mechanism by which this organism induces inflammation and carcinogenesis is not fully understood. In the present study we used insulin-gastrin (INS-GAS) transgenic mice that fully develop gastric adenocarcinoma after infection of H. pylori-related Helicobacter felis. Histological examination revealed that more than half of those mice developed invasive adenocarcinoma after 8 months of infection. These carcinomas were stained by NCC-ST-439 and HECA-452 that recognize 6-sulfated and non-sulfated sialyl Lewis X. Lymphocytic infiltration predominantly to submucosa was observed in most H. felis-infected mice, and this was associated with the formation of peripheral lymph node addressin (PNAd) on high endothelial venule (HEV)-like vessels detected by MECA-79. Time-course analysis of gene expression by using gene microarray revealed upregulation of several inflammation-associated genes including chemokines, adhesion molecules, surfactant protein D (SP-D), and CD74 in the infected stomach. Immunohistochemical analysis demonstrated that SP-D is expressed in hyperplasia and adenocarcinoma whereas CD74 is expressed in adenocarcinoma in situ and invasive carcinoma. These results as a whole indicate that H. felis induces HEV-like vessels and inflammation-associated chemokines and chemokine receptors, followed by adenocarcinoma formation.

Topics: Adenocarcinoma; Animals; Antigens, Differentiation, B-Lymphocyte; Female; Gastric Mucosa; Gastrins; Gastritis; Gene Expression Profiling; Glycosyltransferases; Helicobacter felis; Helicobacter Infections; Histocompatibility Antigens Class II; Hyperplasia; Immunohistochemistry; Insulin; Lymphocytes; Male; Mice; Mice, Transgenic; Oligonucleotide Array Sequence Analysis; Oligosaccharides; Pulmonary Surfactant-Associated Protein D; Sialyl Lewis X Antigen; Stomach; Stomach Neoplasms; Up-Regulation

Helicobacter pylori infection induces chronic gastritis and lowers gastric juice ascorbic acid concentrations. We investigated how H. pylori eradication affected multiple variables that could prevent or delay development of new or occult gastric cancer in patients with early gastric cancer treated by endoscopic mucosal resection. Gastric juice pH, nitrite concentrations, and total vitamin C concentrations, serum concentrations of vitamin C and specific H. pylori antibody, and intensity of neutrophil infiltration in gastric mucosa were determined before and after successful H. pylori eradication. Successful eradication increased acid output and ascorbic acid secretion into gastric juice, accompanied by disappearance of polymorphonuclear infiltration from the surface epithelium and decreased gastric juice nitrite concentrations. Our data suggest that H. pylori eradication decreases the nitrosation rate as the ratio of vitamin C to nitrite increases. This decreases reactive oxygen species and nitric oxide, eliminating their damaging effect on DNA and reducing cell turnover.

Topics: Aged; Aged, 80 and over; Ascorbic Acid; Female; Gastric Juice; Gastric Mucosa; Gastrins; Gastritis, Atrophic; Helicobacter Infections; Helicobacter pylori; Humans; Hydrogen-Ion Concentration; Male; Middle Aged; Nitrites; Stomach Neoplasms

Chronic hypergastrinemia is associated with enterochromaffin-like (ECL) cell hyperplasia, which may progress to gastric carcinoid tumors. The latter consists of epithelial cells and stroma, and both compartments usually regress after normalization of hypergastrinemia. We previously showed that matrix metalloproteinase (MMP)-7 in gastric epithelial cells was upregulated by Helicobacter pylori and described MMP-7-dependent reciprocal signaling between the epithelium and a key stromal cell type, the myofibroblast. Here, we describe the regulation of gastric MMP-7 by gastrin and the potential significance for recruiting and maintaining myofibroblast populations. Biopsies of the gastric corpus and ECL cell carcinoid tumors were obtained from hypergastrinemic patients. Western blot analysis, ELISA, immunohistochemistry, and promoter-luciferase (luc) reporter assays were used to study MMP-7 expression. Gastric myofibroblasts were identified by alpha-smooth muscle actin (alpha-SMA) expression, and the effects of MMP-7 on myofibroblast proliferation were investigated. In hypergastrinemic patients, there was an increased abundance of MMP-7 and alpha-SMA in gastric corpus biopsies and ECL cell carcinoid tumors. In the latter, MMP-7 was localized to ECL cells but not stromal cells, which were nevertheless well represented. Gastrin stimulated MMP-7-luc expression in both AGS-G(R) and primary human gastric epithelial cells. Conditioned medium from gastrin-treated human gastric glands stimulated myofibroblast proliferation, which was inhibited by neutralizing antibodies to MMP-7. MMP-7 increased the proliferation of myofibroblasts via the MAPK and phosphatidylinositol 3-kinase (PI3K) pathways. In conclusion, stimulation of gastric MMP-7 by elevated plasma gastrin may activate epithelial-mesenchymal signaling pathways regulating myofibroblast function via MAPK and PI3K pathways and contribute to stromal deposition in ECL cell carcinoid tumors.

Topics: Actins; Animals; Carcinoid Tumor; Cell Line, Tumor; Cell Proliferation; Culture Media, Conditioned; Dose-Response Relationship, Drug; Enterochromaffin-like Cells; Enzyme Induction; Epithelial Cells; Fibroblasts; Gastric Mucosa; Gastrins; Humans; MAP Kinase Signaling System; Matrix Metalloproteinase 7; Mice; Mice, Inbred C57BL; Mice, Knockout; Multiple Endocrine Neoplasia Type 1; Paracrine Communication; Phosphatidylinositol 3-Kinases; Signal Transduction; Stomach; Stomach Neoplasms; Time Factors; Tissue Culture Techniques; Transcription, Genetic; Transfection

Currently the screening and diagnosis of gastric cancer and atrophic gastritis are mainly made by endoscopy and biopsy. The aim of this study was to evaluate the use of serum tests: serum pepsinogen I (PGI pepsinogen I/II ratio (PGR), gastrin-17 (G-17) and H. pylori-immunoglobulin G (IgG) antibodies to screen atrophic gastritis and gastric cancer.. A total of 458 patients were recruited, and each underwent endoscopy with biopsies before the serum tests were performed. These patients were divided into five groups based on the endoscopic and histological findings: 92 patients in the atrophic gastritis group, 58 in the gastric ulcer group, 90 in the duodenal ulcer group, 141 in the gastric cancer group (40 early gastric cancer and 101 advanced gastric cancer) and 77 (including mild non-atrophic gastritis) served as a control group. Serum samples for PGI and II, G-17, and H. pylori-IgG antibodies estimation were analyzed by ELISA.. PGI and PGR values decreased significantly both in atrophic gastritis and gastric cancer groups (P<0.01). For the best discrimination of atrophic gastritis, the cut-off values of PGI and PGR were 82.3 microg/L and 6.05, respectively. The PGI, PGR and G-17 values were related significantly with the grades and/or sites of atrophic gastritis (P<0.01). Patients with atrophic corpus gastritis had low PGI and PGR values and high G-17 level, and patients with atrophic antral gastritis had low G-17 level. G-17 increased significantly in the gastric cancer group (P<0.01). PGI and PGR values were significantly lower in patients with advanced gastric cancer than in patients with early gastric cancer, while there was no difference in G-17 level between them. The positivity rate of H. pylori-IgG antibodies was 54.55% in the control group. The PGI level was higher in H. pylori positive patients than in H. pylori negative ones (P<0.001), while there was no difference in G-17 level between them. The positivity rates of H. pylori-IgG antibodies were over 85% in all other four groups.. Low serum PGI, PGR and G-17 values are biomarkers of atrophic antral gastritis. Atrophic be screened by serum PGI and PGR values. Gastric cancer can be screened on the basis of increased serum G-17 and remarkedly low serum PGI and PGR values. The H. pylori infection is related to the change of PG level.

Topics: Antibodies, Bacterial; Biomarkers; Biomarkers, Tumor; Endoscopy, Gastrointestinal; Female; Gastrins; Gastritis, Atrophic; Helicobacter pylori; Humans; Immunoglobulin G; Male; Middle Aged; Pepsinogens; Stomach Neoplasms

Non-cardia gastric adenocarcinoma is positively associated with Helicobacter pylori infection and atrophic gastritis. The role of H pylori infection and atrophic gastritis in cardia cancer is unclear.. To compare cardia versus non-cardia cancer with respect to the premorbid state of the stomach.. Nested case-control study. To each of 129 non-cardia and 44 cardia cancers, three controls were matched. Serum collected a median of 11.9 years before the diagnosis of cancer was tested for anti-H pylori antibodies, pepsinogen I:II and gastrin.. Non-cardia cancer was positively associated with H pylori (OR 4.75, 95% CI 2.56 to 8.81) and gastric atrophy (pepsinogen I:II <2.5; OR 4.47, 95% CI 2.71 to 7.37). The diffuse and intestinal histological subtypes of non-cardia cancer were of similar proportions and both showed a positive association with H pylori and atrophy. Cardia cancer was negatively associated with H pylori (OR 0.27, 95% CI 0.12 to 0.59), but H pylori-positive cardia cancer showed an association with gastric atrophy (OR 3.33, 95% CI 1.06 to 10.5). The predominant histological subtype of cardia cancer was intestinal and was not associated with gastric atrophy compared with the diffuse subtype ((OR 0.72, 95% CI 0.19 to 2.79) vs (OR 3.46, 95% CI 0.32 to 37.5)). Cardia cancer in patients with atrophy had an intestinal: diffuse ratio (1:1) similar to non-cardia cancer (1.9:1), whereas cardia cancers in patients without atrophy were predominantly intestinal (7:1).. These findings indicate two aetiologies of cardia cancer, one associated with H pylori atrophic gastritis, resembling non-cardia cancer, and the other associated with non-atrophic gastric mucosa, resembling oesophageal adenocarcinoma. Serological markers of gastric atrophy may provide the key to determining gastric versus oesophageal origin of cardia cancer.

Topics: Adenocarcinoma; Adult; Biomarkers; Cardia; Case-Control Studies; Female; Gastrins; Gastritis, Atrophic; Helicobacter Infections; Helicobacter pylori; Humans; Male; Middle Aged; Pepsinogen A; Pepsinogen C; Precancerous Conditions; Risk Factors; Stomach Neoplasms

Clinical features of patients who develop gastric cancer after successful eradication of Helicobacter pylori are still unclear. We attempted to identify host factors associated with the discovery of gastric cancer, including changes in the background gastric mucosa in patients with atrophic gastritis.. We enrolled 101 patients (59 men, 42 women; mean age 56.0 years) who underwent successful eradication therapy. All patients had no neoplastic lesion in the stomach and were diagnosed with corpus atrophic gastritis histologically before the eradication therapy. After successful eradication, these patients were followed up by an annual endoscopic examination (mean follow-up time 63.2 months; range 12-157 months). Fasting sera were obtained before and after eradication therapy and the serum levels of gastrin/pepsinogens were evaluated.. Gastric cancer occurred during follow-up in eight of the 101 patients (7.9%). We compared the host features between the cancer-discovered group (n = 8) and the non-discovered group (n = 93). We found no difference in gender, history of previous treatment of gastric cancer, and serum pepsinogen/gastrin levels at entry between them. The trends in alterations of serum markers did not differ between the two groups. However, gastric cancer was more frequently found in older patients (>54 years at eradication) than in others (P < 0.05).. Improvement of gastric inflammation did not correlate with the discovery of gastric cancer after eradication; however, age at the time of eradication seemed to be important. Strict follow-up after eradication is needed in older patients with atrophic gastritis.

Topics: Aged; Female; Gastrins; Helicobacter Infections; Helicobacter pylori; Humans; Male; Middle Aged; Pepsinogen A; Stomach Neoplasms

The Swedish variant of moist oral smokeless tobacco (snus) is popular in Sweden and Norway, banned from sale within the European Union and is currently being introduced in USA. The aim of the present study was to determine if snus is carcinogenic to the stomach, particularly in Helicobacter pylori (H.P.)-infected hosts at increased risk for gastric cancer development. Snus (Generaltrade mark; Swedish Match, Sweden) was mixed with powdered standard mouse chow at a concentration of 5-9% (wt/wt) and given to wild-type (WT, FVB) and gastrin transgenic (INS-GAS, FVB) mice for 6 months with or without H.P. (strain 67:21, CagA+, VacA+) infection. At necropsy, pathological evaluation of stomachs from uninfected snus-treated WT mice showed mild morphological changes, whereas 50% snus-treated INS-GAS mice developed carcinoma in situ (CIS), compared with 25% not exposed to snus. When snus was given to H.P.-infected mice, 9 of 17 WT mice developed CIS with intramucosal invasion, and the remaining 8 of 17 WT mice developed high-grade dysplasia (score >1.5) that was associated with increased gastritis, epithelial defects, oxyntic atrophy, hyperplasia and intestinal metaplasia. Twelve of 12 H.P.-infected INS-GAS mice developed CIS with intramucosal invasion and submucosal herniation. We suggest that snus is a potential gastric carcinogen in mice. The development of CIS was associated with increased rates of the epithelial cell proliferation and apoptosis, common features of gastric carcinogenesis.

Topics: Animals; Carcinogens; Cotinine; Gastrins; Helicobacter Infections; Helicobacter pylori; Humans; Kidney; Male; Mice; Mice, Inbred Strains; Mice, Transgenic; Stomach Neoplasms; Sweden; Tobacco, Smokeless

A 70-year-old man was found to have at least 12 type I gastric carcinoids and microcarcinoidosis. We performed an extended octreotide suppression test to determine if the tumors were gastrin-dependent and would likely regress after antrectomy. He was given an octreotide infusion at 12.5-25 mcg/h for 86 hr followed by depot octreotide 20 mg intramuscularly every four weeks for eight months. Fasting serum gastrin and chromogranin A levels were measured, and endoscopy with biopsies was performed before and after the infusion and at five months and eight months. Total RNA was extracted for quantitation of histidine decarboxylase mRNA using real-time PCR. Fasting serum gastrin decreased from 306 pg/ml pretreatment to 31 pg/ml at the end of infusion and 115 pg/ml at eight months. Chromogranin A decreased from four to six times the upper limit of normal to normal. Tissue histidine decarboxylase mRNA decreased 50-fold. At eight months, only a few diminutive nodules were present on endoscopy. These results demonstrated that the carcinoid tumors in this patient were under neuroendocrine control and were expected to respond to antrectomy.

Topics: Aged; Carcinoid Tumor; Gastrins; Humans; Male; Octreotide; Stomach Neoplasms

We successfully established a spontaneously cisplatin-resistant tumor cell line (designated as IGSK-1) derived from original gastric carcinoma. The patient was a 75-year-old Japanese woman. The histopathological diagnosis was gastric poorly differentiated adenocarcinoma accompanied with metastatic foci in lymph nodes, pT3, N2 M0, stage IIIB. The IGSK-1 cells grew as adhesive and monolayered cultures on the bottom of dishes. The susceptibility of the IGSK-1 cells to anti-cancer drugs was examined using oxygen electrode apparatus (Daikin, Tsukuba, JPN), and the results suggested TXL was effective, and CDDP, CPT-11 and 5-FU were not effective. Gastrin and somatostatin secretions were confirmed by immunohistochemical staining and also radioimmunoassay. Immunohistochemistry and radioimmunoassay for serotonin suggested the IGSK-1 cells might incorporate serotonin from the growth media. Spontaneously cisplatin-resistant gastric carcinoma cell line secreted gastrin and somatostatin is very important material for chemotherapy.

Topics: Adenocarcinoma; Aged; Antineoplastic Agents; Cell Line, Tumor; Cisplatin; Drug Screening Assays, Antitumor; Female; Gastrins; Humans; Somatostatin; Stomach Neoplasms

Topics: Adult; Anemia, Iron-Deficiency; Carcinoid Tumor; Gastrins; Humans; Male; Multiple Endocrine Neoplasia Type 1; Stomach Neoplasms

To investigate the influence of gender, age, site of lesion, disease type and Helicobacter pylori (H. pylori) infection on the human serum gastrin-17 level and to study the diagnostic value of serum gastrin-17 in gastric precancerous lesions and gastric cancer.. Serum gastrin-17 and serum H. pylori IgG antibody were detected by the ELISA method. The different gastric disease groups were confirmed by endoscopy and histopathology.. Among the 3906 serum samples according to the gender, age, site of lesion and the data of different gastric disease groups, the serum gastrin-17 level was markedly higher in people>or=60 years old than that in younger age groups. The serum gastrin-17 level increased progressively in the following order: healthy control group, nonatrophic gastritis group, gastric ulcer group, and the serum gastrin-17 level was higher in the atrophic gastritis with dysplasia group than that without it, the lowest level being in the gastric cancer group. Among the 2946 serum samples matched with the site of the lesion, the serum gastrin-17 level was higher in those with antral diseases than in those with gastric corpus diseases. Among the 3805 serum samples matched with the H. pylori infection data, the serum gastrin-17 level was higher in the H. pylori-positive group than in the H. pylori-negative group.. In people over 60 years of age, the serum gastrin-17 level tends to increase. In subjects with precancerous gastric lesions, it may increase significantly with the progression of gastric disease, and ultimately decrease in gastric cancer. Serum gastrin-17 is a good biomarker to differentiate benign from malignant gastric diseases. The site of the gastric lesions is an important factor affecting the serum gastrin-17 level, whereas H. pylori infection is usually associated with its increment.

Topics: Adolescent; Adult; Age Factors; Aged; Aged, 80 and over; China; Female; Gastrins; Gastritis; Helicobacter Infections; Helicobacter pylori; Humans; Male; Middle Aged; Precancerous Conditions; Retrospective Studies; Stomach Neoplasms

Topics: Anti-Ulcer Agents; Carcinoid Tumor; Gastrins; Humans; Proton Pump Inhibitors; Stomach Neoplasms

Helicobacter pylori-induced gastritis is an important factor for gastric carcinogenesis. However, it is still controversial whether it is also applicable for cardiac cancer development. Recently, we reported that H. pylori is an important factor for the induction of cardiac inflammation. We examined the status of H. pylori-induced gastritis in patients with cardiac cancer.. Seventy-five Japanese patients (58 men; mean age, 64.2 years) with cardiac cancer were studied. Cardiac cancer was defined as that mainly located within 2 cm from the squamo-columnar junction (SCJ). Histological gastritis including the cardiac region was evaluated using the biopsy or surgically resected sections. Cardiac inflammation was evaluated at 1 cm distal from SCJ in lesser curvature. Sera were collected and several markers were evaluated. The status of H. pylori infection was evaluated by histology and serum antibodies. Expressions of cytokeratins were examined by immunohistochemical analysis.. Out of 75 patients with cardiac cancer, H. pylori was positive in 71 (95%) patients. The cardiac inflammation was examined in 30 patients (26 with H. pylori and four without H. pylori infection) and we found cardiac inflammation was present in all cases with H. pylori infection. Histologically, H. pylori-related gastritis was also found in the gastric corpus and antrum. Serological data were consistent with the presence of chronic atrophic gastritis. Intestinal metaplasia was found in 18 cases in the cardiac mucosa, and their cytokeratin 7/20 pattern was judged as a gastric pattern in all cases.. H. pylori infection is closely associated with cardiac cancer.

Topics: Adult; Aged; Aged, 80 and over; Autoantibodies; Cardia; Chronic Disease; Enzyme-Linked Immunosorbent Assay; Female; Gastric Mucosa; Gastrins; Gastritis; Helicobacter Infections; Helicobacter pylori; Humans; Immunohistochemistry; Male; Middle Aged; Parietal Cells, Gastric; Pepsinogen A; Stomach Neoplasms

Gastric neuroendocrine tumors are rare neoplasms that originate from gastric enterochromaffin-like (ECL) cells in the oxyntic mucosa. Gastrin and its derivates have been reported to regulate epithelial cell proliferation, migration, and differentiation. Mutations in the epithelial cadherin (E-cadherin) gene have been shown to be associated with the occurrence of diffuse gastric carcinomas in affected families.. In this study we investigated the histopathological and molecular findings in the gastrointestinal wall of a patient with multiple endocrine neoplasia type 1 with malignant duodenal gastrinoma and multiple gastric ECL cell tumors, who additionally developed a signet-ring cell carcinoma of the stomach.. Biopsies from the gastrointestinal tract of a patient with multiple endocrine neoplasia type 1 were immunostained for vesicular monoamine transporter-2 and E-cadherin. Nonamidated gastrin products were measured in the serum of the patient using antibodies that react with progastrin, Gly-extended, and amidated gastrins. Genetic analyses were performed to exclude germ-line mutations within the E-cadherin gene.. Immunohistochemical studies of gastric ECL cell tumors showed a largely diminished E-cadherin expression in comparison to gastric surface mucosa cells and a loss of E-cadherin expression in the cells of the signet-ring carcinoma. Detailed biochemical measurements revealed progastrin concentrations that were approximately 20%, and Gly-gastrin concentrations that were approximately 10% the amidated gastrin concentrations in plasma. Molecular analyses revealed no E-cadherin germ-line mutation.. Our immunohistochemical studies might suggest that the gastrinoma-associated excessive progastrin tissue concentrations led to diminished expression of E-cadherin within the gastric mucosa and promoted tumor development of a signet-ring cell carcinoma.

Topics: Cadherins; Carcinoma, Signet Ring Cell; Gastrins; Humans; Male; Middle Aged; Models, Biological; Multiple Endocrine Neoplasia Type 1; Stomach Neoplasms; Ultrasonography; Zollinger-Ellison Syndrome

Enterochromaffin-like (ECL) cell has been identified as the histamine-containing argyrophil cell in rat gastric mucosa and vigorously studied. However, there are few reports of the distribution of ECL cell in human stomach. The aim of the present study was to determine the precise distribution of ECL cell by immunohistochemical staining of histidine decarboxylase (HDC) and gastrin-cholecystokinin B receptor (CCK-BR) in human stomach, and the correlation between their distribution and that of parietal cells. Thirty specimens of surgically resected stomach were used. Parietal cell, Grimelius-silver-positive cell, gastrin, HDC- and CCK-BR-immunoreactive cell were studied on continuous cell counting in the restricted field along the lamina muscularis from the oral to the anal ends. The percentage of HDC-immunoreactive cells of endocrine cells was smaller (15%) than that of a previous report (35%) in the fundic region. HDC- and CCK-BR-immunoreactive cells were found not only in the fundic region, but also in the intermediate and pyloric regions. In the pyloric region, HDC- and CCK-BR-immunoreactive cells were found mainly in the mucosa with intestinal metaplasia. Double-positive cells were also found, but only in small numbers. This suggests that ECL cell, or a cell sharing its function, is present in the pyloric region.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Cell Count; Enterochromaffin Cells; Female; Gastric Mucosa; Gastrins; Histidine Decarboxylase; Humans; Immunoenzyme Techniques; Male; Middle Aged; Neoplasm Proteins; Receptor, Cholecystokinin B; Stomach Neoplasms

The presence of neuroendocrine (NE) cells in gastric adenocarcinoma (GCa) is well documented, however, their significance is controversial. There is no evidence in the literature concerning the possible effect of these cells on the expression of TGF-alpha and EGFR, which are believed to confer growth advantage to tumor cells. 101 partial or total gastrectomy specimens from patients operated for conventional gastric adenocarcinoma were included in the study. In each case immunohistochemistry was performed on sequential tissue sections for chromogranin A (ChrA), TGF-alpha and EGFR. Samples were graded based on the number of ChrA-positive cells (0-3). TGF-alpha and EGFR expressions were evaluated according to both the intensity (0-2) and quantification of the positively stained areas (0-3). Follow-up data was available in 54 patients. Twenty-seven patients died of disease, while 27 patients were alive with a follow-up of at least 15 months. ChrA expression was detected in 54.4% of the tumor specimens. TGF-alpha was stained positively in 42.6% and EGFR in 49.5% of the cases. NE cells in GCa was related to TGF-alpha (p<0.0001) and EGFR expression (p<0.05), and TGF-alpha/EGFR coexpression (p<0.001). Among histopathologic variables, the presence of NE cells was significantly related to grade, stage and lymph node status. Although the presence of NE cells had no effect on survival, the expression of EGFR (p<0.0001) and TGF-alpha (p=0.002) were related to survival. The results of our study suggest that the presence of NE cells may have an effect on the expression of TGF-alpha and EGFR in GCa, and the autocrine mechanism between TGF-alpha and EGFR plays an important role in the prognosis of gastric carcinoma.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Chromogranin A; ErbB Receptors; Female; Follow-Up Studies; Gastrins; Gene Expression Regulation, Neoplastic; Humans; Hyperplasia; Kaplan-Meier Estimate; Male; Middle Aged; Neurosecretory Systems; Prognosis; Retrospective Studies; Stomach Neoplasms; Transforming Growth Factor alpha

Gastrointestinal (GI) hormones regulate several GI functions, including the proliferation and repair of normal mucosa, and hormone receptors may therefore be implicated in the growth, invasion, and metastasis of cancers of the GI tract. The aim of this study was to determine the cellular distribution of gastrin in intestinal-type gastric cancers, and to determine its relationship to outcomes after R0 gastrectomy.. Eighty-six consecutive patients undergoing R0 gastrectomy for adenocarcinoma were studied. Normal gastric mucosa and tumor were stained for gastrin and their specific cellular distribution was determined.. The duration of survival of patients whose tumors exhibited well-differentiated gastrin-positive tumor (GPT) cells (n = 12) was significantly poorer than that of patients whose tumors were GPT-negative (5-year survival, 30% vs 54%; P = 0.037). Patients with GPT-positive intestinal-type gastric cancer (5 of 47 patients) had the poorest survival of all (median, 14 months; 5-year survival, 0%; P = 0.006). In a multivariate analysis, only lymph node metastases (hazard ratio [HR], 2.13; 95% confidence interval [CI], 1.2 to 3.79; P = 0.01) and the presence of GPT cells (HR, 6.61; 95% CI, 1.74 to 25.09; P = 0.01) were independently and significantly associated with durations of survival in patients with intestinal-type gastric cancer.. The presence of GPT cells in patients with gastric adenocarcinoma is a significant and independent prognostic indicator.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Confidence Intervals; Female; Gastrectomy; Gastrins; Gene Expression; Humans; Lymph Nodes; Lymphatic Metastasis; Male; Middle Aged; Multivariate Analysis; Neoplasm Metastasis; Neoplasm Staging; Prognosis; Stomach Neoplasms; Survival Rate

Topics: Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Chronic Disease; Duodenal Ulcer; Female; Gastric Mucosa; Gastrins; Gastritis; Helicobacter Infections; Helicobacter pylori; Humans; Male; Middle Aged; Pepsinogen A; Pepsinogen C; Pyloric Antrum; Retrospective Studies; Stomach Neoplasms; Stomach Ulcer

Topics: Gastric Antral Vascular Ectasia; Gastric Mucosa; Gastrins; Gastroscopy; Humans; Hyperplasia; Laser Coagulation; Polyps; Postoperative Complications; Stomach Neoplasms; Stomach Ulcer

Gastrin is a growth factor of cancerous and normal cells of the gastrointestinal tract, and its effect is known to be mediated by gastrin/cholecystokinin B (CCKB) receptor. This study was performed to investigate the prognostic significance and the expression profiles of gastrin and gastrin receptor in human gastric carcinoma tissues.. We analyzed the expressions of gastrin and gastrin receptor by immunohistochemical staining using anti-gastrin Ab (Sigma, St. Louis, MO, USA) and anti-gastrin receptor Ab (Aphton Corp., Woodland, CA, USA) in 279 gastric adenocarcinoma patients. Patients' clinicopathologic features and prognoses were analyzed.. The gastrin expression rate in these patients was 47.7% (133/279) and the gastrin receptor expression rate was 56.5% (158/279). Gastrin expression was significantly higher in men than in women (54.3% vs. 34.1%), and higher in differentiated gastric adenocarcinoma than in the undifferentiated type (55.1% vs. 43.0%). The gastrin receptor expression rate was also significantly higher in men than in women (61.2% vs. 47.3%), and was higher in the differentiated type than in the undifferentiated type (72.9% vs. 46.5%), and significantly higher in the intestinal type than in the diffuse type (75.2% vs. 42.9%). Gastrin and gastrin/CCKB receptor expressions were not found to be significant prognostic factors in themselves. When focused on correlation between the co-expression of gastrin and gastrin/CCKB receptor and the survival, the prognosis of patients positive for both gastrin and gastrin receptor was significantly poorer than for those negative for gastrin and gastrin receptor in diffuse-type gastric cancer patients. However, multivariate analysis showed that only TNM stage was an independent prognostic factor of survival in diffuse-type gastric cancer patients.. This study shows that the expression rates of gastrin and gastrin receptor are high (about a half) in gastric carcinoma tissues, and that there is an association between gastrin and gastrin receptor expression. We also found that patients with diffuse-type gastric carcinoma tissues expressing both gastrin and gastrin receptor have a poorer prognosis than those negative for both, which suggests that gastrin acts as an autocrine growth factor in a subgroup of gastric carcinomas.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Female; Gastrins; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; Male; Middle Aged; Neoplasm Staging; Predictive Value of Tests; Prognosis; Receptor, Cholecystokinin B; Sex Factors; Stomach Neoplasms; Survival Analysis

Gastrin promotes gastric mucosal growth, and hypergastrinemia induces gastric mucosal hypertrophy. Recently, it has been reported that gastrin induces cyclooxygenase-2 (COX-2) in human gastric and colorectal cancer cell lines. However, whether COX-2 is involved in gastrin-induced gastric mucosal growth in vivo is unknown. We investigated the role of COX-2 in gastrin-induced gastric mucosal hypertrophy using gastrin transgenic mice. Hypergastrinemic mice [mice with mutated gastrin under the control of the beta-actin promoter (ACT-GAS mice)] received the COX-2 inhibitor celecoxib (0, 200, or 500 mg/kg of diet) from 5 wk of age and were killed at 16 or 24 wk. Some ACT-GAS mice received celecoxib from 16 wk and were killed at 24 wk. Eighty-week-old ACT-GAS mice without celecoxib treatment were also examined. The thickness of the gastric mucosa, cell populations, COX-2 expression, and PGE(2) levels were evaluated. All ACT-GAS mice showed gastric mucosal hypertrophy, and four of six 80-wk-old ACT-GAS mice developed gastric cancer. COX-2 was expressed in interstitial cells of the hypertrophic gastric mucosa and gastric cancers. Moreover, PGE(2) levels in the gastric mucosa of ACT-GAS mice were significantly higher than those of normal mice. With treatment with celecoxib, PGE(2) levels, the gastric mucosal thickness, and the number of total gastric cells per gastric gland of ACT-GAS mice were significantly decreased. The decrease in gastric mucosal thickness was caused by a reduction of foveolar hyperplasia. The thickness of glandules and the number of Ki67-positive cells were not significantly changed. In conclusion, COX-2 contributes to gastrin-induced mucosal hypertrophy of the stomach.

Topics: Animals; Apoptosis; Celecoxib; Cyclooxygenase 2; Dinoprostone; Gastric Mucosa; Gastrins; Gene Expression; Hypertrophy; Mice; Mice, Transgenic; Pyrazoles; Stomach Neoplasms; Sulfonamides

Helicobacter pylori infection in Mongolian gerbils is an established experimental model of gastric carcinogenesis that mimics H. pylori-positive patients developing gastric ulcer and gastric cancer, but the effect of probiotic therapy on functional aspects of this infection remains unknown.. We compared the effects of intragastric inoculation of gerbils with H. pylori strain (cagA+ vacA+, 5 x 10(6) colony forming units/ml) with or without triple therapy including omeprazole, amoxicillin, and tinidazol or probiotic bacteria Lacidofil. Histology of glandular mucosa, the viable H. pylori, and density of H. pylori colonization were evaluated. The gastric blood flow was measured by H2-gas clearance method; the plasma gastrin and gastric luminal somatostatin were determined by RIA and expression of cyclooxygenase (COX)-2 and apoptotic Bax and Bcl-2 proteins were evaluated by Western blot.. The gastric H. pylori infection was detected in all animals by histology and H. pylori culture. Basal gastric acid was significantly reduced in H. pylori-infected animals but not in those with triple therapy or Lacidofil. Early lesions were seen already 4 weeks upon H. pylori inoculation and consisted of chronic gastritis and glandular atypia associated with typical regenerative hyperplasia and increased mitotic activity and formation of apoptotic bodies. The H. pylori infection was accompanied by the fall in gastric blood flow, the marked increase in plasma gastrin, the significant fall in gastric somatostatin levels and Bcl-2 protein expression, and the rise in expression of COX-2 and Bax proteins. These mucosal changes were counteracted by the triple therapy and Lacidofil.. H. pylori infection in gerbils, associated with regenerative hyperplasia of glandular structure, results in the suppression of gastric secretion, overexpression of COX-2, and enhancement in apoptosis and impairment of both, gastric blood flow and gastrin-somatostatin link that were reversed by anti-H. pylori triple therapy and attenuated by probiotics.

Topics: Amoxicillin; Animals; Anti-Bacterial Agents; Apoptosis; bcl-2-Associated X Protein; Cyclooxygenase 2; Gastric Acid; Gastric Mucosa; Gastrins; Gerbillinae; Helicobacter Infections; Helicobacter pylori; Male; Omeprazole; Probiotics; Proto-Oncogene Proteins c-bcl-2; Regional Blood Flow; Somatostatin; Stomach; Stomach Neoplasms; Tinidazole

Topics: Cell Transformation, Neoplastic; Enterochromaffin-like Cells; Gastric Acid; Gastrinoma; Gastrins; Gastrointestinal Agents; Humans; Iatrogenic Disease; Proton Pump Inhibitors; Risk Assessment; Stomach Neoplasms; Zollinger-Ellison Syndrome

Topics: Carcinoid Tumor; Female; Gastrins; Humans; Male; Prognosis; Stomach Neoplasms

The aim of this study was to review the presentation, treatment, and outcome of patients with Type 1 gastric carcinoid tumors.. A retrospective review of 1,600 carcinoid patients was analyzed to identify patients with gastric carcinoid tumors.. Eighteen patients were found to have biopsy-confirmed Type 1 gastric carcinoid tumors on upper endoscopy. Reasons for endoscopy included abdominal pain (n = 4), gastrointestinal bleeding (n = 4), surveillance for pernicious anemia (n = 8), and other (n = 2). The mean pre-treatment serum gastrin and chromogranin A levels were 1,436 ng/ml (+/-771 ng/ml) and 91.6 ng/ml (+/-68.6 ng/ml), respectively. Imaging revealed evidence of gastric carcinoid in 4 of 10 patients undergoing CT scanning and 3 of 10 patients undergoing octreotide scintigraphy. Of the 18 patients, 8 were treated medically (acidification or octreotide) and 10 were treated with surgery (laparoscopic antrectomy or partial gastrectomy). Mean gastrin levels decreased by 37.2% in the medically treated group (median follow-up 6 months), versus 94.0% in the surgically treated patients (median follow-up 5 months). Mean chromogranin A levels decreased by 56.2% in patients undergoing surgery.. Gastric antrectomy is the most efficacious treatment for Type 1 gastric carcinoid, leading to a significant reduction in serum gastrin levels and regression of carcinoid tumors.

Topics: Antineoplastic Agents, Hormonal; Biomarkers, Tumor; Carcinoid Tumor; Chromogranin A; Chromogranins; Enterochromaffin-like Cells; Female; Gastrectomy; Gastrins; Humans; Male; Middle Aged; Octreotide; Pyloric Antrum; Retrospective Studies; Somatostatin; Stomach Neoplasms; Treatment Outcome

We have previously reported that Helicobacter pylori infection prevents reflux esophagitis (RE) and Barrett's esophagus (BE) by decreasing gastric acid secretion. Gastroesophageal (GE) junction adenocarcinoma, including Barrett's adenocarcinoma, has been thought to be a complication of gastroesophageal reflux disease (GERD). However, the relationship between H. pylori infection, gastric acid secretion, and GE junction adenocarcinoma has not yet been investigated in Japan. The aim of this study was to evaluate this relationship in the Japanese population.. A total of 168 Japanese patients (RE alone: 80, short-segment BE (SSBE): 16, long-segment BE (LSBE): 20, GE junction adenocarcinoma: 12, distal early gastric cancer (EGC): 40; male/female = 106/62; mean age 61.5 yr) and 80 Japanese control subjects who had no localized lesions in the upper gastrointestinal tract (male/female = 43/37, mean age 58.1 yr) were enrolled for this study. The prevalence of H. pylori infection was determined by biopsy, the rapid urease test, and measurement of the serum H. pylori IgG antibody. Gastric acid secretion was assessed by the endoscopic gastrin test (EGT). RE was diagnosed according to the Los Angeles classification.. The prevalence of H. pylori infection in the patients with RE alone (30%) was significantly lower than that in control subjects (71.2%). There was also a tendency for the prevalence of H. pylori infection to be lower in patients with BE (SSBE, 18.7%; LSBE, 0%) when compared to that in patients with RE alone. On the other hand, while the prevalence of H. pylori infection in patients with GE junction adenocarcinoma (58.3%) was significantly lower than that in patients with EGC (87.5%), it tended to be higher than that in patients with RE alone or BE. The mean EGT value in patients with RE alone (3.74 mEq/10 min) was significantly higher than that in control subjects (1.83). The mean EGT value in patients with BE (SSBE, 4.74; LSBE, 4.76) tended to be even higher than that in patients with RE alone. The mean EGT value in patients with GE junction adenocarcinoma (3.94) was significantly higher than that in control subjects and patients with EGC (0.67), but it was comparable to that independent of the H. pylori infection status in patients with RE alone or BE.. Preservation of gastric acid secretion may be important for the development of GE junction adenocarcinoma in Japanese people, irrespective of the H. pylori infection status.

Topics: Adenocarcinoma; Barrett Esophagus; Esophageal Neoplasms; Esophagitis, Peptic; Esophagogastric Junction; Female; Gastric Acid; Gastric Acidity Determination; Gastrins; Helicobacter Infections; Helicobacter pylori; Humans; Male; Middle Aged; Prevalence; Stomach Neoplasms

To construct two kinds of anti-gastrin immunogen based on P64K protein from Neisseria meningitids and to compare their immunogenic effect.. G17P64K gene was cloned and ligated into pET28a plasmid, then transformed into BL21(DE3). After inoculation of LB medium and IPTG induction, the recombinant protein was solubly expressed at a high level. The purification of G17P64K fusion protein was similar to that of P64K. An initial step of purification consisting of 30% saturated ammonium sulfate precipitation was done. Additional fine optimizations included phenyl-sepharose, G200 Sephadex gel filtration and Q-sepharose anion exchanger chromatography. Highly purified protein was obtained and sequenced at the N-terminal amino acid residues. Polypeptide was synthesized by Fmoc solid phase chemical method and cross-linked to carrier protein P64K and DT mutant by MBS method and then the rabbit anti-gastrin 17 antibody was prepared by immunizing rabbit with cross-linked and fused protein. The titer and the activity in vitro of antibody were assessed.. G17P64K gene and the recombinant bacteria were obtained. After four steps purification, protein sample that has the purity above 90% was achieved. At the 84(th) day after the first immunization, the titer of antibody against cross-linked protein reached 51,200. Evaluation of the antibody in vitro manifested that it had a high inhibitory activity on the growth of tumor cell SW480.. The P64K-polypeptide cross-linked immunogen immunized rabbit and achieved a higher titer antibody against gastrin 17 than the G17P64K fusion protein immunogen, which could inhibit the growth of the tumor cell SW480.

Topics: Amino Acid Sequence; Animals; Antibodies; Bacterial Outer Membrane Proteins; Cancer Vaccines; Gastrins; Immunization; Mice; Mice, Inbred BALB C; Molecular Sequence Data; Rabbits; Recombinant Fusion Proteins; Stomach Neoplasms

p73, a new p53 family member, is a transcription factor that is increasingly recognized in cancer research as an important player in tumorigenesis as well as in chemotherapeutic drug sensitivity. Despite the substantial structural and functional similarities to p53, accumulating evidence suggests that p53 and p73 may differently regulate their transcriptional targets. In this study, we have investigated the role of p73 in regulation of the gastrin gene promoter. Gastrin is a peptide hormone and an important factor in determining the progression of a number of human malignancies. Our results show that p73 can bind to the gastrin promoter. This leads to transcriptional upregulation of gastrin mRNA. We also found that the levels of gastrin and p73 transcripts correlate in primary gastric tumors. Taken together, our results demonstrate a novel mechanism for regulation of gastrin gene transcription and support a concept that p53 and p73 may have different biological roles in tumors.

Topics: Animals; Cell Line, Tumor; DNA-Binding Proteins; Gastrins; Humans; Lung Neoplasms; Mice; Nuclear Proteins; Promoter Regions, Genetic; Protein Isoforms; RNA, Messenger; Stomach Neoplasms; Tumor Protein p73; Tumor Suppressor Proteins

Topics: Cancer Vaccines; Cisplatin; Combined Modality Therapy; Fluorouracil; Gastrins; Humans; Stomach Neoplasms; Treatment Outcome

Type I gastric carcinoid tumors result from hypergastrinemia in 1%-7% of patients with pernicious anemia. We diagnosed pernicious anemia in a 48-year-old female patient with complaint of fatigue for three months. She had no gastrointestinal symptoms. Endoscopic examination ot the upper gastrointestinal tract revealed atrophic gastritis and a polypoid lesion in the corpus of 3-4 mm in size. Endoscopic polypectomy was performed. Histopathological examination of the specimen revealed positive chromogranin A and synaptophysin stainings compatible with the diagnosis of a carcinoid tumor. Serum gastrin level was increased, urinary 5-hydroxyindoleacetic acid was within the normal range. There was no other symptom, sign, or laboratory finding of a carcinoid syndrome in the patient. No metastasis was found with indium-111 octreotide scan, computed tomographies of abdomen and thorax. Type I gastric carcinoid tumors are only rarely solitary and patients with tumors < 1 cm in size may benefit from endoscopic polypectomy.

Topics: Anemia, Pernicious; Carcinoid Tumor; Endoscopy; Female; Gastrins; Humans; Middle Aged; Polyps; Stomach Neoplasms

Gastrin deficiency and proton pump inhibitor treatment cause achlorhydria, which predisposes to disease. To elucidate the underlying molecular biology, we examined the changes in gastric gene expression in both types of achlorhydria. We also explored the associated changes in the gastric microflora and the long-term consequences of gastrin-deficient achlorhydria.. Expression profiles were generated from gastric RNA from wild-type mice, gastrin knockout (KO) mice, gastrin KO mice after 1 week of gastrin infusion, and wild-type mice treated for 1 month with a proton pump inhibitor. The results were confirmed using real-time polymerase chain reaction and immunohistochemistry. Selective media were used to characterize the gastric microflora.. The number of gastric bacteria was increased in both gastrin KO and PPI-treated mice. The expression profiles revealed activation of immune defense genes, interferon-regulated response genes, and intestinal metaplasia of the gastric mucosa. In young gastrin-deficient mice, gastrin infusions reversed the changes. Over time, the changes accumulated, became irreversible, and progressed into metaplasia and polyp development. Finally, the study showed that gastrin regulated the expression of genes encoding extracellular matrix proteins.. Independently of gastrin, achlorhydria is associated with gastric bacterial overgrowth and intestinal gene expression patterns and is associated with predisposition to disease. Gastrin is therefore essential for prevention of gastric disease, mainly through control of acid secretion but to a lesser extent also through control of gastric gene expression. The gastrin-deficient mouse serves as a useful new model for gastric metaplasia and neoplasia.

Topics: Animals; CDX2 Transcription Factor; Disease Models, Animal; DNA, Neoplasm; Female; Gastric Mucosa; Gastrins; Gastritis; Gene Expression; Homeodomain Proteins; Hormones; Immunohistochemistry; Male; Metaplasia; Mice; Mice, Inbred C57BL; Mice, Knockout; Polymerase Chain Reaction; Stomach Neoplasms; Transcription Factors

Both gastrin and Helicobacter pylori have been shown capable of up-regulating gene expression and protein shedding of heparin-binding epidermal growth factor (HB-EGF). Furthermore, the bacteria have previously been shown to induce serum hypergastrinemia in infected individuals. The aim of this work was to assess the extent to which the ability of H. pylori to up-regulate expression of HB-EGF can be attributed to its effect on gastrin. Gastric cells, transfected with either gastrin small interfering RNA or antisense plasmid or the gastrin/cholecystokinin-2 receptor (CCK-2R), were cultured for 24 hours with H. pylori(+/-), a CCK-2R antagonist. Gene expression levels were measured using reverse transcription-PCR, whereas protein changes were measured using ELISA, Western blotting, and immunofluorescence. H. pylori induced significantly higher levels of HB-EGF gene expression and ectodomain shedding in the CCK-2R-transfected cells than the vector control (P < 0.01). Addition of the CCK-2R inhibitor significantly decreased gene and shedding up-regulation. Gastrin down-regulation reduced the effect of the bacteria on HB-EGF gene and protein expression levels. Endogenous gastrin and CCK-2R expression were also found to be significantly up-regulated in all cell lines as a result of exposure to H. pylori (P < 0.02). Gastric mucosal tissue from H. pylori-infected individuals had significantly higher CCK-2R expression levels than noninfected (P < 0.003), and in hypergastrinemic mice, there was an increase in HB-EGF-expressing cells in the gastric mucosa and colocalization of HB-EGF with CCK-2R-positive enterochromaffin-like cells. In conclusion, gastrin and the CCK-2R play significant roles in the induction of HB-EGF gene and protein expression and ectodomain shedding by H. pylori.

Topics: Adenocarcinoma; Animals; Cell Line, Tumor; Disease Models, Animal; DNA, Antisense; Enterochromaffin Cells; Epidermal Growth Factor; Gastrins; Helicobacter Infections; Helicobacter pylori; Heparin-binding EGF-like Growth Factor; Humans; Intercellular Signaling Peptides and Proteins; Mice; Plasmids; Receptor, Cholecystokinin B; Reverse Transcriptase Polymerase Chain Reaction; RNA, Small Interfering; Stomach Neoplasms; Transfection; Up-Regulation

Hypergastrinemia in INS-GAS mice leads to accelerated carcinogenesis of the stomach, but the mechanisms have not been well defined. We investigated the possible role of gastrin-induced gastric cell apoptosis in the development of gastric cancer. We examined apoptosis and the expression of Bcl-2 family proteins in INS-GAS mice of different ages, as well as in gastrin-deficient (GAS-KO) mice after gastrin-17 (G-17) infusion. In addition, we studied the effects of the gastrin/cholecystokinin-2 (CCK-2) receptor antagonist YF476 and/or histamine H2 (H-2) receptor antagonist loxtidine on apoptosis and atrophy in INS-GAS mice with or without Helicobacter felis (H. felis) infection. INS-GAS mice had age-associated increases in Bax protein expression and decreases in Bcl-2 protein expression, along with increased glandular and epithelial cell apoptosis. At 8-week gastrin infusions in GAS-KO mice resulted in a similar pattern of altered Bax and Bcl-2 expression, followed by gastric cell apoptosis. H. felis infection of INS-GAS mice led to increased apoptosis and the development of atrophy, whereas treatment with either YF476 and/or loxtidine strongly inhibited both apoptosis and atrophy. In vitro studies with Fas-expressing RGM1 cells showed that gastrin stimulation alone directly induced apoptosis via gastrin/CCK-2 receptor and synergized with FasL stimulation. These results indicate that gastrin can induce apoptosis in gastric epithelial cells and contribute to the development of gastric carcinogenesis.

Topics: Animals; Apoptosis; Atrophy; Disease Models, Animal; Gastrins; Helicobacter felis; Helicobacter Infections; Male; Mice; Mice, Knockout; Proto-Oncogene Proteins c-bcl-2; Receptor, Cholecystokinin B; Receptors, Histamine H2; Stomach Neoplasms

Intestinal metaplasia has been investigated extensively as a possible premalignant condition for stomach cancer but its pathogenesis is still not fully understood. In the present study, we examined the relationship between endocrine and mucous cell marker expression periodically after Helicobacter pylori infection in the Mongolian gerbil model. The numbers of chromogranin A (CgA)-positive, gastrin-positive and gastric inhibitory polypeptide (GIP)-positive cells in H. pylori-infected groups was increased significantly compared with the non-infected case. However, CgA-positive and gastrin-positive cells then decreased from 50 through 100 experimental weeks after H. pylori infection, whereas GIP-positive cells increased. Coexistence of gastrin-positive and GIP-positive cells was detected in the same gastric and intestinal mixed phenotypic glandular-type glands. In conclusion, the endocrine cell phenotype is in line with that of the mucous counterpart in the glands of H. pylori-infected Mongolian gerbil stomach, supporting the concept that development of intestinal metaplasia is due to the abnormal differentiation of a stem cell.

Topics: Animals; Chromogranin A; Chromogranins; Endocrine Glands; Gastric Inhibitory Polypeptide; Gastric Mucosa; Gastrins; Gerbillinae; Helicobacter Infections; Helicobacter pylori; Immunohistochemistry; Intestines; Metaplasia; Precancerous Conditions; RNA, Messenger; Stomach; Stomach Neoplasms

The gp130(757F/F) mouse is a well-characterized and robust model of distal gastric tumorigenesis displaying many of the characteristics of human intestinal type gastric cancer. Key to the development of tumors in this model, and in many examples of human tumor development, is hyperactivation of the transcription factor STAT3. This study addressed the requirement for STAT3 activation in tumor initiation and characterized some of the genes downstream of STAT3 required for tumor development. Furthermore, the interaction among STAT3, the microbial environment, and tumorigenesis was evaluated.. The role of STAT3 in gastric tumor development was assessed in detail in gp130(757F/Y757F):STAT3(+/-) mice displaying reduced STAT3 activity. Tumor size was quantified morphologically, and the effects on endocrine cell populations, neovascularization, and inflammatory cell infiltration as well as the outcome of STAT3 activation on transcription of a number of genes relevant in growth and inflammation were quantified.. Loss of one STAT3 allele in gp130(757F/F) mice reduced the frequency and rate of tumor development because of inhibition of proliferation-induced glandular hyperplasia. There was also a concomitant reduction in the degree of inflammatory infiltration and cytokine and chemokine expression, angiogenesis, and expression of metalloproteinases and growth factors. Antimicrobial treatment of gp130(757F/F) mice slowed tumor growth coincident with reduced macrophage and neutrophil infiltration.. Activation of STAT3 and the microbial environment are pivotal for gastric tumor initiation and development in the gp130(757F/F) mouse, thus supporting the notion that STAT3 activation may play a role in human gastric cancer development.

Topics: Animals; Cell Division; Cell Movement; Cytokine Receptor gp130; Disease Models, Animal; Extracellular Matrix; Gastric Mucosa; Gastrins; Gastritis; Gene Expression Regulation, Neoplastic; Leptin; Macrophages, Peritoneal; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Neovascularization, Pathologic; Neutrophils; Phosphorylation; Pyloric Antrum; Somatostatin; STAT3 Transcription Factor; Stomach Neoplasms

To study whether gastrin/cholecystokinin-B (CCK-B) receptor autocrine loop exists in human gastric cancer cells and the effects of gastrin/CCK-B receptor autocrine loop on the growth and apoptosis of human gastric cancer cells.. Human gastric cancer cells of the line SGC-7901 were cultured. The expression of gastrin and CCK-B was detected by RT-PCR, immunocytochemistry and radioimmunoassay. Antibody against gastrin was added so as to block the autocrine loop to observe the growth rate, cell cycle and apoptosis by 3-(4.5-dimethylthiazol-z-yl) -2, 5-diphenyl tertrazolium blue (MMT) colorimetric assay and flow cytometry (FCM).. The SGC-7901 cells co-expressed gastrin and CCK-B receptor mRNAs, confirmed by sequencing, thus forming gastrin/the CCK-B receptor autocrine loop. After the blocking of the autocrine loop by antibody against gastrin, the cell growth rate and the number of cells residing in the S-phase of the cell cycle decreased and the apoptotic rate increased in an antibody concentration-dependent manner.. Human gastric cancer SGC-7901 cells possess the gastrin/the CCK-B receptor autocrine loop. Blocking the autocrine loop inhibits the cell proliferation and promotes the cell apoptosis.

Topics: Actihaemyl; Animals; Antibodies, Monoclonal; Apoptosis; Autocrine Communication; Cell Line, Tumor; Cell Proliferation; Gastrins; Humans; Receptor, Cholecystokinin B; RNA, Messenger; Stomach Neoplasms

To validate a non-invasive method to detect gastric mucosal atrophy in a Chilean population with high prevalence of gastric cancer and a poor survival rate.. We first determined the optimal cut-off level of serum pepsinogen (PG)-1, PG-1/PG-2 ratio and 17-gastrin in 31 voluntary symptomatic patients (mean age: 66.1 years), of them 61% had histologically confirmed gastric atrophy. Then, in a population-based sample of 536 healthy individuals (209 residents in counties with higher relative risk and 327 residents in counties with lower relative risk for gastric cancer), we measured serum anti-H pylori antibodies, PG and 17-gastrin and estimated their risk of gastric cancer.. We found that serum PG-1 < 61.5 microg/L, PG-1/PG-2 ratio < 2.2 and 17-gastrin > 13.3 pmol/L had a high specificity (91%-100%) and a fair sensitivity (56%-78%) to detect corpus-predominant atrophy. Based on low serum PG-1 and PG-1/PG-2 ratio together as diagnostic criteria, 12.5% of the asymptomatic subjects had corpus-predominant atrophy (0% of those under 25 years and 20.2% over 65 years old). The frequency of gastric atrophy was similar (12% vs 13%) but H pylori infection rate was slightly higher (77% vs 71%) in the high-risk compared to the low-risk counties. Based on their estimated gastric cancer risk, individuals were classified as: low-risk group (no H pylori infection and no atrophy; n = 115; 21.4%); moderate-risk group (H pylori infection but no atrophy; n = 354, 66.0%); and high-risk group (gastric atrophy, with or without H pylori infection; n = 67, 12.5%). The high-risk group was significantly older (mean age: 61.9+/-13.3 years), more frequently men and less educated as compared with the low-risk group.. We propose to concentrate on an upper gastrointestinal endoscopy for detection of early gastric cancer in the high-risk group. This intervention model could improve the poor prognosis of gastric cancer in Chile.

Topics: Adult; Aged; Aged, 80 and over; Atrophy; Chile; Female; Gastric Mucosa; Gastrins; Humans; Male; Middle Aged; Pepsinogen A; Pepsinogen C; Reference Values; Risk Factors; Stomach Neoplasms

The conventional view of gastric acid secretion is that a negative feedback mechanism arises in response to high acidity, such that somatostatin keeps G-cells and parietal cells from producing more gastrin and acid, respectively. When the stomach becomes infected, for example with Helicobacter pylori (H. pylori), the feedback mechanism is impaired. In animal models, our laboratory has demonstrated that other types of bacteria besides H. pylori can cause gastritis. For example, under conditions of low acidity, gastritis is secondary to bacterial overgrowth, not production of excessive acid, thus suggesting a new paradigm for the regulation of gastric acid secretion under inflammatory conditions. Cytokines, released during the gastric inflammatory response, including IFN gamma, TNF alpha and IL-1 beta stimulate the G-cell to produce gastrin. Gastrin in turn triggers the release of acid, and hypergastrinemia suppresses somatostatin, the inhibitor of acid. The overall response results in maximal gastric acid output that acts as the stomach's most important anti-microbial agent. The increased acid secretion by the stomach in the presence of H. pylori seems to be part of the innate immune response, in that gastrin and somatostatin are reciprocally regulated by Th1 or Th2 cytokines, respectively. In a mouse model, we showed that octreotide, a somatostatin, analog, is an efficacious treatment for Helicobacter gastritis. In humans, octreotide might accelerate recovery from H. pylori infection, reducing the duration of antibiotic therapy.

Topics: Cytokines; Feedback; Gastric Acid; Gastrins; Gastritis; Helicobacter Infections; Humans; Stomach Neoplasms

The preoperative localization of gastrinomas often fails despite all modern imaging methods. Therefore, after biochemical confirmation of the diagnosis and exclusion of diffuse metastases, a meticulous surgical exploration including intraoperative ultrasound (IOUS) and duodenal exploration after duodenotomy should be performed. The experienced surgeon will be able to identify more than 90% of the primary tumors. Depending on the localization, excision of the tumor in the duodenal wall or enucleation from the pancreatic head should be performed. If the tumor is localized in the tail of the pancreas, distal pancreatectomy is the treatment of choice. Complete resection of the tumor is the only curative approach for the patients. For MEN-1 gastrinomas a spleen-preserving distal pancreatectomy with enucleation of tumors of the pancreatic head and duodenotomy with excision of duodenal gastrinomas should be performed. If the source of gastrin secretion can be regionalized to the pancreatic head by a preoperative SASI angiography, a pylorus-preserving partial pancreaticoduodenectomy might be the treatment of choice.

Topics: Adult; Aged; Chromosomes, Human, Pair 11; Duodenal Neoplasms; Endosonography; Female; Follow-Up Studies; Gastrinoma; Gastrins; Genes, Dominant; Germ-Line Mutation; Humans; Male; Middle Aged; Multiple Endocrine Neoplasia Type 1; Pancreatic Neoplasms; Pancreaticoduodenectomy; Reoperation; Secretin; Stomach Neoplasms; Survival Rate; Zollinger-Ellison Syndrome

Corpus dominant gastritis and intestinal metaplasia (IM) are considered markers of increased risk of gastric carcinoma. The aim of our study was to determine serum and histologic risk markers of gastric cancer. Antral and corpus histology, pepsinogen and gastrin 17 levels were compared among patients with history of endoscopic mucosal resection (EMR) for early gastric cancer and controls. Serum pepsinogen (PG) and gastrin 17 levels were measured by RIA. There were 53 gastric cancer patients and 75 controls. The scores for IM in each region and atrophy at the lesser curvature of the corpus were significantly higher in the cancer group than in the H. pylori-positive control group. IM at the greater curvature of the corpus and atrophy at the lesser curvature of the corpus were associated with multiple malignant lesions. Although corpus gastritis was associated with an increased risk of gastric cancer (odds ratio [OR] = 3.4; 95% confidence interval [CI] 1.6-7.0) (p = 0.001), the most important marker was the presence of IM at the lesser curvature of the corpus (OR = 15.1; 95% CI 4.3-52.6) (p < 0.001)). The best cut-off points of serum markers for gastric cancer were a PG I concentration of 45 ng/mL or less and a gastrin 17 >60 pg/mL (sensitivity = 83%; specificity = 68%). IM at the lesser curvature of the corpus and the combination of serum gastrin 17 and PG I identified a group at high risk for development of gastric cancer. Annual endoscopic follow-up is warranted for patients with IM found at the greater curvature of the corpus.

Topics: Aged; Biomarkers; Case-Control Studies; Endoscopy; Female; Gastric Mucosa; Gastrins; Helicobacter Infections; Helicobacter pylori; Humans; Intestinal Mucosa; Male; Metaplasia; Pepsinogen A; Pepsinogen C; Pyloric Antrum; Stomach Neoplasms

The current study tests the hypothesis that chronic atrophic gastritis from hypochlorhydria in the gastrin-deficient mouse predisposes the stomach to gastric cancer. Gross morphology and histology of 12-month-old wild-type (WT), gastrin-deficient (G-/-) and somatostatin-deficient (SOM-/-) mice were examined. Parietal and G cells, Ki67, TUNEL, villin and MUC2 expression were analysed by immunohistochemistry. RUNX3 and STAT3 expression was analysed by Western blot. Anchorage-independent growth was determined by cell cluster formation in soft agar. Compared to the WT and SOM-/- mice, hypochlorhydric G-/- mice developed parietal cell atrophy, significant antral inflammation and intestinal metaplasia. Areas of metaplasia within the G-/- mouse stomach showed decreased RUNX3 expression with elevated MUC2 and villin expression. Cells isolated from the tumor grew in soft agar. However, the cells isolated from WT, nontransformed G-/- and SOM-/- gastric tissue did not form colonies in soft agar. Consistent with elevated antral proliferation, tumor tissue isolated from the G-/- mice showed elevated phosphorylated STAT3 expression. We then examined the mechanism by which STAT3 was constitutively expressed in the tumor tissue of the G-/- mice. We found that IFNgamma expression was also significantly higher in the tumor tissue of G-/- mice compared to WT and SOM-/- animals. To determine whether STAT3 was regulated by IFNgamma, MKN45 cells were cocultured with IFNgamma or gastrin. IFNgamma significantly stimulated phosphorylation of STAT3 in the MKN45 cell line, but not gastrin. Therefore, we show here that in the hypochlorhydric mouse stomach, the chronic gastritis, atrophy, metaplasia, dysplasia paradigm can be recapitulated in mice. Moreover, neoplastic transformation of the antral gastric mucosa does not require gastrin.

Topics: Adenocarcinoma; Animals; Base Sequence; Blotting, Western; Chronic Disease; Disease Progression; DNA Primers; Gastrins; Gastritis; Immunohistochemistry; Mice; Radioimmunoassay; Reverse Transcriptase Polymerase Chain Reaction; Stomach Neoplasms

It is controversial as to whether the development of gastric cancer is influenced by Helicobacter pylori eradication. If eradication itself influences the tumour morphology, this may affect the tumour discovery rate.. To investigate the morphological changes in the gastric neoplasm after H. pylori eradication.. We studied 37 patients with eradication therapy. After a 1-month follow-up, endoscopic re-evaluation was performed and the appearance was compared with first image. All lesions were resected endoscopically, and were subjected to histological assessment and to immunohistochemistry. Serum gastrin levels were determined before and after eradication.. Twenty-nine of 37 patients underwent successful eradication. The appearance of 11 lesions (33% of 33 lesions) became indistinct after successful eradication. All lesions were of the superficial-elevated type and the height of the lesions decreased. We detected normal columnar epithelium over the neoplasm in eight of the lesions. Higher expression of single-stranded deoxyribonucleic acid in the deep area was characteristic in tumours with an indistinct appearance. These changes did not correlate with the serum gastrin levels.. The morphology of the gastric neoplasm change after eradication in the short-term. This may contribute to the decreased tumour discovery rate.

Topics: Adenocarcinoma; Adenoma; Aged; Aged, 80 and over; Endoscopy, Gastrointestinal; Female; Follow-Up Studies; Gastrins; Helicobacter Infections; Helicobacter pylori; Humans; Immunohistochemistry; Ki-67 Antigen; Male; Middle Aged; Pepsinogen A; Stomach Neoplasms

Little is known about the natural course of multiple gastric carcinoids associated with type A gastritis. Between 1993 and 2003, we enrolled eight patients, diagnosed as having multiple gastric carcinoids associated with type A gastritis, in a follow-up program without surgical resection. In these patients, endoscopy showed multiple small polyps on the gastric body, with nonantral atrophic gastritis. Histologically, biopsy specimens obtained from the polyps revealed carcinoid tumors. The serum gastrin level was found to be very high in all patients, and testing for anti-parietal cell antibody was positive in seven. The mean follow-up was 5.8 years (range, 1.5-10.8 years). The levels of serum gastrin increased in all patients, but, endoscopically, the carcinoid tumors did not change in size. Neither hepatic nor lymphatic metastasis was detected on abdominal computed tomography (CT). These patients were free of the development or metastasis of carcinoids, in spite of their continuous hypergastrinemia. It was concluded that multiple gastric carcinoids associated with type A gastritis may be indolent.

Topics: Aged; Biopsy; Carcinoid Tumor; Endoscopy, Gastrointestinal; Female; Follow-Up Studies; Gastrins; Gastritis; Humans; Male; Middle Aged; Neoplasm Metastasis; Prognosis; Stomach Neoplasms

Intestinal metaplasia (IM) in the human stomach has previously been classified into a gastric and intestinal mixed (GI-IM) and a solely intestinal phenotype (I-IM). The phenotypes of mucous and endocrine cells were evaluated in 3034 glandular ducts associated with chronic gastritis. In the pyloric region, the relative expression of gastric endocrine cell markers, such as gastrin and somatostatin, decreased gradually from glandular ducts with only gastric mucous cell phenotype (G type) to GI-IM toward I-IM, while that of the intestinal endocrine cell markers, glicentin, gastric inhibitory polypeptide (GIP), and glucagon-like peptide-1 (GLP-1) was inversely correlated. In the fundic region, gastrin-positive cells emerged in the pseudo-pyloric and GI-IM glands, whereas I-IM glands did not possess any gastrin-positive cells, suggesting the presence of a distinct pathway of intestinalization. Double staining revealed coexistence of gastrin- and GLP-1-positive cells in the same gland and occasionally in the same cell in GI-IM glands. These results suggest that the phenotypes of endocrine cells are in line with those for mucous counterparts and support the concept that all of the different types of mucous and endocrine cells in normal and IM glands might be derived from a single progenitor cell in each gland.

Topics: Aged; Chromogranin A; Chromogranins; Endocrine Glands; Female; Gastric Fundus; Gastric Inhibitory Polypeptide; Gastric Mucosa; Gastrins; Glicentin; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Humans; Immunohistochemistry; Intestines; Male; Metaplasia; Middle Aged; Peptide Fragments; Protein Precursors; Pyloric Antrum; Somatostatin; Stomach Neoplasms

To study the effect of IGF-1/IGF-1R and gastrin/CCK-BR on carcinogenesis and development of human gastric carcinoma and to explore its mechanism and provide a credible theoretical foundation for early diagnosis and molecular therapy of gastric carcinoma.. mRNA expression levels of IGF-1/IGF-1R and gastrin/CCK-BR were assessed by RT-PCR method in gastric cancer tissues, adjacent mucosa, and tumor-free tissues from 56 patients with gastric carcinoma and normal gastric mucosae from 56 healthy controls. Tissue specimens were obtained by biopsy and confirmed by histological evaluation.. The mRNA levels of IGF-1/IGF-1R were increased in gastric cancer tissues compared with normal tissues from healthy controls and successively increased in tumor-free tissues, adjacent mucosa, and gastric cancer tissues. The mRNA levels of gastrin/CCK-BR were increased in gastric cancer tissues compared with normal tissues from healthy controls. There was a significant difference between gastric cancer tissues and adjacent mucosa and tumor-free tissues, but the mRNA levels of gastrin were not significantly increased in adjacent mucosa and gastric cancer tissues compared with tumor-free tissues. The mRNA levels of CCK-BR were increased in gastric cancer tissues and adjacent mucosa compared with tumor-free tissues, but not significantly increased in adjacent mucosa and gastric cancer tissues compared with gastric cancer tissues.. Overexpression of IGF-1/IGF-1R and gastrin/CCK-BR promotes the disorderly proliferation of gastric mucosa epithelia and it is of great significance in the carcinogenesis and development of gastric carcinoma.

Topics: Gastrins; Gene Expression Regulation, Neoplastic; Humans; Insulin-Like Growth Factor I; Receptor, Cholecystokinin B; Receptor, IGF Type 1; Stomach Neoplasms

Apart from its importance as an acid secretogogue, the role of histamine as a downstream target of gastrin has not been fully explored. Previous studies have shown that the combination of hypergastrinemia and Helicobacter infection resulted in accelerated gastric cancer in mice. We used this model to examine the role of cholecystokinin 2 (CCK2)/gastrin receptor and histamine H2-receptor signaling in the development of gastric atrophy and cancer.. Male hypergastrinemic mice (INS-GAS mice) were infected with Helicobacter felis and given the CCK2/gastrin receptor antagonist YF476 and/or the histamine H2-receptor antagonist loxtidine for 3 or 6 months. In addition, mice were treated with omeprazole alone or in combination with either YF476 or loxtidine for 3 months.. Mice treated with YF476 or loxtidine alone showed partial suppression of both gastric acid secretion and progression to neoplasia. The combination of YF476 plus loxtidine treatment resulted in nearly complete inhibition of both parameters. YF476 and/or loxtidine treatment did not alter the overall level of H. felis colonization but did result in significant down-regulation of the growth factors regenerating gene I and amphiregulin. Loxtidine treatment, with or without YF476, induced a mild shift in T-helper cell polarization. In contrast, omeprazole treatment resulted in mild progression of gastric hyperplasia/dysplasia, which was ameliorated by the addition of YF476 or loxtidine.. The combination of CCK2/gastrin- and histamine H2-receptor antagonists has synergistic inhibitory effects on development of gastric atrophy and cancer in H. felis/INS-GAS mice, while the proton pump inhibitor showed no such effects. These results support an important role for the gastrin-histamine axis in Helicobacter-induced gastric carcinogenesis.

Topics: Achlorhydria; Animals; Atrophy; Benzodiazepinones; Disease Models, Animal; Gastrins; Helicobacter felis; Helicobacter Infections; Histamine H2 Antagonists; Male; Mice; Mice, Transgenic; Phenylurea Compounds; Receptor, Cholecystokinin B; Receptors, Cholecystokinin; Receptors, Histamine H2; Stomach Neoplasms; Triazoles

To analyze tumor biology and the outcome of differentiated treatment in relation to tumor subtype in patients with gastric carcinoid.. Gastric carcinoids may be subdivided into ECL cell carcinoids (type 1 associated with atrophic gastritis, type 2 associated with gastrinoma, type 3 without predisposing conditions) and miscellaneous types (type 4). The biologic behavior and prognosis vary considerably in relation to type.. A total of 65 patients from 24 hospitals (51 type 1, 1 type 2, 4 type 3, and 9 type 4) were included. Management recommendations were issued for newly diagnosed cases, that is, endoscopic or surgical treatment of type 1 and 2 carcinoids (including antrectomy to abolish hypergastrinemia) and radical resection for type 3 and 4 carcinoids.. Infiltration beyond the submucosa occurred in 9 of 51 type 1, 4 of 4 type 3, and 7 of 9 type 4 carcinoids. Metastases occurred in 4 of 51 type 1 (3 regional lymph nodes, 1 liver), the single type 2 (regional lymph nodes), 3 of 4 type 3 (all liver), and 7 of 9 type 4 carcinoids (all liver). Of the patients with type 1 carcinoid, 3 had no specific treatment, 40 were treated with endoscopic or surgical excision (in 10 cases combined with antrectomy), 7 underwent total gastrectomy, and 1 underwent proximal gastric resection. Radical tumor removal was not possible in 2 of 4 patients with type 3 and 7 of 9 patients with type 4 carcinoid. Five- and 10-year crude survival rates were 96.1% and 73.9% for type 1 (not different from the general population), but only 33.3% and 22.2% for type 4 carcinoids.. Subtyping of gastric carcinoids is helpful in the prediction of malignant potential and long-term survival and is a guide to management. Long-term survival did not differ from that of the general population regarding type 1 carcinoids but was poor regarding type 4 carcinoids.

Topics: Adult; Aged; Aged, 80 and over; Carcinoid Tumor; Cohort Studies; Female; Gastrectomy; Gastric Mucosa; Gastrins; Gastroscopy; Humans; Male; Middle Aged; Neoplasm Staging; Probability; Prognosis; Proportional Hazards Models; Prospective Studies; Risk Assessment; Stomach Neoplasms; Survival Rate; Treatment Outcome

The role of enterochromaffin-like (ECL) cells in gastric carcinogenesis is not fully understood. Spontaneous tumours developing in hypergastrinemic female cotton rats have an adenocarcinoma phenotype, but numerous cells in the dysplastic mucosa as well as in the carcinomas are positive for neuroendocrine markers. In the present study of female cotton rats with 2 and 8 months' hypergastrinemia, the oxyntic mucosa of the stomach was examined histologically and immunolabelled for histidine decarboxylase (HDC) and pancreastatin, and hyperplastic and neoplastic ECL cells were evaluated by electron microscopy. These animals developed hyperplasia of the oxyntic mucosa in general and of the ECL cells in particular after 2 months and dysplasia and carcinomas after 8 months. The immunoreactivity of the ECL cells in the oxyntic mucosa was increased at 2 months and declined at 8 months. These histological changes were associated with progressive loss of secretory vesicles and granules in ECL cells. We suggest that ECL cells in hypergastrinemic cotton rats dedifferentiate with time and that the gastric carcinomas may develop from ECL cells.

Topics: Animals; Carcinoma; Cell Transformation, Neoplastic; Chromogranin A; Enterochromaffin-like Cells; Female; Gastrins; Histidine Decarboxylase; Hyperplasia; Pancreatic Hormones; Parietal Cells, Gastric; Rats; Sigmodontinae; Stomach Neoplasms

To investigate the expression of gastrin in human gastric cancer cell line SGC-7901 and the effects of gastrin-17 and anti-gastrin mAb on its growth.. The expression of gastrin was determined by immunohistochemistry with anti-gastrin mAb prepared by our group. In a series of experiments, the growth of SGC-7901 cells was evaluated by MTT assay on cells grown in serum-free medium and treated with gastrin-17 and/or anti-gastrin mAb.. Immunohistochemical examination of SGC-7901 cells revealed a specific gastrin immunoreactivity. Gastrin-17 significantly stimulated cell growth at the concentrations of 1 x 10(-9) mol/L approximately 1 x 10(-5) mol/L in a dose-dependent manner. The growth of SGC-7901 cells treated with anti-gastrin mAb, either alone or in combination with gastrin-17 (1 x 10(-7) mol/L), was significantly inhibited.. Growth of human gastric cancer cells SGC-7901 can be stimulated in an autocrine fashion. The gastrin-stimulated growth of gastric cancer cells can be blocked by anti-gastrin mAb bound specifically with gastrin. Further study on the significance of anti-gastrin mAb in designing immunotherapy targeting to gastrin or gastrin receptor is warranted.

Topics: Antibodies, Monoclonal; Cell Line, Tumor; Cell Proliferation; Gastrins; Humans; Receptor, Cholecystokinin B; Stomach Neoplasms

This study was aimed at investigating the effect of gastrin on the growth of gastric cancer and evaluating postoperative hypergastrinemia in patients that had received various types of gastrectomy for gastric cancer. RT-PCR for gastrin/CCKB receptor mRNA was performed in human gastric cancer cell lines and tissue. The effect of gastrin or glycine-extended gastrin on the growth of gastric cancer cell lines was determined by MTT assay. Serum gastrin levels were compared with respect to the resection type of gastric cancer surgery. Gastrin/CCKB receptor mRNA expression was detected in all 9 gastric cancer cell lines, and in 19 of 29 (62%) gastric cancer tissue samples. Growth of gastric cancer cell lines containing the gastrin/CCKB receptor was significantly enhanced by gastrin and glycine-extended gastrin. The proximal gastrectomy group had a significantly higher mean serum gastrin level than the distal subtotal gastrectomy, total gastrectomy, or preoperative groups (p<0.05). Our study confirms that a high proportion of gastric cancer tissue samples express the gastrin/CCKB receptor, which can stimulate the growth of gastrin/CCKB receptor-positive gastric cancer cells. In addition, we confirm that hypergastrinemia can be induced in about half of patients after proximal gastrectomy. More studies are needed to clarify the relationship between hypergastrinemia and tumor recurrence after proximal gastrectomy.

Topics: Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Gastrectomy; Gastrins; Humans; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Stomach Neoplasms

To study the expression of gastrin(GAS) and gastrin releasing peptide(GRP) in patients with gastric cancer and investigate the clinical significance.. The expression of GAS and GRP in sixty patients with gastric cancer was detected by using tissue chip technique and immunohistochemical methods.. The positive rates of GAS and GRP were 30.0% and 11.7% respectively in 60 cases with gastric cancer. The positive rates of GAS and GRP were higher in moderately and poorly differentiated cancers than those in well differentiated cancer (P< 0.05). The positive rates of GAS and GRP were significantly higher in mucinous adenocarcinoma and signet-ring cell carcinoma than those in other types of gastric cancer (P< 0.05). The positive expression of GAS and GRP in gastric cancer was correlated with lymph node metastasis (P< 0.05).. Tissue chip technique is a feasible,rapid,economic and accurate approach for screening clinical tissue specimens on a large scale.

Topics: Adult; Aged; Female; Gastrin-Releasing Peptide; Gastrins; Humans; Immunohistochemistry; Male; Middle Aged; Neoplasm Invasiveness; Neoplasm Staging; Protein Array Analysis; Stomach Neoplasms

Topics: Carcinoid Tumor; Female; Gastrins; Gastritis; Humans; Middle Aged; Multiple Endocrine Neoplasia Type 1; Proto-Oncogene Proteins; Stomach Neoplasms

Determining how Helicobacter pylori promotes gastric cancer and whether H pylori eradication decreases cancer risk would be helped by suitable murine models. Mice lacking the cyclin-dependent kinase inhibitor p27kip1 are susceptible to carcinogen-induced tumors. Furthermore, p27 stimulates gastric epithelial apoptosis and inhibits proliferation, expression is decreased by H pylori, and low levels are associated with a poor prognosis in gastric cancer. We therefore evaluated p27-deficient mice as a model for H pylori-associated gastric cancer.. Wild-type and p27-/- C57BL/6 mice were infected with H pylori mouse-adapted Sydney strain at 6-8 weeks of age and 6-10 mice of each type were euthanized 15, 30, 45, 60, and 75 weeks later.. Uninfected p27-/- mice developed gastric hyperplasia. H pylori-infected p27-/- mice frequently developed intestinal metaplasia (40% at 30 weeks, 67% at 45 weeks), and after 60 weeks 7 of 12 mice developed significant dysplasia and gastric cancer, recapitulating human intestinal-type gastric carcinogenesis. Wild-type mice developed intestinal metaplasia only after 75 weeks of infection; significant gastric dysplasia was observed in 1 animal (P < .05 for each comparison with p27-/- mice). No disease developed in uninfected mice. H pylori infection in p27-/- mice was associated with significantly decreased apoptosis and increased epithelial proliferation, inflammation, and H pylori density compared with infection in wild-type mice.. p27 loss and H pylori colonization cooperate to produce gastric cancer. The p27-deficient mouse affords opportunities to examine the pathogenesis of H pylori in gastric carcinogenesis and to test eradication and chemopreventive strategies.

Topics: Animals; Apoptosis; Cell Division; Cyclin-Dependent Kinase Inhibitor p27; Female; Gastrins; Gastritis; Genetic Predisposition to Disease; Helicobacter Infections; Helicobacter pylori; Hyperplasia; Male; Metaplasia; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Stomach Neoplasms

Topics: Aged; Diagnosis, Differential; Female; Gastrins; Gastritis, Atrophic; Gene Expression Regulation, Enzymologic; Helicobacter Infections; Helicobacter pylori; Humans; Middle Aged; Ornithine Decarboxylase; Prostaglandin-Endoperoxide Synthases; Stomach Neoplasms

We have developed a mouse model of gastric cancer that resembles human intestinal-type adenocarcinoma. The aim of this study was to determine the identity and temporal changes in mediators of IL-6 signaling regulating tumor development.. gp130(757F/F) Mice that lack the SHP2-binding site on the IL-6 family receptor gp130 and have increased STAT 3 activity and wild-type littermates were used. Cohorts were assessed by quantitative histology and immunohistochemistry for gastric cell phenotype and proliferation markers from 4 to 40 weeks of tumor development. Northern blotting and in situ hybridization were used to quantify expression of the tumor suppressor TFF1 and the mitogens gastrin and Reg I. Expression of epidermal growth factor receptor (EGFr) and its ligands was measured by RT-PCR analysis. Age-matched differences in gene expression profiles were tested by ANOVA.. Hyperplastic antral tumors with inflammation and ulceration were evident in gp130(757F/F) mice at 4 weeks of age and reached maximum size by 20 weeks. Tumor progression was marked by gastritis, atrophy, intestinal metaplasia, dysplasia, and submucosal invasion after 30 weeks. Both TFF1 and gastrin expression were progressively inhibited during tumorigenesis, whereas Reg I was stimulated. The EGFr and its ligands transforming growth factor (TGF)-alpha and heparin-binding EGF had increased expression corresponding to maximal tumor growth.. gp130(757F/F) Mice rapidly develop distal stomach tumors, with loss of SHP2/Erk/AP-1 transcriptional regulation exemplified by decreased TFF1 expression and increased STAT1/3 regulated genes such as Reg I. Tumor development occurs in a hypogastrinemic environment. Balanced IL-6 signaling is required for maintaining gastric homeostasis.

Topics: Adenoma; Animals; Antigens, CD; Binding Sites; Calcium-Binding Proteins; Cytokine Receptor gp130; Down-Regulation; Gastric Mucosa; Gastrins; Lithostathine; Membrane Glycoproteins; Mice; Mice, Transgenic; Mucins; Muscle Proteins; Mutation; Nerve Tissue Proteins; Peptides; Stomach Neoplasms; Trefoil Factor-1; Trefoil Factor-2

Many studies have investigated the expression of c-met and c-erbB2 protein in human gastric adenocarcinomas, but the expression of gastrin protein in human gastric cancer and the relationship between gastrin and c-met are unknown. We have constructed a tissue microarray containing 408 formalin-fixed and paraffin-embedded human tissue blocks, including tissues containing intestinal metaplasia (IM, n=72) and primary tumors (n=232), as well as normal gastric mucosa (n=104) from patients with gastric cancer. Immunohistochemistry (IHC) was used for detecting gastrin, c-met and c-erbB2 proteins. Gastrin was detected in 13.5% (7/52) and c-met in 15.3% (11/72) of IM cases. In gastric carcinomas, 48.4% (103/213) of cases expressed gastrin, 68.8% (148/215) expressed c-met, and 5.5% (11/200) expressed c-erbB2. Gastrin and c-met protein expression were significantly higher in gastric tumor tissue than in IM (P<0.0001). Overexpression of c-erbB2 protein was detected in gastric carcinomas but not in normal gastric mucosa (P<0.05). Expression of gastrin and c-met protein was associated (P<0.01), but no significant difference was found on the changes of gastrin, c-met and c-erbB2 expression in gastric cancer with tumor stage, grade of differentiation or tumor type. These results indicate that gastrin and c-met play a role in the early process during malignant transformation of the gastric mucosa.

Topics: Adenocarcinoma; Adult; Aged; Diagnosis, Differential; Female; Gastric Mucosa; Gastrins; Humans; Intestinal Mucosa; Intestine, Small; Male; Metaplasia; Middle Aged; Oligonucleotide Array Sequence Analysis; Proto-Oncogene Proteins c-met; Reference Values; Retrospective Studies; Stomach Neoplasms

Among inbred female cotton rats (Sigmodon hispidus) 25-50% of the animals develop spontaneous gastric carcinomas; the corresponding figure for male cotton rats is approximately 1%. Animals with carcinomas have hypergastrinaemia and gastric hypo-anacidity and the tumours are derived from enterochromaffin-like (ECL) cells. The mechanism behind the hypo-anacidity is unknown. Carcinomas are found in all female cotton rats with hypergastrinaemia lasting more than 4 months and this represents an excellent animal model for studying gastric carcinogenesis. In this study, the somatostatin analogue octreotide was given to female cotton rats to prevent carcinoma development caused by hypergastrinaemia. Twelve female cotton rats were given monthly injections of long-acting octreotide (5 mg i.m.) for 6 months. A control group of 20 animals was not given injections. Of the 20 control animals, 13 developed hypergastrinaemia and histologically invasive carcinomas or dysplasia. Of the 12 animals in the octreotide group, five developed hypergastrinaemia. None of these five animals developed histological cancer (P<0.05), whereas three had dysplasia. However, octreotide did not affect plasma gastrin concentration or antral gastrin mRNA abundance significantly. Dysplasia of the oxyntic mucosa in hypergastrinaemic animals was accompanied by a marked increase in chromogranin A-immunoreactive cells and cells positive for Sevier-Munger staining. The malignant tissue also contained groups of cells with Sevier-Munger staining. In conclusion, octreotide prevented ECL cell carcinomas in hypergastrinaemic cotton rats without lowering the gastrin concentration.

Topics: Animals; Antineoplastic Agents, Hormonal; Carcinoma; Chromogranin A; Chromogranins; Enterochromaffin-like Cells; Female; Gastrins; Immunochemistry; Octreotide; Parietal Cells, Gastric; Rats; RNA, Messenger; Sigmodontinae; Stomach Neoplasms

To compare the expression patterns of cholecystokinin-B (CCK-B)/gastrin receptor genes in matched human gastric carcinoma and adjacent non-neoplastic mucosa of patients with gastric cancer, inflammatory gastric mucosa from patients with gastritis, normal stomachs from 2 autopsied patients and a gastric carcinoma cell line (SGC-7901), and to explore their relationship with progression to malignancy of human gastric carcinomas.. RT-PCR and sequencing were employed to detect the mRNA expression levels of CCK-B receptor and gastrin gene in specimens from 30 patients with gastric carcinoma and healthy bordering non-cancerous mucosa, 10 gastritis patients and normal stomachs from 2 autopsied patients as well as SGC-7901. The results were semi-quantified by normalizing it to the mRNA level of beta-actin gene using Lab Image software. The sequences were analyzed by BLAST program.. CCK-B receptor transcripts were detected in all of human gastric tissues in this study, including normal, inflammatory and malignant tissues and SGC-7901. However, the expression levels of CCK-B receptor in normal gastric tissues were higher than those in other groups (P<0.05), and its expressions did not correlate with the differentiation and metastasis of gastric cancer (P>0.05). On the other hand, gastrin mRNA was detected in SGC-7901 and in specimens obtained from gastric cancer patients (22/30) but not in other gastric tissues, and its expression was highly correlated with the metastases of gastric cancer (P<0.05).. Human gastric carcinomas and gastric cancer cell line SGC-7901 cells coexpress CCK-B receptor and gastrin mRNA. Gastrin/CCK-B receptor autocrine or paracrine pathway may possibly play an important role in the progression of gastric cancer.

Topics: Base Sequence; Cell Line, Tumor; Gastric Mucosa; Gastrins; Gene Expression; Humans; Molecular Sequence Data; Receptor, Cholecystokinin B; Stomach Neoplasms

Duodenogastric reflux is known to cause an increased frequency of cancer in the glandular portion of the stomach in rats. Furthermore, it is debated whether inhibition of gastric acid secretion may promote gastric carcinogenesis. In the present study we examined the combined effect of gastroduodenal reflux and acid inhibition with respect to the development of gastric carcinoma in the rat.. Following the construction of a gastrojejunostomy in male Wistar rats, half of them were given the proton pump inhibitor lanzoprazole for 1 year. The rats were then killed and the pH in the stomach and gastrin in blood were measured. The stomach was examined macroscopically as well as histologically.. Gastrin levels at autopsy were significantly increased in treated rats compared to the control group, confirming an effect of lanzoprazole on gastric acid secretion. Body weight was significantly reduced in the treated rats. Thirty of 79 rats developed gastric cancer, and they were all adenocarcinomas of the Lauren intestinal type. Gastric cancers occurred significantly more often in lanzoprazole-treated rats (50%) compared with controls (27%).. Lanzoprazole given orally enhances the carcinogenic effect of duodenogastric reflux in rats.

Topics: 2-Pyridinylmethylsulfinylbenzimidazoles; Adenocarcinoma; Administration, Oral; Animals; Duodenogastric Reflux; Enzyme Inhibitors; Gastrins; Lansoprazole; Male; Omeprazole; Rats; Rats, Wistar; Stomach Neoplasms

Ghrelin, a recently discovered peptide isolated from the gastric corpus mucosa, is believed to be important in the regulation of growth hormone secretion and has been shown to increase appetite and food intake as well. It may also have other gastrointestinal and cardiac functions. Because a cell of origin for ghrelin has not been convincingly identified in the gastric mucosa thus far, we studied the immunohistochemical expression of ghrelin in proliferative lesions of the enterochromaffin-like (ECL) cells-a cell that is not only exclusively confined to the gastric corpus mucosa but is its dominant endocrine cell type as well. Formalin-fixed, paraffin embedded tissues from three cases of gastric ECL cell hyperplasia and five ECL carcinoids (three with coexisting foci of diffuse, linear, and micronodular hyperplasia) were immunohistochemically stained for ghrelin, using a commercially available antibody. The Sevier-Munger stain for ECL cells and immunohistochemical stains for chromogranin, gastrin, serotonin, somatostatin, and vesicular monoamine transporter-2 (VMAT-2) were performed on parallel sections for correlation with the ghrelin staining results. All ECL cell carcinoids and hyperplastic lesions were positive for both the Sevier-Munger and the immunohistochemical stains for chromogranin and VMAT-2. Immunoreactivity for ghrelin was seen in 4/5 ECL carcinoids, all cases of ECL cell hyperplasia, as well as in all areas with linear and micronodular hyperplasia adjacent to the ECL cell carcinoids. In each instance, such staining was confined to the Sevier-Munger, and VMAT-2 positive cells only. Our findings indicate that the ECL cells are either the ghrelin-producing cells of the gastric mucosa or acquire the capability to synthesize ghrelin during proliferative states encompassing the entire hyperplasia to neoplasia spectrum. In view of the orexigenic and other known actions of ghrelin, the functional and/or biologic significance of ghrelin production in such ECL cell proliferations needs to be investigated further.

Topics: Carcinoid Tumor; Chromogranins; Enterochromaffin-like Cells; Gastric Mucosa; Gastrins; Ghrelin; Humans; Hyperplasia; Immunohistochemistry; Membrane Glycoproteins; Membrane Transport Proteins; Peptide Hormones; Retrospective Studies; Serotonin; Somatostatin; Stomach Neoplasms; Vesicular Biogenic Amine Transport Proteins; Vesicular Monoamine Transport Proteins

Topics: Aged; Carcinoid Tumor; Female; Gastrins; Humans; Neoplastic Processes; Stomach Neoplasms

The expression of members of the Reg family of secreted lectin-like proteins is increased in response to stress, inflammation and damage in many tissues. In the stomach, Reg is located in enterochromaffin-like cells, where its expression is stimulated by the gastric hormone gastrin. We have examined the mechanisms by which gastrin stimulates expression of Reg-1. Deletional mutations of 2.1 to 0.1 kb of the rat Reg-1 promoter in a luciferase reporter vector were transiently transfected into gastric cancer AGS-G(R) cells. All promoter fragments tested showed similar relative increases in luciferase expression in response to gastrin (1 nM). The response to gastrin of the smallest (104 bp) construct was 4.2+/-0.4-fold over basal. These responses were reduced by Ro-32-0432, a protein kinase C inhibitor, by C3-transferase, a Clostridium botulinum toxin and a selective inhibitor of the Rho family GTPase RhoA, and by co-transfection with a dominant negative form of RhoA. Co-transfection with a constitutively active form of RhoA stimulated expression 11.6+/-1.7-fold over basal. Mutations through the 104 bp construct identified a C-rich element (C-79CCCTCCC-72) required for responses to gastrin, PKC (protein kinase C) and L63RhoA (the constitutively active form of human RhoA protein containing a glutamine-to-leucine substitution at position 63). EMSAs (electrophoretic-mobility-shift assays) using nuclear extracts of control and gastrin-stimulated AGS-G(R) cells and a probe spanning -86 to -64 bp revealed multiple binding proteins. There was no effect of gastrin on the pattern of binding. Supershift assays indicated that transcription factors Sp1 and Sp3 bound the C-rich sequence. We conclude that gastrin stimulates Reg expression via activation of PKC and RhoA, that a C-rich region (-79 to -72) is critical for the response and that Sp-family transcription factors bind to this region of the promoter.

Topics: Animals; Base Sequence; Binding Sites; Cytokines; Cytosine; DNA-Binding Proteins; Enzyme Activation; Gastrins; Gene Expression Regulation; Humans; Luciferases; Membrane Proteins; Nerve Tissue Proteins; Promoter Regions, Genetic; Protein Kinase C; Rats; Recombinant Fusion Proteins; rhoA GTP-Binding Protein; Sequence Deletion; Sp1 Transcription Factor; Sp3 Transcription Factor; Stomach Neoplasms; Transcription Factors

Gastrin and its precursors promote proliferation in different gastrointestinal cells. Since mature, amidated gastrin (G-17) can induce cyclin D1, we determined whether G-17-mediated induction of cyclin D1 transcription involved Wnt signaling and CRE-binding protein (CREB) pathways. Our studies indicate that G-17 induces protein, mRNA expression and transcription of the G(1)-specific marker cyclin D1, in the gastric adenocarcinoma cell line AGSE (expressing the gastrin/cholecystokinin B receptor). This was associated with an increase in steady-state levels of total and nonphospho beta-catenin and its nuclear translocation, indicating the activation of the Wnt-signaling pathway. In addition, G-17-mediated increase in cyclin D1 transcription was significantly attenuated by axin or dominant-negative (dn) T-cell factor 4(TCF4), suggesting crosstalk of G-17 with the Wnt-signaling pathway. Mutational analysis indicated that this effect was mediated through the cyclic AMP response element (CRE) (predominantly) and the TCF sites in the cyclin D1 promoter, which was also inhibited by dnCREB. Furthermore, G-17 stimulation resulted in increased CRE-responsive reporter activity and CREB phosphorylation, indicating an activation of CREB. Chromatin immunoprecipitation studies revealed a G-17-mediated increase in the interaction of beta-catenin with cyclin D1 CRE, which was attenuated by dnTCF4 and dnCREB. These results indicate that G-17 induces cyclin D1 transcription, via the activation of beta-catenin and CREB pathways.

Topics: beta Catenin; Cyclic AMP Response Element-Binding Protein; Cyclin D1; Cytoskeletal Proteins; G1 Phase; Gastrins; Humans; Proto-Oncogene Proteins; S Phase; Signal Transduction; Stomach Neoplasms; Trans-Activators; Transcription, Genetic; Wnt Proteins; Zebrafish Proteins

Spontaneously hypergastrinemic cotton rats (Sigmodon hispidus) develop tumors that have the phenotype of an adenocarcinoma but most likely originate from the enterochromaffin-like (ECL) cells. Among inbred animals approximately 50% of the females, but <1% of males develop spontaneous gastric carcinomas. Gastrin is the principle carcinogen in this model, as >4 months of hypergastrinemia results in carcinoma, but a gastrin receptor antagonist prevents carcinomas. Carcinomas can also be induced by partial corpectomy. In the present study, the insurmountable H2-receptor antagonist loxtidine (200 mg/kg/day) was given to male cotton rats for 6 months. The loxtidine-dosed animals developed hypergastrinemia, whereas control animals remained normogastrinemic. At termination, 4 of 5 cotton rats had cancer located to the oxyntic mucosa, whereas 1 animal had dysplasia. The gastric mucosa of all of the control animals was normal. In the dysplastic mucosa of loxtidine-dosed animals there was a marked increase in chromogranin A-positive cells, where numerous groups of cells also stained positive with the Sevier-Munger technique. In areas of high proliferation and cancer there were also histidine decarboxylase, chromogranin A, and Sevier-Munger-positive cells, altogether indicating an ECL cell origin of the tumors. This represents an interesting animal model where ECL cell-derived gastric cancer can be induced by pharmacological acid inhibition in 6 months.

Topics: Animals; Enterochromaffin-like Cells; Female; Gastric Mucosa; Gastrins; Histamine H2 Antagonists; Immunohistochemistry; Male; Organ Size; Rats; Sigmodontinae; Stomach; Stomach Neoplasms; Triazoles

This study was conducted to explore whether cholecystokinin-B/gastrin receptor (CCKBRwt) gene and its alternative splicing variant (CCKBRi4sv) are expressed in human gastric carcinomas cell line and tissues, and to find out their relationship with the development and progression of human gastric carcinoma. The mRNA expression levels of CCKBRwt and CCKBRi4sv were detected in 30 human gastric carcinomas and normal tissues adjacent to cancer, 10 gastritis specimens, 2 autopsied normal stomach specimens as well as in a gastric carcinoma cell line SGC-7901 cells. The results revealed that the transcripts of CCKBRwt and CCKBRi4sv were observed in all of the human gastric specimens tested, but only CCKBRwt was expressed in gastric cancer cell line SGC-7901 cells. The expression levels of the two receptors were not correlated with the differentiation and metastases of gastric cancers. From the results, we infer that human gastric tissues simultaneously express CCKBRwt and CCKBRi4sv, and CCKBRi4sv may have unknown physiological functions in gastric epithelial cells.

Topics: Base Sequence; Epithelial Cells; Gastric Mucosa; Gastrins; Gastritis; Humans; Molecular Sequence Data; Receptor, Cholecystokinin B; RNA, Messenger; Stomach Neoplasms; Tumor Cells, Cultured

We evaluated the relationship between Helicobacter pylori and various factors associated with gastric cancer in two areas in Japan with different risks for mortality due to gastric cancer.. A total of 250 sera from Niigata and 209 from Okinawa were used. H. pylori antibody and CagA antibody were measured by antigen-specific ELISAs. Serum gastrin and pepsinogen levels were determined by RIA.. Although there was no significant difference in H. pylori prevalence among the persons in Niigata (50%) and Okinawa (42%), CagA prevalence in these populations was significantly different, at 41% and 26%, respectively (OR = 1.98, 95%CI: 1.33-2.95, P < 0.01). Serum gastrin levels in Niigata were significantly lower than those in Okinawa in H. pylori-negative persons (P < 0.01). The serum pepsinogen I/II ratio in Niigata was significantly lower than that in Okinawa in H. pylori positive persons (P < 0.01), whereas there was no significant difference in H. pylori-negative persons. Among those positive for H. pylori, serum pepsinogen I/II ratio in Niigata was significantly lower than that in Okinawa in CagA-negative persons (P < 0.01), whereas no significant difference was observed in CagA-positive persons.. These results suggest that the difference in the mortality ratio of gastric cancer between Niigata and Okinawa is mainly associated with the difference between areas in the prevalence of cagA-positive strains rather than that of H. pylori itself.

Topics: Adult; Aged; Antigens, Bacterial; Bacterial Proteins; Enzyme-Linked Immunosorbent Assay; Female; Gastrins; Helicobacter Infections; Helicobacter pylori; Humans; Japan; Male; Middle Aged; Pepsinogens; Risk Factors; Stomach Neoplasms

In patients with Helicobacter pylori infection, the concentration of nitrite in gastric juice is elevated. The degree of elevation correlates with that of inflammation and H. pylori density.. The aim of this study was to examine hypoacidity and high nitrite levels related to H. pylori infection in patients with gastric cancer.. We studied 88 patients with more than one history of endoscopic mucosal resection (EMR) for early gastric cancer and 88 age-matched controls. Concentration of nitrite in gastric juice was measured by Griess reaction, and serum pepsinogen levels were measured by RIA.. Multiple malignant lesions were found in 20 of the 88 patients. Serum gastrin, gastric juice pH and nitrite levels in patients with gastric cancer were significantly higher and pepsinogen I and pepsinogen I/II significantly lower than in control subjects. Pepsinogen I level and I/II ratio were lower and gastric juice pH was higher in the protruded-type group than in the depressed-type group. Pepsinogen I and pepsinogen I/II were lower and gastric juice pH was higher in multiple than in single cases.. Hypoacidity combined with high gastric juice nitrite induced by H. pylori infection is associated with the intestinal type of gastric cancer, especially protruded lesions.

Topics: Aged; Case-Control Studies; Female; Gastric Acid; Gastric Acidity Determination; Gastric Juice; Gastrins; Helicobacter Infections; Helicobacter pylori; Humans; Hydrogen-Ion Concentration; Male; Nitrites; Pepsinogens; Prospective Studies; Stomach Neoplasms

Hypergastrinemia in patients with pernicious anemia is a major regulator contributing to enterochromaffin-cell hyperplasia and, ultimately, to gastric carcinoids.. Between 1990 and 2003, we studied 8 women and 10 men with pernicious anemia and gastric carcinoids; their mean age was 50 years. Serum gastrin levels ranged from 740 to 4,000 pg/mL (mean 1,000 pg/mL). Six patients underwent antrectomy, four total gastrectomy, and eight endoscopic resection or biopsy. During the same period, 22 patients with Zollinger-Ellison tumors and hypergastrinemia (20 men and 2 women, mean age 49 years) had no gastric carcinoids, but 1 of 7 patients with Zollinger-Ellison and multiple endocrine neoplasia (MEN1) tumors had hypergastrinemia and gastric carcinoids.. Mean followup for pernicious anemia patients was 6 years after antrectomy and 1 to 10 years after endoscopic resection or biopsy. Tumor regression was observed in one patient after antrectomy and one patient after biopsy. There were no deaths in this group in spite of lymph node metastasis in two patients. The patient with Zollinger-Ellison and MEN1 syndrome has been followed 3 years after diagnosis and 2 years after total gastrectomy.. Gastric carcinoids are indolent tumors occurring with increasing frequency in patients with pernicious anemia. Antrectomy or biopsy and observation are preferred methods of treatment. Total gastrectomy is reserved for patients with extensive tumor involvement of the gastric wall or for emergency bleeding.

Topics: Adult; Aged; Aged, 80 and over; Anemia, Pernicious; Biopsy; Carcinoid Tumor; Female; Gastrectomy; Gastric Mucosa; Gastrinoma; Gastrins; Gastroscopy; Humans; Hyperplasia; Male; Middle Aged; Multiple Endocrine Neoplasia Type 1; Retrospective Studies; Stomach Neoplasms; Zollinger-Ellison Syndrome

Among inbred female cotton rats (Sigmodon hispidus) 25%-50% of the animals develop spontaneous gastric carcinomas, whereas males have an incidence of less than 1%. The carcinomas are enterochromaffin-like (ECL)-cell derived. Animals with gastric carcinomas also have hypergastrinaemia and gastric hypoacidity, but the mechanism behind the hypoacidity is unknown. Carcinomas have been found in all female cotton rats with spontaneous hypergastrinaemia lasting more than 4 months, and a gastrin receptor antagonist prevents the development of carcinoma. The purpose of the present study was to investigate whether induced hypergastrinaemia in male cotton rats would also result in carcinomas.. Hypergastrinaemia was induced by partial corpectomy of male cotton rats, aiming at removal of 80%-90% of the corpus. A control group was sham-operated.. All partially corpectomized animals developed persistent hypergastrinaemia. Six months after the operation, 9 out of 13 partially corpectomized animals developed gastric cancer. In the dysplastic mucosa surrounding the tumours there was an increase in chromogranin A immunoreactive cells, where numerous cells also were stained using the Sevier-Munger technique. Tumour tissue also contained cells that were chromogranin A positive and stained by Sevier-Munger.. ECL-cell carcinomas can be induced in male cotton rats by partial corpectomy. This supports a previous statement that spontaneous carcinomas in female cotton rats are caused by gastric hypoacidity and hypergastrinaemia. In hypergastrinaemic animals, ECL-cell carcinomas develop independently of gender within a relatively short period of time, and cotton rats therefore represent an interesting model for studying gastric carcinogenesis.

Topics: Animals; Biopsy, Needle; Carcinoma; Disease Models, Animal; Enterochromaffin-like Cells; Gastrectomy; Gastrins; Hydrogen-Ion Concentration; Immunohistochemistry; Male; Probability; Rats; Sensitivity and Specificity; Sigmodontinae; Statistics, Nonparametric; Stomach Neoplasms

In Japan, where the incidence of gastric cancer is high, Helicobacter pylori infection could affect gastric acid secretion differently from that in Western countries. The aim of this study was to investigate the relationship between H. pylori infection, acid secretion, aging, and gender in normal Japanese subjects.. The study comprised 193 Japanese subjects who had undergone routine endoscopy. Gastrin-stimulated acid output was performed during the routine endoscopic examination using the endoscopic method of gastric acid secretory testing (EGT: endoscopic gastrin test), which has been reported previously. H. pylori status was determined by histology, rapid urease test, and serology.. Mean EGT values were 3.9 +/- 1.5 mEq/10 min in H. pylori-negative men, 1.6 +/- 2.5 in H. pylori-positive men, 2.2 +/- 0.9 in H. pylori-negative women, and 1.5 +/- 1.2 in H. pylori-positive women. Although acid secretion was lower in H. pylori-positive subjects compared with H. pylori-negative subjects in both men and women, the decrease was more marked in men with H. pylori infection. Multiple linear regression analysis showed that aging is positively associated with gastric acid secretion in the H. pylori-negative subjects, whereas a negative association was found between them in the H. pylori-positive subjects.. In Japanese subjects, aging affects gastric acid secretion differently depending on the status of H. pylori infection. H. pylori infection showed a stronger inhibitory effect on the acid secretion in men than in women. This gender-related difference in the susceptibility of acid secretion to H. pylori infection may explain the higher rates of gastric cancer in men in Japan.

Topics: Adult; Aged; Aging; Antibodies, Bacterial; Endoscopy, Gastrointestinal; Female; Gastric Acid; Gastric Mucosa; Gastrins; Gastritis; Helicobacter Infections; Helicobacter pylori; Humans; Japan; Male; Middle Aged; Reference Values; Sex Characteristics; Stomach Neoplasms

To detect the Helicobacter pylori (H. pylori)-induced gastric precancerous lesions leading to cancer formation, and to evaluate the possibility of non-invasive screening of dyspeptic patients to identify those having high risk of gastric cancer.. 178 consecutive H. pylori-positive dyspeptic patients after assessment of serum pepsinogen-1 (PG-1) and gastrin-17 (G-17) levels by enzyme immunoassay were examined with endoscopy and histology. The serologic and morphologic results were compared with estimating the sensitivity, specificity and prognostic values of the tests.. There was statistically significant reverse dependence between the presence and severity of stomach mucosal atrophy (in antrum or corpus) and the proper serologic markers of stomach functional activity (G-17 or PG-1). On the other hand, the presence and the degree of intestinal metaplasia, dysplasia and gastric cancer did not correspond to the serum levels of G-17 or PG-1. The serologic method was quite sensitive in the diagnosis of non-atrophic and severe antral and corpus gastritis. Also, it was characterized by the high positive and negative prognostic values. Additionally, we have established the obvious advantage of the chromoendoscopy method in the diagnosis of intestinal metaplasia in the stomach epithelium.. The assays of serum G-17 and PG-1 levels can be offered as the screening tool for atrophic gastritis. The positive serologic results require further chromoendoscopic examination with mucosal biopsy to disclose the probable progression of atrophic process with development of intestinal metaplasia, dysplasia or gastric cancer.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Atrophy; Female; Gastric Mucosa; Gastrins; Helicobacter Infections; Helicobacter pylori; Humans; Male; Middle Aged; Pepsinogen A; Precancerous Conditions; Predictive Value of Tests; Risk Factors; Sensitivity and Specificity; Stomach Neoplasms

We have encountered an unusual case of gastric carcinoid tumors. Gastroscopic examination of a 71-year-old male patient showed eight smooth protrusions at the greater curvature of the gastric body, some of which had central depressions. Endoscopic ultrasonography demonstrated that the largest tumor (2.6 cm in diameter) was located in the submucosal layer. The patient had a normal serum gastrin level and was negative for antiparietal cell antibody. The patient was also found to have a pituitary tumor, an adenomatous goiter, and bilateral Warthin's tumors of the parotid glands. Histological examination of the resected stomach identified 12 discrete carcinoid tumors. There was no evidence of atrophic gastritis or of endocrine cell micronests. No mutations of the MEN1 gene were found on genomic DNA analysis. Despite the multiplicity of carcinoid tumors, we diagnosed type 3 gastric carcinoid in this patient.

Topics: Aged; Carcinoid Tumor; Endosonography; Gastrins; Gastroscopy; Humans; Laparoscopy; Male; Stomach Neoplasms

Gastrin is a gastrointestinal (GI) peptide that possesses potent trophic effects on most of the normal and neoplastic mucosa of the GI tract. Despite abundant evidence for these properties, the mechanisms governing gastrin-induced proliferation are still largely unknown. To elucidate the mechanisms by which gastrin might influence mitogenesis in gastric adenocarcinoma, we analyzed its effects on the human cell line AGS-B. Amidated gastrin (G-17), one of the major circulating forms of gastrin, induced a concentration-dependent increase in [3H]thymidine incorporation of cells in culture, with the maximum effective concentration occurring with 20 nM G-17. This effect was significantly attenuated by the gastrin-specific receptor antagonist L-365260. In addition, we found that G-17 induced a significant increase in the levels of cyclin D1 transcripts, protein, and promoter activity. The results of these studies indicate that gastrin appears to exert its mitogenic effects on gastric adenocarcinoma, at least in part, through changes in cyclin D1 expression.

Topics: Adenocarcinoma; beta Catenin; Cell Division; Cyclin D1; Cytoskeletal Proteins; Dose-Response Relationship, Drug; Gastrins; Gene Expression Regulation, Neoplastic; Hormones; Humans; Promoter Regions, Genetic; RNA, Messenger; Stomach Neoplasms; Trans-Activators; Tumor Cells, Cultured

Topics: Adult; Carcinoid Tumor; Duodenal Diseases; Endoscopy, Gastrointestinal; Female; Gastrectomy; Gastrins; Hematemesis; Humans; Neoplasm Recurrence, Local; Polyps; Prolapse; Stomach Neoplasms

Several studies have shown a link between gastrin and gastric cancer, both in humans and animals, especially infected with Helicobacter pylori (H. pylori). However, the exact role of hypergastrinemia in gastric carcinogenesis remains still undetermined. The aim of the present study was to evaluate the interaction between gastrin, cyclooxygenase-2 (COX-2), hepatocyte growth factor (HGF) and apoptosis-related proteins (Bax, Bcl-2, caspase-3, survivin) in cultured gastric epithelial cancer cells.. In the present study, gastric cultured cancer cells (KATO III cells) were exposed to increasing concentrations of gastrin (1-1000 nM). Cells incubated with culture medium alone, without added gastrin, served as controls. Using RT-PCR and Western blot, we examined the mRNA and protein expression for COX-2, HGF and apoptosis-related proteins (Bax, Bcl-2, caspase-3 and survivin). In addition, the gene expression of gastrin and gastrin receptor (CCK-2) as well as the release of gastrin in culture medium in the unstimulated cells were examined by RT-PCR and RIA, respectively. The apoptosis rate in cells was measured by flow cytometric analysis.. The present study shows that the gastric cultured epithelial cells exhibit the expression of gastrin and CCK-2 receptors and release of gastrin into the culture medium. The epithelial gastric cancer cells incubated with gastrin showed a concentration-dependent increase of COX-2 and HGF expression. Although no significant changes in apoptosis rate were observed, the exposure of these cells was associated with a dose-dependent increase in the expression of antiapoptotic proteins Bcl-2 and survivin.. This study demonstrates that 1) gastrin stimulates the gene and protein expression of COX-2 and HGF in human cultured gastric cancer cells and 2) gastrin shows antiapoptotic activity through the upregulation of Bcl-2 and survivin.

Topics: Apoptosis; Carcinoma, Signet Ring Cell; Caspase 3; Caspases; Cyclooxygenase 2; DNA, Neoplasm; Epithelial Cells; Gastrins; Gene Expression Regulation; Hepatocyte Growth Factor; Humans; In Vitro Techniques; Inhibitor of Apoptosis Proteins; Isoenzymes; Membrane Proteins; Microtubule-Associated Proteins; Neoplasm Proteins; Prostaglandin-Endoperoxide Synthases; Proto-Oncogene Proteins; Receptors, Cholecystokinin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Stomach Neoplasms; Survivin; Tumor Cells, Cultured; Up-Regulation

To investigate the incidence of neuroendocrine (NE) cells and their hormone products in adenocarcinomas and evaluate their significance in clinical pathology and prognosis.. By using tissue sectioning and immunocyto-chemistry, 356 cases of adenocarcinomas were studied to examine the presence of chromorgranin and polypeptide hormones in adenocarcinoma samples from our hospital.. The positive rate of NE cells and hormone products was 41.5 % (54/130) and 59.3 % (32/54), respectively in large intestinal adenocarcinoma cases; 39.6 % (38/96) and 36.8 % (14/38), respectively in gastric cancer cases; 38.1 % (8/21) and 50.0 % (4/8), respectively in prostatic cancer cases; 21.0 % (17/81) and 17.6 % (3/17), respectively in breasr cancer cases; 17.9 % (5/28) and 60.0 % (3/5), respectively in pancreatic cancer cases. Among carcinomas of large intestine, pancreas and breast, the highly differentiated NE cell numbers were higher than the poorly differentiated NE cell numbers; while the gastric carcinoma cases had more poorly differentiated NE cells than highly differentiated NE cells. The higher detection rate of NE cells and their hormone products, the higher 5-year survival rate among the large intestine cancer cases.. Close correlation was observed between NE cells and their hormone products with the cancer differentiations. For colorectal carcinomas, there is a close correlation of the presence of NE cells and their hormone products with the tumor staging and prognosis.

Topics: Adenocarcinoma; Adrenocorticotropic Hormone; Biomarkers; Calcitonin; Gastrins; Glucagon; Humans; Intestinal Neoplasms; Lymph Node Excision; Lymphatic Metastasis; Norepinephrine; Retrospective Studies; Serotonin; Somatostatin; Stomach Neoplasms

To study the clinicopathological features of gastric neuroendocrine tumors.. Twenty cases were reviewed. The specimens were formalin-fixed, paraffin-embedded and immunostained by S-P method.. Among the twenty cases, one case was carcinoid, three were malignant carcinoids, six had small cell carcinomas and ten had mixed extocrine--endocrine carcinomas. Immunohistological examination of tumor cells found 80% positive for S-100, NSE (85%), CgA (50%), SY (50%), gastrin (30%), serotonin (65%), AE1/AE3 (50%), and CEA (80%).. In the WHO classification, there are five histological types in endocrine tumors of gastrointestinal tract. They are carcinoid, malignant carcinoid, small cell carcinoma, mixed exocrine--endocrine carcinoma and tumor-like lesions. But some cases in our paper were so different that they could not be classified. The gastric endocrine tumors are different from intestinal endocrine tumors and in classification, treatment and prognosis.

Topics: Adult; Aged; Carcinoembryonic Antigen; Carcinoid Tumor; Carcinoma, Small Cell; Female; Gastrins; Humans; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Invasiveness; Neuroendocrine Tumors; Phosphopyruvate Hydratase; Prognosis; Stomach Neoplasms

Topics: Atrophy; Biopsy; Carcinoid Tumor; Endoscopy, Digestive System; Fatal Outcome; Female; Gastrins; Gastritis; Humans; Immunohistochemistry; Middle Aged; Pulmonary Emphysema; Stomach Neoplasms; Tomography, X-Ray Computed

Gastric carcinoid is a rare tumour that is associated with chronic atrophic gastritis in the majority of cases. It usually occurs in the 6th or 7th decade of life and is rarely diagnosed in patients under 30 years of age.. We describe a case of multiple gastric carcinoids in a 23-year-old woman with systemic lupus erythematosus and atrophic autoimmune gastritis--an association that has not been reported previously.. The combination of atrophic autoimmune gastritis and gastric carcinoid with other autoimmune disorders has rarely been reported in the English medical literature.. The fact that it mostly concerns (relatively) young patients may suggest a potential causative relation between those autoimmune disorders and the early development of atrophic gastritis with hypergastrinaemia, which subsequently leads to the occurrence of gastric carcinoid tumours at a young age.

Topics: Adult; Antiphospholipid Syndrome; Carcinoid Tumor; Female; Gastrectomy; Gastrins; Gastritis, Atrophic; Gastroscopy; Humans; Lupus Erythematosus, Systemic; Stomach; Stomach Neoplasms

Helicobacter pylori cag(+) strains and high-expression host interleukin 1beta (IL-1beta) polymorphisms augment the risk for intestinal-type gastric adenocarcinoma, a malignancy that predominates in males. We examined the effects of an H. pylori cancer-associated determinant (cagE), IL-1beta, and host gender in a transgenic hypergastrinemic (INS-GAS) murine model of gastric carcinogenesis.. Male and female INS-GAS mice infected with wild-type H. pylori, an H. pylori cagE(-) mutant, or H. felis were killed 2-24 weeks postchallenge. Gastric injury was scored from 0 to 4, and mucosal IL-1beta levels were quantified by ELISA.. Male INS-GAS mice infected with H. pylori uniformly developed atrophy, intestinal metaplasia, and dysplasia by 6 weeks and carcinoma by 24 weeks. Mucosal IL-1beta concentrations increased 12 weeks following Helicobacter challenge, but levels then decreased by 24 weeks. Inactivation of cagE delayed the progression to carcinoma, but neoplasia ultimately developed in all males infected with the H. pylori mutant. In contrast, none of the H. pylori-infected female mice developed cancer, and injury scores, but not IL-1beta levels, were significantly higher in males compared with females.. H. pylori infection induces gastric adenocarcinoma in an experimental mouse model of disease. Cancer is restricted to males and loss of cagE temporally retards but does not abrogate pathologic progression. Mucosal levels of IL-1beta increase prior to the development of gastric cancer but are not related to gender. The INS-GAS model is effective for investigating discrete host-microbial interactions that culminate in gastric cancer within the context of biologic conditions induced by H. pylori.

Topics: Adenocarcinoma; Animals; Bacterial Proteins; Disease Models, Animal; Female; Gastric Mucosa; Gastrins; Helicobacter Infections; Helicobacter pylori; Interleukin-1; Male; Mice; Precancerous Conditions; Sex Factors; Stomach; Stomach Neoplasms

Helicobacter pylori infection of Mongolian gerbils is an established model of gastric carcinogenesis, but gastric secretory aspects of this carcinogenesis have not been studied.. The effects of single intragastric inoculation of gerbils with H. pylori strain (cagA+ vacA+, 5 x 10(6) CFU/ml) or vehicle (saline) were examined at 1, 2, 4, 6, 9, 12 and 30 weeks from inoculation. Gastric morphology, the presence of H. pylori using the rapid urease test, the density of H. pylori and 16S rRNA and the plasma gastrin and somatostatin were determined.. H. pylori was detected in gastric mucosa in all infected animals. Basal gastric acid in gerbils was reduced by about 50% after H. pylori inoculation. Early lesions seen at 4 weeks after H. pylori inoculation consisted of chronic gastritis with thickened mucosal folds, oedema, congestion and mucosal lymphocytic infiltration. Adenomatous hyperplasia with cellular atypia with increased mitotic activity and the formation of apoptotic bodies and visible erosions and ulcerations were observed at 12-30 weeks after inoculation. The atypical gastric glands were situated 'back-to-back', suggesting gastric pre-cancer. The gastric blood flow in H. pylori-infected gerbils was significantly lower than that in the controls. Six- to seven-fold increase in plasma gastrin levels combined with significant fall in gastric somatostatin contents and the intraepithelial neoplasia were noticed in gerbils at all tested periods.. H. pylori-infection in gerbils resulted in gastric pre-cancer associated with functional changes, such as suppression of gastric secretion and impairment of both gastric mucosal microcirculation and the gastrin-somatostatin link.

Topics: Animals; Cell Transformation, Neoplastic; Disease Models, Animal; Gastric Acid; Gastric Mucosa; Gastrins; Gastritis; Gerbillinae; Helicobacter Infections; Helicobacter pylori; Male; Microcirculation; Precancerous Conditions; Somatostatin; Stomach Neoplasms

Gastric cancer remains the second biggest cause of cancer death worldwide. The most common type of gastric cancer, the intestinal type, is usually preceded by chronic atrophic gastritis. Gastritis serology is therefore of crucial importance for population-based screening and prevention studies. Helicobacter pylori serum antibodies can adequately diagnose inflammation of the gastric mucosa, but the serological diagnosis of atrophic gastritis is more hazardous. Many tests have been used for this purpose, either alone or in various combinations. Depending on the population, pepsinogens and gastrin often have a high specificity but low sensitivity for the diagnosis of atrophic gastritis, whereas antibodies against H. pylori or CagA have a high sensitivity but low specificity. A combination of two tests, e.g. H. pylori antibodies and pepsinogen I, may balance this issue and provide adequate screening tools, although there is a clear need for further improvement and simplification of serological testing for atrophic gastritis.

Topics: Antibodies, Bacterial; Antigens, Bacterial; Atrophy; Bacterial Proteins; Biomarkers; Gastric Mucosa; Gastrins; Gastritis; Helicobacter pylori; Humans; Immunoglobulin G; Pepsinogen A; Sensitivity and Specificity; Stomach Neoplasms

The most common types of benign gastric polyps are fundic gland polyps, hyperplastic polyps, and adenomas. The aim of this study was to determine on which morphological and functional background benign gastric polyps develop. The study includes 85 consecutive patients with gastric polyps and sex- and age-matched controls without polyps selected at random from a general population sample. The type of polyp was hyperplastic in 52 (61%), fundic gland in 18 (21%), adenoma in 10 (12%), carcinoid in 2 (2%), hamartoma in 2 (2%), and inflammatory fibroid in 1 (1%) of the cases. Routine biopsies from the gastric corpus and antrum were examined for presence of gastritis and H. pylori. Blood samples were analyzed for H. pylori antibodies, H+,K+-ATPase antibodies, gastrin, and pepsinogen I. Patients with hyperplastic polyps had increased P-gastrin concentrations and S-H+,K+-ATPase antibody titers and decreased S-pepsinogen I concentrations with a high prevalence of atrophic corpus gastritis or pangastritis. A similar pattern was observed among patients with adenomas, whereas patients with fundic gland polyps had normal serology and a lower prevalence of gastritis and H. pylori infection than controls. In conclusion, hyperplastic polyps and adenomas are generally associated with atrophic gastritis. Patients with fundic gland polyps seem to have a sounder mucosa than controls. Whereas the risk of malignant gastric neoplasia is increased in patients with hyperplastic polyps or adenomas, this does not seem to be the case in patients with fundic gland polyps.

Topics: Adenomatous Polyps; Adult; Aged; Aged, 80 and over; Antibodies; Female; Gastrins; Gastritis, Atrophic; Helicobacter Infections; Humans; Male; Middle Aged; Pepsinogen A; Polyps; Prospective Studies; Sodium-Potassium-Exchanging ATPase; Stomach Neoplasms

Until recently, the association of primary hyperparathyroidism and gastric carcinoid, with or without hypergastrinaemia, had been considered an incomplete form of multiple endocrine neoplasia type 1. This is because it seemed unlikely that the rare joint appearance of these diseases could occur only by chance. It is now possible to evaluate the pathogenetic involvement of the multiple endocrine neoplasia type 1 gene in many, apparently sporadic, clinical conditions. This is a case report of a female mimicking multiple endocrine neoplasia type 1 due to the presence of hyperparathyroidism, gastric carcinoid, and hypergastrinaemia. However, involvement of the MEN-1 gene (exons 2-10) was not detected, whereas hypergastrinaemia was attributed to a chronic atrophic gastritis.

Topics: Aged; Carcinoid Tumor; Diagnosis, Differential; Female; Gastrins; Gastritis, Atrophic; Gene Expression; Humans; Hyperparathyroidism; Multiple Endocrine Neoplasia Type 1; Stomach Neoplasms

Evidence indicates that eradication of Helicobacter pylori leads to the disappearance of hyperplastic polyps in the stomach. However, there are some exceptions. We have compared endoscopic and serologic findings of responder and non-responder cases with hyperplastic polyps to try to identify the cause(s), other than H. pylori infection, of the formation or growth of gastric hyperplastic polyps.. We retrospectively studied 33 patients whose hyperplastic polyps disappeared after eradication of H. pylori and 10 patients whose hyperplastic polyps did not disappear after eradication. The patients were examined both endoscopically and serologically before, 1-3 months after and 12-15 months after the eradication.. The responder and non-responder groups were similar with respect to age, sex, coexisting diseases, and histologic findings. The number and maximum size of polyps tended to be larger before treatment in the non-responder group than in the responder group. The serum gastrin level was higher in the non-responder group than in the responder group before, 1-3 months after and 12-15 months after the eradication (p=0.0096, p>0.2, p=0.0014). On histologic examination, similar reductions in the degree of inflammatory cell infiltration in the gastric mucosa of the antrum and body were seen in both the responder and non-responder groups. In the non-responders, the size and numbers of the polyps regressed in 5 of the 10 patients. The score of glandular atrophy in the antrum and the serum gastrin levels in the non-regressed cases was higher than those in the regressed cases at 1-3 and 12-15 months after eradication.. Persistent high gastrin levels were found in the non-responder cases with gastric hyperplastic polyps.

Topics: Adult; Aged; Anti-Bacterial Agents; Chi-Square Distribution; Drug Therapy, Combination; Endoscopy, Gastrointestinal; Female; Gastrins; Helicobacter Infections; Helicobacter pylori; Humans; Hyperplasia; Immunoglobulin G; Male; Middle Aged; Penicillins; Pepsinogen A; Polyps; Proton Pump Inhibitors; Retrospective Studies; Statistics, Nonparametric; Stomach Neoplasms

Previous reports have suggested a possible association between hyperplastic polyposis and colorectal neoplasms. Increased gastrin may be the link between these two conditions insofar as gastrin has been reported to be a growth-promoting tumoural agent. This report describes gastric polyposis, hypergastrinaemia and colorectal neoplasms in four elderly patients.. Four male patients with no family history of cancer, who were found to have multiple gastric hyperplastic polyps, hypergastrinaemia and colorectal cancers or an adenomatous polyp, were evaluated. Assessment included clinical evaluation, biochemical and haematological profiles, fasting gastrin levels, Helicobacter pylori serology, cobalamin, parietal cell antibodies, gastroscopy with biopsies of polyps and gastric mucosa, urease tests, and colonoscopy with biopsies of colorectal neoplasms. Immunohistochemistry of specimens from gastric polyps and colonic carcinomas was performed for chromogranin A, synaptophysin, Leu 7, neuron-specific enolase and gastrin.. The mean age at diagnosis of gastric polyps was 71.2 years and at removal of colorectal neoplasm was 70.0 years. In two patients, the gastric lesion was diagnosed before the colonic lesion and conversely in the two remaining patients. Gastrin was very high (1604 pg/ml; normal level, < 115 pg/ml) in one patient with pernicious anaemia, and the mean level for the other three was 324 pg/ml. H. pylori were found in two patients. Immunohistochemistry failed to identify neuroendocrine cells in the hyperplastic gastric polyps and three of the colonic carcinomas.. Occurrence of sporadic colorectal neoplastic lesion in patients with diffuse hyperplastic gastric polyposis and hypergastrinaemia may represent a new syndrome. Gastrin is not secreted by the gastric polyps or colonic carcinomas and may be related to gastric mucosal changes and H. pylori colonization. In patients with hyperplastic gastric polyposis and hypergastrinaemia, colorectal neoplasms should be ruled out.

Topics: Aged; Colorectal Neoplasms; Gastrins; Humans; Hyperplasia; Male; Polyps; Stomach Neoplasms; Syndrome

Cyclooxygenase-2 (COX-2) expression and certain growth hormones, such as gastrin, have been related to gastric carcinogenesis, but little is known about the factors that enhance this COX-2 expression and whether specific blockade of this enzyme has any influence on tumor growth and progression. Our objective was to determine the influence of a specific COX-2 inhibitor, rofecoxib (Vioxx), on serum and tumor levels of gastrin and its precursor, progastrin, as well as on tumor gene expression of COX-2, peroxisome proliferator-activated receptor gamma (PPARgamma), and apoptosis-related proteins (Bax and Bcl-2, caspase-3, and survivin). Twenty-four gastric cancer (GC) patients entered this study and were examined twice, once before and then following a 14-day treatment with Vioxx at a dose of 25 mg twice daily. For comparison, 48 age- and sex-matched healthy controls and 24 similarly matched Helicobacter pylori (Hp)-positive subjects were enrolled and treated with Vioxx as GC patients. Serum levels of anti-Hp and anti-CagA antibodies as well as IL-8 and TNF-alpha were measured by enzyme-linked immunosorbent assay (ELISA), while serum and tumor contents of progastrin and amidated gastrin were determined by specific RIA. Tumor gene and protein expressions of COX-2, PPARgamma, Bax and Bcl-2, caspase-3, and survivin were determined by RT-PCR and western blot. The overall Hp and CagA seropositivity in 24 GC patients was significantly higher (82% and 47%) than in 48 controls (61% and 22%) but not in 24 Hp-infected subjects (100% and 38%). Serum IL-8 and TNF-alpha values were significantly higher in GC patients than in controls without GC or Hp-infected controls. Median serum progastrin and gastrin levels were found to be significantly higher in GC than in controls without GC and in Hp-positive subjects. Treatment of GC patients with Vioxx resulted in a significant decrease in plasma and tumor contents of both progastrin and gastrin, and this was accompanied by the increment in tumor expression of COX-2, PPARy, Bax, and caspase-3 with a concomitant reduction in Bcl-2 and survivin expression. We conclude that: (1) GC patients show significantly higher Hp and CagA seropositivity than age- and sex-matched controls, but not Hp-positive subjects, indicating that infection with cytotoxic Hp is linked to GC. (2) Serum progastrin and gastrin levels are significantly higher in GC patients than in matched controls, confirming that both gastrins may be implicated in gastric car

Topics: Aged; Apoptosis; Case-Control Studies; Caspase 3; Caspases; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Cytokines; Female; Gastric Mucosa; Gastrins; Helicobacter Infections; Helicobacter pylori; Humans; Incidence; Inhibitor of Apoptosis Proteins; Isoenzymes; Lactones; Male; Membrane Proteins; Microtubule-Associated Proteins; Middle Aged; Neoplasm Proteins; Prostaglandin-Endoperoxide Synthases; Protein Precursors; Receptors, Cytoplasmic and Nuclear; RNA, Messenger; Stomach Neoplasms; Sulfones; Survivin; Transcription Factors

Numerous studies have shown an association between Helicobacter pylori (Hp) infection and gastric cancer (GC).. This study was designed to determine the role of cytotoxin-associated gene A (CagA)-positive Hp infection, serum amidated gastrins and their precursor, progastrin, gastric acidity and serum pepsinogen I (PG-I) levels in gastric cancerogenesis in 74 cancer patients and in 77 age- and gender-matched controls. Serum IgG antibodies to Hp and CagA and levels of IL-8 and PG-I were measured by ELISA, while progastrin and amidated gastrin by specific radioimmunoassay.. The overall Hp and CagA seropositivity in GC patients were significantly higher (82 and 60%) than in matched controls (61 and 27%, respectively). Progastrin and amidated gastrin levels over their cutoff points (122 and 32 pM, respectively) were found in a significantly larger number of GC (59.4 and 44.5%) than in controls (9.0 and 16.8%, respectively). Histologically, all these GCs with increased serum progastrin and amidated gastrins were of intestinal type and showed CagA and Hp seropositivity. Serum IL-8 and gastric pH, above their cutoff points (pH >4.5), and serum PG-I level below its cutoff point (44.2 microg/l) were observed in a significantly higher number of GC patients as compared to controls.. (1) GC patients have higher Hp and CagA seroprevalence than matched controls, confirming that CagA-positive Hp infection is associated with higher risk of GC; (2) serum levels of amidated gastrins and their precursor, progastrin, as well as IL-8 are significantly higher, while serum PG-I levels are reduced in intestinal type GC compared to controls, and (3) determination of high serum progastrin, amidated gastrins and IL-8 combined with low serum PG-I may be useful biomarkers of GC.

Topics: Aged; Aged, 80 and over; Antigens, Bacterial; Bacterial Proteins; Biomarkers, Tumor; Case-Control Studies; Enzyme-Linked Immunosorbent Assay; Gastric Acid; Gastrins; Helicobacter Infections; Helicobacter pylori; Humans; Interleukin-8; Middle Aged; Pepsinogen A; Protein Precursors; Risk Factors; Seroepidemiologic Studies; Stomach Neoplasms

Relatives of patients with gastric cancer are at increased risk of developing this disease, especially if they are infected by Helicobacter pylori. Moreover, H. pylori-related atrophic gastritis and hypochlorhydria are well-documented risk factors for noncardia gastric cancer. Serum pepsinogen I (sPGI) and II (sPGII) levels are low in this condition. The aim of our study was to assess by means of a 'Gastropanel' blood test, including sPGI, sPGII, gastrin-17 (G-17) and antibodies anti-H. pylori (IgG-Hp). both functional and morphological features of gastric mucosa in Hp + ve subjects with a family history of gastric cancer.. Twenty-five Hp + ve subjects consecutively referred to our department for gastrointestinal complaints, selected as first-degree relatives of patients suffering from gastric cancer, were enrolled in the study and then matched for sex and age with 25 dyspeptic and Hp + ve subjects with no family history of gastric neoplasia. Blood samples were taken for determination of gastropanel in all patients; in addition, antibodies against CagA were analysed.. No statistically significant differences were detected between the two groups as regards alcohol consumption, coffee intake and smoking habits. Mean sPGI levels in Group A (83.4 +/- 58.4 microg/L) were significantly lower than those in Group B (sPGI 159.5 +/- 80.6 microg/L; P < 0.0001) as well as sPGII (12.5 microg/L = 6.24 versus 20.6 +/- 58 microg/L; P < 0.006). No statistical difference was found between the two groups in relation to G-17 levels, IgG-Hp titres and antibodies against CagA.. First-degree relatives of patients with noncardia gastric cancer affected by H. pylori infection present lower sPGI and sPGII levels, possibly due to the increased frequency of atrophic lesions in these patients.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Bacterial; Antigens, Bacterial; Bacterial Proteins; Biomarkers; Dyspepsia; Family Health; Female; Gastrins; Gastritis, Atrophic; Genetic Predisposition to Disease; Helicobacter Infections; Helicobacter pylori; Humans; Immunoglobulin G; Male; Middle Aged; Pepsinogen A; Pepsinogen C; Stomach Neoplasms

Growth hormone (GH), Insulin-like growth factor-I (somatomedine, IGF-I) and gastrin seem to play a significant role in cell proliferation in mammalian and rat cells. The role of these factors in the etiology of gastric and large bowel cancer has not been completely elucidated. The aim of this study was to concurrently estimate the levels of GH, IGF-I and gastrin in a group of patients with gastric and colorectal cancer and to compare the results with those of a group of normal controls.. In 33 consecutive patients with gastric (16 patients) and large bowel (17 patients) cancer, the serum levels of GH, IGF-I and gastrin were measured by radioimmunoassay. Fifty-four normal people were served as controls.. Significantly higher levels of serum GH (3.16 +/- 3.12 ng/ml in gastric cancer patients vs. 3.01 +/- 2.91 ng/ml in colorectal cancer patients vs. 0.69 +/- 1.60 ng/ml in normal controls, adjusted P<0.001) and gastrin (98.2 +/- 87.9 pg/ml in gastric cancer patients vs. 95.3 +/- 85.4 pg/ml in colorectal cancer patients, vs. 47.5 +/- 32.4 pg/ml in normal controls, adjusted P<0.035 and <0.05 respectively) were found in both groups of patients compared with normal controls. The levels of IGF-I in patients with gastric and colorectal cancer although higher compared to normal controls did not reach statistical significance. (98.2 +/- 87.9 pg/ml vs. 95.3 +/- 85.4 vs. 47.5 +/- 32.4 respectively) (adjusted P=0.070).. It is concluded that in patients with gastric and colorectal cancer a significant increase of serum GH and gastrin can be found. This increase is likely to play a role in gastric and colorectal carcinogenesis.

Topics: Aged; Animals; Case-Control Studies; Colonic Neoplasms; Fasting; Female; Gastrins; Human Growth Hormone; Humans; Insulin-Like Growth Factor Binding Protein 1; Male; Middle Aged; Radioimmunoassay; Rats; Stomach Neoplasms

Epithelial organization is maintained by cell proliferation, migration, and differentiation. In the case of the gastric epithelium, at least some of these events are regulated by the hormone gastrin. In addition, gastric epithelial cells are organized into characteristic tubular structures (the gastric glands), but the cellular mechanisms regulating the organization of tubular structures (sometimes called branching morphogenesis) are uncertain. In the present study, we examined the role of the gastrin-cholecystokinin(B) receptor in promoting branching morphogenesis of gastric epithelial cells. When gastric cancer AGS-G(R) cells were cultured on plastic, gastrin and PMA stimulated cell adhesion, formation of lamellipodia, and extension of long processes in part by activation of protein kinase C (PKC) and phosphatidylinositol (PI)-3 kinase. Branching morphogenesis was not observed in these circumstances. However, when cells were cultured on artificial basement membrane, the same stimuli increased the formation of organized multicellular arrays, exhibiting branching morphogenesis. These effects were reversed by inhibitors of PKC but not of PI-3 kinase. We conclude that, in the presence of basement membrane, activation of PKC by gastrin stimulates branching morphogenesis.

Topics: Basement Membrane; Cell Adhesion; Gastrins; Humans; Lysophospholipids; Protein Kinase C; Receptor, Cholecystokinin B; Receptors, Cholecystokinin; Stomach Neoplasms; Tetradecanoylphorbol Acetate; Tumor Cells, Cultured

Despite numerous epidemiological studies, the association between Helicobacter pylori infection and gastric cancer (GC) remains unexplained. This study was designed to determine the seropositivity of H. pylori and cytotoxin-associated gene A (CagA), serum gastrin and interleukin-8 (IL-8) levels as well as basal intragastric pH and maximal histamine-induced gastric acid outputs (MAO) in a large series of GC patients and controls.. 337 GC patients (118 men and 219 women; median age 59.4; range 21-87) and 337 controls randomized for sex and age entered the study. Serum IgG antibodies to H. pylori and CagA and serum levels of IL-8 were measured by enzyme-linked immunosorbent assay, while serum-amidated gastrin was determined by specific radioimmunoassay and correlated with gastric luminal pH.. The numbers of GC patients and controls involved in the study in various age groups, ranging from 20 to > 70 years, were similar, but overall H. pylori IgG seropositivity in GC patients was significantly higher (90.8%) than in controls (79.2%). The overall CagA seropositivity in GC patients was about double (58.2%) that in controls (25.2%). Serum gastrin levels over the calculated cut-off value (38.88 pM/L) were found in several-fold larger number in GC patients (48%) than in controls (8.3%) and. similarly, serum IL-8 values over the cut-off point (1.77 pg/mL) occurred in almost all (99.7%) GC patients but in only a few controls (0.3%). Basal intragastric pH above the cut-off point (pH = 4.50) was observed in about 58.2% of GC patients compared to 15.1% in controls, and strong correlation between the serum gastrin and gastric pH was found in GC but weak in controls. The cut-off value for MAO was 12.3 mml/h; MAO below this cut-off value occurred in 89.9% of GC patients and in only 4.7% of controls. A summary odds ratio (SOR) in GC for H. pylori IgG was 2.59 (95% Cl: 1.61-4.22) for CagA - 4.12 (95% Cl; 2.93-5.8), for serum gastrin - 10.25 (95%; 6.47-16.47) and for MAO - 15.2 (95% Cl; 9.45-39.82). Multivariable analysis of serum gastrin, IgG and CagA, and luminal pH and MAO values revealed that only gastrin and CagA have significant influence on GC formation (OR > 1 in logistic regression).. 1. CG patients show significantly higher H. pylori IgG and CagA seropositivity than dyspeptic age- and gender-matched controls, confirming that gastric infection with CagA expressing H. pylori greatly increases the risk of GC. 2. Serum gastrin levels in GC but not in controls are correlated with the rise in intragastric pH, indicating that excessive gastrin release in GC is affected by lower intragastric pH. 3. Serum gastrin level and CagA seropositivity are significantly increased in the majority of GC patients, and are the only variables in multivariable analysis to have a predominant influence on GC formation, which suggests that both these parameters may be implicated in H. pylori-related gastric carcinogenesis. 4. H. pylori-infected GC patients produce significantly more IL-8 than do non-GC controls, probably reflecting CagA-positive H. pylori-associated gastritis.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Bacterial; Antigens, Bacterial; Bacterial Proteins; Dyspepsia; Enzyme-Linked Immunosorbent Assay; Female; Gastric Acid; Gastrins; Helicobacter Infections; Helicobacter pylori; Humans; Immunoglobulin G; Interleukin-8; Male; Middle Aged; Radioimmunoassay; Stomach Neoplasms

Topics: Acinetobacter Infections; Animals; Gastrins; Gastritis; Helicobacter Infections; Helicobacter pylori; Mice; Stomach Neoplasms

Recently, binding of specific protein 1 (Sp1) and cAMP response element binding protein (CREB) to a GC-rich element at -92/-62 has been identified as a critical step in gastrin-dependent regulation of the chromogranin A (CgA) gene in gastric epithelial cells. Here we demonstrate that binding of early growth response protein 1 (Egr-1) to the distal part of the -92/-62 site is also required for gastrin-dependent CgA transactivation. Gastrin elevated cellular and nuclear Egr-1 levels in a time-dependent manner and also increased Egr-1 binding to the CgA -92/-73 region. Disruption of this site reduced gastrin responsiveness without influencing basal promoter activity, while loss of Sp1 and/or CREB binding sites diminished basal and gastrin-stimulated CgA promoter activity. Ectopic Egr-1 overexpression potently stimulated the CgA promoter, whereas coexpression of Egr-1 with Sp1 and/or CREB resulted in additive effects. Functional analysis of Sp1-, Egr-1-, or CREB-specific promoter mutations in transfection studies confirmed the tripartite organization of the CgA -92/-62 element. Signaling studies revealed that MAPK kinase 1 (MEK1)/ERK1/2 cascades are critical for gastrin-dependent Egr-1 protein accumulation as well as Egr-1 binding to the CgA promoter. Our studies for the first time identify Egr-1 as a nuclear target of gastrin and show that functional interplay of Egr-1, Sp1, and CREB is indispensable for gastrin-dependent CgA transactivation in gastric epithelial cells.

Topics: Binding Sites; Cell Nucleus; Chromogranin A; Chromogranins; Cyclic AMP Response Element-Binding Protein; DNA; DNA-Binding Proteins; Early Growth Response Protein 1; Enzyme Inhibitors; Epithelial Cells; Flavonoids; Gastrins; Humans; Immediate-Early Proteins; Immunoblotting; MAP Kinase Kinase 1; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinase Kinases; Mitogen-Activated Protein Kinases; Phosphorylation; Promoter Regions, Genetic; Protein Serine-Threonine Kinases; Response Elements; Signal Transduction; Stomach Neoplasms; Tetradecanoylphorbol Acetate; Transcription Factors; Transcriptional Activation; Transfection; Tumor Cells, Cultured

It has been reported that external gastrin could facilitate the growth of the cells of gastrointestinal carcinomas. However, the modifying effect of gastrin on apoptosis of the gastric carcinoma has not been well appreciated. This study was designed to investigate the modifying effect of gastrin on apoptosis of the stomach cancer cell.. Flow cytometric analysis (FCM) and immunohistochemical dyeing are used to measure the rates of apoptosis and expression of bcl-2 gene in MKN45 cell line treated with gastrin and its receptor antagonist.. Forty-eight hours later, the percentage of apoptosis cell in gastrin group was 1.39 +/- 0.54%, lower than that in control group (8.58 +/- 0.67%) (P < 0.01), but the expression rate of bcl-2 in gastrin treatment group was 22.3 +/- 5.3% higher than that in control group (P < 0.01). These effects were vanished after combined treatment with proglumide.. External gastrin may restrain the apoptosis of MKN45 cell by inducing the expression of bcl-2 gene, and proglumide can block these effects of gastrin.

Topics: Apoptosis; Gastrins; Genes, bcl-2; Humans; Immunohistochemistry; Stomach Neoplasms; Tumor Cells, Cultured

Gastric carcinoids are strongly associated with chronic atrophic gastritis A, and it is suggested that hypergastrinemia plays a critical role in development of gastric carcinoids. Since Helicobacter pylori infection causes hypergastrinemia, it is held that H. pylori infection produces gastric carcinoids. We followed the histological changes of H. pylori-infected stomachs of Mongolian gerbils for a long time.. Five-week-old-male Mongolian gerbils were infected with H. pylori ATCC 43504 with cagA gene, expressing vacuolating cytotoxin. Determination of the serum gastrin and histopathological examination of the stomach at 6, 12, 18, and 24 months after H. pylori inoculation was studied and compared with uninfected animals.. In infected animals, the gastric carcinomas appeared 18 and 24 months after infection. Endocrine cell dysplasias and carcinoids with marked atrophic gastritis of the oxyntic mucosa were observed in the infected animals 24 months after H. pylori inoculation. The serum gastrin level in the infected group increased from an average of 86.2 pg/ml at the beginning of the study to an average of 498 pg/ml and 989 pg/ml at 18 and 24 months after infection, respectively. These changes in the serum gastrin levels were significant compared with uninfected controls that showed no changes.. H. pylori infection caused not only gastric carcinomas but also enterochromaffin-like cell tumors in Mongolian gerbils, due to hypergastrinemia. This model is thought to be useful to study the relationship between hypergastrinemia and gastric carcinoids.

Topics: Adenocarcinoma; Animals; Carcinoid Tumor; Disease Models, Animal; Gastric Mucosa; Gastrins; Gerbillinae; Helicobacter Infections; Helicobacter pylori; Male; Stomach Neoplasms

Our aim was to study the serum pepsinogen levels in gastric cancer patients in our population in relation to histology and the presence of Helicobacter pylori.. Forty-six patients with gastric cancer and 70 controls were studied prospectively in a 1-year period. Serum levels of pepsinogen I (PG I), pepsinogen II (PG II), and gastrin were measured by radioimmunoassay.. The mean PG I levels for cancer patients and controls were 83.5 microg/l and 60.9 microg/l, respectively (P = 0.03), the mean PG II levels were 27.2 microg/l and 12.1 microg/l respectively (P < 0.0001). The PG I/II ratio was significantly lower in cancer patients (P = 0.04) and in those with Helicobacter infection. Serum pepsinogen levels were not affected by any pathological characteristics. Histology showed that the prevalence of chronic gastritis, intestinal metaplasia, and gastric atrophy was 97%, 56%, and 15%, respectively.. The prevalence of gastric atrophy is low in our population, and serum pepsinogen measurement is not useful as a screening tool for gastric cancer in this population.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Case-Control Studies; Female; Gastrins; Gastritis, Atrophic; Helicobacter Infections; Helicobacter pylori; Humans; Male; Middle Aged; Pepsinogen A; Pepsinogen C; Prospective Studies; Stomach Neoplasms

Helicobacter pylori (H. pylori) is now well known to be associated with stomach cancer, with infection during childhood rather than as an adult considered to be more important for carcinogenesis. To evaluate the difference in susceptibility to stomach carcinogenesis in relation to age of acquisition of H. pylori infection, we designed an experiment involving inoculation of H. pylori ATCC43504 followed by N-methyl-N-nitrosourea (MNU) treatment at different ages. Four-week-old male Mongolian gerbils (MGs) were divided into twelve groups. H. pylori was inoculated at 4, 18 and 32 weeks of age, as representatives of early, middle and late infection, respectively. Two weeks later, the animals were treated with MNU. Groups without H. pylori and/or MNU were included as controls. The incidences of adenocarcinomas at 52 weeks after the inoculation in the early (H. pylori+MNU), middle (H. pylori+MNU), and late (H. pylori+MNU) group were 60% (12/20), 18.4% (2/11), and 10% (2/20), respectively. The corresponding figures were 14.8% (4/27), 0% (0/11), and 0% (0/21) in the MNU-alone groups. A higher titer of serum IgG for H. pylori and higher gastrin level were seen in the early-infected compared to the middle and the late groups (P<0.01). The results clearly demonstrated that early acquisition of H. pylori significantly increases gastric chemical carcinogenesis with MNU, as compared to the case with later infection, possibly because of differences in host gastric mucosal factors and immunologic responses.

Topics: Adenocarcinoma; Animals; Antibodies, Bacterial; Gastrins; Gerbillinae; Helicobacter Infections; Helicobacter pylori; Immunoglobulin G; Male; Methylnitrosourea; Risk; Stomach Neoplasms

In Japan, most cases of gastric carcinoid tumor (GCT) are unassociated with either autoimmune gastritis (AIG) showing type-A chronic atrophic gastritis (CAG-A) or Zollinger-Ellison syndrome (ZES). However, the pathogenesis of this tumor remains unknown. Recent studies have determined that Helicobacter pylori infection induces gastric carcinoid in Mongolian gerbils and that H. pylori lipopolysaccharide exerts a mitogenic effect on ECL cells. We examined five patients with histologically diagnosed GCT, 40 patients with H. pylori-positive gastric ulcer (Hp+GU), 24 patients with H. pylori-positive duodenal ulcer (Hp+DU), and 12 patients with AIG showing CAG-A topographically. We compared the prevalence of H. pylori infection, and the levels of gastrin and pepsinogen (PG) in the serum of patients with GCT with those of patients with Hp+GU, or Hp+DU, and AIG. We also investigated the histological characteristics of the tumor and the gastric corpus mucosa in the GCT patients. The levels of serum gastrin and PG I and II were measured using an RIA kit. In all five (100%) patients with GCT, H. pylori infection was present, without any evidence of AIG or ZES. The serum levels of gastrin in the GCT patients were higher than those in either Hp+GU or Hp+DU patients and lower than those in the AIG patients. In contrast, serum PG I levels and the PG I/II ratio were lower in the GCT group than in the Hp+GU or Hp+DU groups. Histologically, all GCTs were ECL cell tumors and peritumoral corporal mucosal atrophy was observed in four of the five patients with GCT. In conclusions, H. pylori infection and hypergastrinemia were found in the patients with GCT without AIG. This finding suggests that H. pylori infection may induce corporal mucosal atrophy and hypergastrinemia that can produce a GCT with time.

Topics: Adult; Aged; Aged, 80 and over; Autoimmune Diseases; Carcinoid Tumor; Duodenal Ulcer; Female; Gastrins; Gastritis; Gastritis, Atrophic; Helicobacter Infections; Helicobacter pylori; Humans; Male; Middle Aged; Pepsinogen A; Pepsinogen C; Peptic Ulcer; Stomach Neoplasms

Patients with hypergastrinemia secondary to achlorhydria have an increased risk of developing ECL cell carcinoids and gastric adenocarcinomas. Hypergastrinemia is central in the pathogenesis of ECL cell carcinoids, but the link between gastrin and gastric carcinomas is controversial. During neoplastic transformation ECL cells may, however, lose many of their neuroendocrine characteristics, making them difficult to recognise as neuroendocrine with conventional immunohistochemical techniques. Neuroendocrine differentiation was therefore examined in eight gastric adenocarcinomas found in seven patients with severe hypergastrinemia and/or pernicious anemia using a monoclonal antibody towards chromogranin A and immunohistochemistry without and with a sensitive signal amplification technique. The Sevier-Munger method was used as a more specific marker of ECL cells. Seven of the carcinomas contained scattered neuroendocrine tumour cells. When using signal amplification, an increase in the number of immunoreactive neoplastic cells was seen. In many tumours, clusters or confluent sheets of such cells were disclosed, suggesting a neuroendocrine and ECL cell origin. These tumours may therefore be ECL cell carcinomas and hypergastrinemia may thus be involved in the tumourigenesis.

Topics: Adenocarcinoma; Anemia, Pernicious; Biomarkers, Tumor; Cell Differentiation; Chromogranin A; Chromogranins; Enterochromaffin-like Cells; Female; Gastrins; Humans; Male; Neuroendocrine Tumors; Staining and Labeling; Stomach Neoplasms

A stepwise progression through premalignant stages has been identified for the intestinal type of gastric carcinoma. As gastrin has been identified as a growth factor for the intestinal type of gastric adenocarcinoma, the aim of this study was to investigate whether gastrin is expressed in premalignant gastric conditions.. Ninety archival samples of atrophic gastritis, intestinal metaplasia, mild gastric epithelial dysplasia, moderate gastric epithelial dysplasia, severe gastric epithelial dysplasia and intestinal-type gastric adenocarcinoma were obtained. Immunocytochemistry was performed using antibodies directed against gastrin and its post-translational precursors, and the gastrin/cholecystokinin B receptor. Positive staining was identified using the avidin--biotin immunoperoxidase method and quantified using an image analysis system.. Gastrin and its receptor were shown to be expressed in specimens of atrophic gastritis, intestinal metaplasia, epithelial dysplasia and the intestinal type of gastric carcinoma.. Gastrin seems to be an important growth factor in gastric carcinogenesis.

Topics: Adenocarcinoma; Biomarkers, Tumor; Gastrins; Humans; Immunohistochemistry; Protein Precursors; Pyloric Antrum; Receptor, Cholecystokinin B; Receptors, Cholecystokinin; Stomach Neoplasms

Gastric cancer is one of the most frequent neoplasms and a leading cause of the death world-wide. In recent years, epidemiological and animal studies demonstrated a link between gastric cancer and chronic infection with H. pylori. The exact mechanism responsible for the development of gastric cancer in H. pylori-infected patients still remains unclear. There is evidence that the up-regulation of certain growth factors could play an important role in the promotion of the gastric carcinogenesis.. The present study was designed to determine the gene expression of major known growth factors such as transforming growth factor alpha (TGFalpha), hepatocyte growth factor (HGF) and gastrin in the gastric cancer tissue, the surrounding mucosa and, for comparison, in the normal gastric mucosa. Furthermore, the luminal and plasma levels of gastrin in patients with gastric cancer were determined. In addition, the gene and protein expressions of apoptosis-related proteins such as Bax and Bcl-2 were investigated by reverse transcription-polymerase chain reaction and Western blot. Twenty-five gastric cancer patients and 40 age- and gender-matched control subjects hospitalized with non-ulcer dyspepsia were included into this study.. An overall H. pylori-seropositivity among gastric cancer patients was about 72% and was significantly higher than in the controls (56%). The prevalence of CagA-positive strains was also significantly higher among gastric cancer patients than in controls (56% vs. 32%). The gene expression of HGF and TGFalpha was detected more frequently in gastric cancer tissue samples than in normal gastric mucosa (52% vs. 12% for HGF and 48% vs. 24% for TGFalpha). The extent of protein expression in Western blotting analysis for HGF and TGFalpha correlated with the mRNA expression of these factors. Gene expression of gastrin was detected in the antrum of all tested patients and in the majority (84%) of gastric cancer patients. The median plasma and luminal concentrations of gastrin in gastric cancer patients were significantly higher than in controls. The gene expression of bcl-2 was detected in all (100%) and that of proapoptotic bax only in 56% of gastric cancer samples. In comparison to the surrounding non-tumorous tisssue, the gene expression of bax was significantly down-regulated and the gene expression of bcl-2 was up-regulated in gastric cancer tissue. At the protein level, Bax was not detectable and Bcl-2 was seen in 80% of gastric cancer samples.. It is concluded that the patients infected with H. pylori, especially with CagA-positive strains, are at a higher risk of developing a gastric cancer. An increased production and release of gastrin, as well as an over-expression of growth factors such as HGF and TGFalpha, might contribute to the gastric carcinogenesis. In addition, a dysregulation of the Bax/Bcl-2 system with significant up-regulation of Bcl-2 is observed in gastric cancer.

Topics: Adult; Aged; Apoptosis; bcl-2-Associated X Protein; Case-Control Studies; DNA, Neoplasm; Down-Regulation; Female; Gastrins; Gene Expression Regulation, Neoplastic; Helicobacter Infections; Helicobacter pylori; Hepatocyte Growth Factor; Humans; Male; Middle Aged; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; Reverse Transcriptase Polymerase Chain Reaction; Stomach Neoplasms; Transforming Growth Factor alpha; Up-Regulation

Gastrointestinal carcinoids are derived from the diffuse intestinal endocrine system and may produce amines and many peptides, including serotonin, chromogranin A (CGA), and tachykinins. Most peptide hormones are synthesized as bigger prohormones, which are processed to smaller active hormones by prohormone convertases (PCs). A total of 35 cases of gastrointestinal carcinoids, including gastric, duodenal, small intestinal, appendiceal, and large intestinal carcinoids, were immunocytochemically stained for serotonin, CGA, and PC 1/3 and 2, in order to colocalize CGA and PCs in the carcinoids. All carcinoids were positive for CGA and PCs. Carcinoids that stained strongly for CGA were generally weakly stained for PCs and those weakly staining for CGA were more strongly stained for PCs in the majority of the small and large intestinal tumors. Gastrointestinal carcinoids were positive for CGA and PCs, and the presence of PCs may suggest that the conversion of peptide prohormones to smaller peptide hormones occurs in gastrointestinal carcinoids. PCs immunocytochemistry may be added as a new phenotypic characterization for gastrointestinal carcinoids.

Topics: Adult; Aged; Appendiceal Neoplasms; Aspartic Acid Endopeptidases; Carcinoid Tumor; Child; Chromogranin A; Chromogranins; Duodenal Neoplasms; Female; Gastrins; Gastrointestinal Neoplasms; Humans; Immunohistochemistry; Intestinal Neoplasms; Intestine, Large; Intestine, Small; Male; Middle Aged; Proprotein Convertase 2; Proprotein Convertases; Serotonin; Stomach Neoplasms; Subtilisins

Topics: Adenocarcinoma; Biomarkers, Tumor; Gastrins; Humans; Receptors, Cholecystokinin; Stomach Neoplasms

Chromogranin A (CgA) is a sensitive marker for neuroendocrine neoplasia. Enterochromaffin-like cell hyperplasia secondary to hypergastrinemia also leads to CgA increase in blood. Treatment with inhibitors of acid secretion, atrophic gastritis and infection with Helicobacter pylori are prevalent conditions leading to hypergastrinemia. We therefore wanted to study whether concomitant determination of gastrin could increase the utility of CgA as a marker of neuroendocrine neoplasia.. CgA and gastrin concentrations were determined by radioimmunoassay methods, while pepsinogen I (used to diagnose severe atrophic gastritis) was determined by a commercial immunoenzymatic assay.. Among 100 patients with elevated CgA, we found that 29% had hypergastrinemia. Vice versa, CgA was elevated in 23 out of 26 (88.5%) in a population of patients with hypergastrinemia. By determining pepsinogen I in blood in patients with hypergastrinemia, a proportion of them was diagnosed as having severe atrophic gastritis.. We conclude that determination of gastrin in blood in patients with CgA elevation will increase the utility of CgA in the diagnosis of neuroendocrine tumors.

Topics: Biomarkers, Tumor; Chromogranin A; Chromogranins; Enterochromaffin-like Cells; Gastric Mucosa; Gastrinoma; Gastrins; Gastritis, Atrophic; Humans; Hyperplasia; Immunoenzyme Techniques; Neuroendocrine Tumors; Pepsinogen A; Radioimmunoassay; Stomach; Stomach Neoplasms

Helicobacter pylori and proinflammatory cytokines have a direct stimulatory effect on gastrin release from isolated G cells, but little is known about the mechanism by which these factors regulate gastrin gene expression. We explored whether tumor necrosis factor (TNF)-alpha and interleukin (IL)-1 directly regulate gastrin gene expression and, if so, by what mechanism. TNF-alpha and IL-1 significantly increased gastrin mRNA in canine G cells to 181 +/- 18% and 187 +/- 28% of control, respectively, after 24 h of treatment. TNF-alpha and IL-1 stimulated gastrin promoter activity to a maximal level of 285 +/- 12% and 415 +/- 26% of control. PD-98059 (a mitogen-activated protein kinase kinase inhibitor), SB-202190 (a p38 kinase inhibitor), and GF-109203 (a protein kinase C inhibitor) inhibited the stimulatory action of both cytokines on the gastrin promoter. In conclusion, both cytokines can directly regulate gastrin gene expression via a mitogen-activated protein kinase- and protein kinase C-dependent mechanism. These data suggest that TNF-alpha and IL-1 may play a direct role in Helicobacter pylori-induced hypergastrinemia.

Topics: Adenocarcinoma; Animals; Cells, Cultured; Dogs; Enzyme Inhibitors; Flavonoids; Gastrins; Gene Expression; Humans; Imidazoles; Interleukin-1; Mitogen-Activated Protein Kinases; Mutagenesis; p38 Mitogen-Activated Protein Kinases; Polymerase Chain Reaction; Promoter Regions, Genetic; Protein Kinase C; Pyridines; RNA, Messenger; Stomach Neoplasms; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha

In the presence of atrophic body gastritis, gastric carcinoid develops from gastric-body mucosa enterochromaffin-like cells. Few data exist on the prevalence of enterochromaffin-like dysplastic lesions in atrophic body gastritis patients and their presumed risk of evolution to carcinoid has never been assessed prospectively in humans. The aim of the present study was to investigate the prevalence and incidence of dysplastic and neoplastic enterochromaffin-like cell lesions in a consecutive series of patients with atrophic body gastritis.. A total of 130 atrophic body gastritis patients at diagnosis and 96 atrophic body gastritis patients at follow-up (median 30 months) underwent gastroscopy with multiple biopsies and fasting gastrinaemia evaluation. In patients with enterochromaffin-like cell dysplasia, a more detailed bioptic sampling at follow-up was performed.. Of the 130 atrophic body gastritis patients, only one (0.7%) had a gastric carcinoid polyp, whereas enterochromaffin-like cell dysplasia was found in five patients (3.8%). At follow-up only one out of the 96 atrophic body gastritis patients (1%) was diagnosed as having a carcinoid polyp at 41 months. Enterochromaffin-like cell dysplasia was present in four additional patients (4.2%). Two atrophic body gastritis pernicious anaemia patients with enterochromaffin-like cell dysplasia developed a gastric carcinoid in the follow-up. Among nine atrophic body gastritis patients with enterochromaffin-like cell dysplasia, the incidence of carcinoid tumour was 22% compared to 1.1% of atrophic body gastritis patients without dysplasia (odds ratio: 26.00; 95% confidence interval: 2.089-323.52). During the follow-up, fasting gastrin levels increased significantly only in atrophic body gastritis patients with enterochromaffin-like cell dysplasia (mean 677.4 +/- 66.1 vs 1112.2 +/- 185.6; P = 0.0287).. This study provides the first clinical evidence that, in hypergastrinaemic atrophic body gastritis patients, enterochromaffin-like cell dysplasia carries a markedly increased risk for development of type I gastric carcinoid. This suggests that a more detailed endoscopic/bioptic procedure in this subgroup of atrophic body gastritis patients is able to detect gastric carcinoid at an early stage.

Topics: Adult; Aged; Aged, 80 and over; Carcinoid Tumor; Enterochromaffin-like Cells; Female; Follow-Up Studies; Gastrins; Gastritis, Atrophic; Humans; Immunohistochemistry; Male; Middle Aged; Odds Ratio; Precancerous Conditions; Prevalence; Prospective Studies; Risk; Stomach Neoplasms

We have identified cotton rats with a high female-predominant occurrence of spontaneous gastric carcinomas localized to the oxyntic mucosa, classified as malignant enterochromaffin-like (ECL) omas. The present study was made to further characterize these ECLomas and surrounding oxyntic mucosa, both morphologically using histochemical and immunohistochemical methods, and for gene expression by northern blot analysis. Among eight female cotton rats, three had an irregularly thickened oxyntic mucosa, increased stomach weight and a high serum gastrin level. Histopathological examination showed adenomatous hyperplasia of the thickened oxyntic mucosa with areas of an invasive neoplastic tumour. Immunohistochemistry, using the general neuroendocrine cell marker chromogranin A (CgA) and the specific ECL cell marker histidine decarboxylase (HDC), showed a considerably increased ECL cell density. These ECL cells displayed active proliferation, with hyperplasia, dysplasia and neoplasia. Parietal cells were not found in the tumour tissue. Parietal cell density was only slightly reduced in the surrounding oxyntic mucosa. The antral mucosa was histopathologically normal with a normal number of gastrin-immunoreactive cells. Likewise, somatostatin-immunoreactive cells did not show any differences in the antral and oxyntic mucosa between rats with pathological and normal oxyntic mucosa. Northern blot analysis revealed increased expression of CgA and HDC mRNA in the thickened oxyntic mucosa, whereas H(+)/K(+) ATPase mRNA was similar in the oxyntic mucosa of those with thickened and normal oxyntic mucosa. Gastrin mRNA in the antral mucosa was high in animals with thickened oxyntic mucosa. Somatostatin mRNA expression was similar in the antral mucosa of control animals and animals with a thickened oxyntic mucosa. We conclude that the spontaneous gastric carcinoma occurring in female cotton rats is an ECLoma developing secondary to hypergastrinaemia due to reduced intragastric pH. The mechanism for reduced acidity is not known, but is not gastric atrophy.

Topics: Animals; Blotting, Northern; Chromogranin A; Chromogranins; Enterochromaffin Cells; Female; Gastric Acidity Determination; Gastrins; H(+)-K(+)-Exchanging ATPase; Histidine Decarboxylase; Immunohistochemistry; Parietal Cells, Gastric; RNA, Messenger; Rodent Diseases; Sigmodontinae; Somatostatin; Stomach Neoplasms

Hypergastrinemia occurs frequently in association with acid suppression and Helicobacter infection, but its role in the progression to gastric atrophy and gastric cancer has not been well defined.. The effects of hypergastrinemia, and possible synergy with Helicobacter felis infection, were investigated in insulin-gastrin (INS-GAS) transgenic mice.. INS-GAS mice initially showed mild hypergastrinemia, increased maximal gastric acid secretion, and increased parietal cell number but later progressed to decreased parietal cell number and hypochlorhydria. Development of gastric atrophy was associated with increased expression of growth factors, heparin-binding epidermal growth factor and transforming growth factor alpha. At 20 months of age, INS-GAS mice showed no evidence of increased enterochromaffin-like cell number, but instead exhibited gastric metaplasia, dysplasia, carcinoma in situ, and gastric cancer with vascular invasion. Invasive gastric carcinoma was observed in 6 of 8 INS-GAS mice that were >20 months old. Helicobacter felis infection of INS-GAS mice led to accelerated (< or = 8 mo) development of intramucosal carcinoma (85%), with submucosal invasion (54%) and intravascular invasion (46%; P < or = 0.05).. These findings support the unexpected conclusion that chronic hypergastrinemia in mice can synergize with Helicobacter infection and contribute to eventual parietal cell loss and progression to gastric cancer.

Topics: Animals; Cell Count; Epidermal Growth Factor; Epithelial Cells; Gastric Acid; Gastrins; Gastritis, Atrophic; Helicobacter Infections; Heparin; Heparin-binding EGF-like Growth Factor; Hyperplasia; Hypertrophy; Intercellular Signaling Peptides and Proteins; Metaplasia; Mice; Mice, Transgenic; Stomach Neoplasms; Transforming Growth Factor alpha

To ascertain the frequency and the clinico-functional correlations of intramucosal cysts in the gastric body of patients with the Zollinger-Ellison syndrome (ZES) and to clarify the relevant mechanism of development, a total of 106 consecutive ZES patients (58 M, 48 F; mean age: 53 yrs, range 19-93 yrs) were investigated with a mean of 7.2 biopsy specimens of the body mucosa per patient proved to be suitable for the study. Biopsies of endoscopically detectable polypoid lesions were not considered. Cystic changes were evaluated with respect to their severity by assessing the cyst grade (0, absent, 1; <30%, 2; 30-60%; 3 >60% of the mucosal area of the biopsy specimen of individual patients showing the most pronounced finding, respectively) and to their intragastric distribution by assessing the ratio of biopsy specimens showing cystic changes over the total number of biopsies examined in each patient. Intramucosal cysts were found in biopsies of non-polypoid gastric body mucosa in 71.7% of 106 patients with Zollinger-Ellison syndrome (ZES) and showed grade 2 and 3 severity in 22 and 8 cases, respectively. The severity of cystic changes correlated with the gastrin levels (p = 0.0005) and was more advanced in patients with active than in those with cured disease (p = 0.037). In the former group, furthermore, advanced cystic changes correlated with age (p = 0.03), male gender (p = 0.014), years of disease from onset (p < 0.02), years of omeprazole treatment (p = 0.033), basal acid output (p < 0.02), severity of ECL cell proliferative changes (p = 0.028), and absence of previous gastrinoma resection (p = 0.039) whereas they did not correlate with MEN-1 status, gastritis, maximal acid output, total duration of any antisecretory drug treatment, daily doses of omeprazole (> 20 mg vs 20 mg), years from surgery, duodenal localization of gastrinoma(s), presence of gastric carcinoid tumor(s) and of liver metastases. In groups of patients subdivided according to three levels of serum gastrin, the duration of omeprazole treatment was not related to the severity of cystic changes. It is concluded that intramucosal cysts in non polypoid gastric body mucosa of ZES patients are by far more common than the already reported fundic gland polyps, to which they likely give raise. Circulating levels of gastrin have an important independent role in their development.

Topics: Adult; Aged; Aged, 80 and over; Aging; Biopsy; Cell Division; Cysts; Enterochromaffin Cells; Female; Gastric Acid; Gastric Mucosa; Gastrinoma; Gastrins; Humans; Male; Middle Aged; Omeprazole; Sex Characteristics; Stomach; Stomach Neoplasms; Zollinger-Ellison Syndrome

Topics: Gastric Fundus; Gastrins; Humans; Polyps; Stomach Neoplasms; Zollinger-Ellison Syndrome

Topics: Adult; Antineoplastic Agents; Carcinoid Tumor; Female; Gastrins; Humans; Male; Middle Aged; Multiple Endocrine Neoplasia Type 1; Octreotide; Peptides, Cyclic; Somatostatin; Stomach Neoplasms; Zollinger-Ellison Syndrome

Gastrinoma is a rare endocrine tumor that is frequently associated with liver metastasis. The liver metastasis is usually seen simultaneously or soon after a primary operation. A 47-year-old woman who had had a total gastrectomy 20 years earlier developed liver metastasis. An interval of this length between surgery and metastasis is extremely rare. The total gastrectomy prevented the patient from developing the usual symptoms of hypergastrinemia that would have enabled early diagnosis of the metastasis. Laboratory examinations on admission revealed a high serum gastrin concentration (1500 pg/ml). Computed tomography showed an irregularly enhanced mass lesion with an uneven, low-density central area in the right anterior inferior segment of the liver. An extended right hepatectomy was performed. Intraoperative ultrasonography showed no abnormalities in the remnant pancreas. Examination of the cut surface of the specimen revealed a yellow, firm, elastic tumor, 55 mm in diameter. The interior of the tumor appeared necrotic. Histopathologically, the tumor was composed of cells with hyperchromatic, dysplastic nuclei arranged in a trabecular pattern with nest formation. Gastrin staining was positive. A histologic diagnosis of metastatic gastrinoma was made. The patient's gastrin concentration returned to normal and she was well at 2-year follow-up.

Topics: Female; Gastrectomy; Gastrinoma; Gastrins; Humans; Liver; Liver Neoplasms; Middle Aged; Stomach Neoplasms; Time Factors; Tomography, X-Ray Computed

Hypergastrinemia secondary to low acid secretion is associated with gastric carcinoid formation in Mastomys. We investigated the effect of gastrin on oxyntic epithelial apoptosis and proliferation in this model.. Hypergastrinemia and mucosal hyperplasia were induced by irreversible H(2) receptor blockade with loxtidine. Gastrin levels were normalised in some animals by 10 days' loxtidine withdrawal. Serum gastrin was determined by radioimmunoassay, proliferative, enterochromaffin-like cells and Bcl-2 protein family expression by immunohistochemistry, and apoptotic cells by terminal deoxyuridine nucleotide nick end labeling (TUNEL).. Proliferating cells were increased 4-fold in loxtidine-treated animals, and returned to normal upon loxtidine withdrawal. Enterochromaffin-like cell number increased 2-fold with loxtidine, and did not decrease after withdrawal. Apoptotic epithelial cells were located at the luminal surface and increased 1.8-fold with loxtidine, returning to control levels upon withdrawal. The ratio of proliferative to apoptotic cells was lower in the control and withdrawn groups than in the loxtidine group (0.26+/-0.05 and 0.26+/-0.08 vs. 0.77+/-0.12). With hypergastrinemia, the expression of Bcl-2 and Bak was increased and Bax decreased in the middle of the gland.. Hypergastrinemia is associated with alterations in both proliferation and apoptosis in Mastomys gastric mucosa. This may contribute to the pathogenesis of mucosal hyperplasia in this model.

Topics: Animals; Apoptosis; Carcinoid Tumor; Cell Division; Disease Models, Animal; Female; Gastric Acid; Gastric Mucosa; Gastrins; Immunohistochemistry; Male; Muridae; Proto-Oncogene Proteins c-bcl-2; Stomach Neoplasms

Tumors arising in the stomach have worldwide distribution and the infection with Helicobacter pylori (HP) has been implicated in causation of this disease. The HP discovery, which is considered as the greatest advance of gastroenterology at the dawn of 3rd millennium, is accompanied by hypergastrinemia, which seems to play a key role in gastric cancerogenesis but no study was undertaken to assess the relationship between the HP infection and coexpression of gastrin and cyclooxygenases (COX), the rate limiting enzymes in the eicosanoids production.. Since gastrin is recognized as a effective gastric mitogen, it could be capable to induce COX-2, a potent tumor growth promoting and angiogenic factor, we decided 1) to compare the seroprevalence of HP and its cytotoxic protein, CagA, in gastric cancer patients with those in age- and gender-matched controls; 2) to determine the gene expression of gastrin and its receptors (CCK(B)-R) in gastric cancer, 3) to assess the plasma levels, gastric lumen and tumor tissue contents of gastrin and 4) to examine the mRNA and enzyme protein expression of COX-1 and COX-2 in cancer tissue and intact gastric mucosa before and after HP eradication.. The trial material included 20 patients with gastric cancers and 100 age- and gender-matched controls. Anti-HP and anti-CagA IgG seroprevalence was estimated by specific antisera using ELISA tests. Gene expressions of gastrin, CCK(B)-R, COX-1 and COX-2 was examined using RT-PCR with GAPDH as a reference and employing Western blot for COX-2 expression, while gastrin was measured by RIA.. The seroprevalence of HP, especially that expressing CagA, was significantly higher in gastric cancers than in controls. Both gastrin and CCK(B)-R mRNA were detected by RT-PCR in the cancer tissue and similarly COX-2 mRNA and protein were found in most of cancers and in the HP infected antral mucosa but not in HP eradicated patients in whom only cancer tissue but not gastric mucosa expressed COX-2. The gastric cancer tissue contained 20 times more of immunoreactive gastrin than the HP infected antral gastric mucosa and following HP eradication the gastrin content in the tumor and antrum showed a marked and significant reduction. No significant change in CCK(B)-R expression was noticed before and after HP eradication in the tumor and the corpus mucosa.. 1). Gastric carcinoma coexpresses gastrin, its receptors (CCK(B)-R), and COX-2; 2) HP infection may contribute to gastric cancerogenesis via gastrin andCOX-2 that may account for the stimulation of tumor growth, angiogenesis, and reduction in apoptosis 3) HP positive patients developing gastric cancer should be considered for HP eradication to reduce the HP provoked hypergastrinemia and COX-2 overexpression in the tumor tissue.

Topics: Aged; Aged, 80 and over; Antigens, Bacterial; Bacterial Proteins; Biopsy; Blotting, Western; Enzyme-Linked Immunosorbent Assay; Female; Gastric Mucosa; Gastrins; Helicobacter pylori; Humans; Male; Middle Aged; Prostaglandin-Endoperoxide Synthases; Receptors, Cholecystokinin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Seroepidemiologic Studies; Stomach Neoplasms

We have experienced a case of the stomach with hypergastrinemia and type A gastritis with multiple carcinoids in a 37-year-old woman. An upper gastrointestinal series revealed multiple minute polyps in the upper body of the stomach. All polyps were diagnosed as carcinoid using endoscopic biopsies. She had neither symptom or signs of typical carcinoid disease. The serum gastrin level was as high as 725 pg/ml. Total gastrectomy was performed, and the diagnosis of multiple gastric carcinoids (sm, no) with type A gastritis was histologically confirmed. After the operation, the serum gastrin level returned to normal, and the patient has been doing well and is disease-free to date at 7 years after the operation. This case suggested that multiple gastric carcinoid lesions may be precipitated by chronic atrophic gastritis accompanying hypergastrinemia. In the treatment of multiple gastric carcinoids with type A gastritis, total gastrectomy with lymph node dissection should be standard operative procedure, in order to resect the fundic gland area completely which could be the origin of carcinoids and endocrine cell micronest.

Topics: Adult; Carcinoid Tumor; Female; Gastrins; Gastritis; Humans; Stomach Neoplasms

The aim of this study was to determine the correlation between serum gastrin and resectability in patients with gastric cancer, and to see whether any difference could be demonstrated according to the histologic type and survival. Between 1994 and 1996 records of 34 consecutive patients with gastric carcinoma serum gastrin levels were measured and correlated with age, gender, lymph node positiveness, metastasis, Lauren's classification and survival. The mean serum gastrin level of patients was 98.38 pg/ml (normal range: 25-125 pg/ml). Twenty-six of 34 patients (76.5%) had normal gastrin levels and eight patients (23.5%) had high gastrin levels. Sixty-five per cent of patients with normogastrinaemia underwent resection with extended lymphadenectomy, while 38% patients with hypergastrinaemia underwent extended resection. All the hypergastrinaemic patients died within the first year, but in the normogastrinaemic group one, two and five-year survival rates were 39%, 23% and 4%, respectively. Even though these results are not statistically significantly different in regard to preoperative serum gastrin levels, we conclude that preoperative hypergastrinaemia is associated with unresectability and poor survival in patients with gastric cancer.

Topics: Adult; Aged; Aged, 80 and over; Analysis of Variance; Female; Gastrins; Humans; Male; Middle Aged; Preoperative Care; Prospective Studies; Stomach Neoplasms; Survival Analysis; Treatment Outcome

EGF stimulates gene expression through a variety of signal transduction pathways that include the ras-Erk pathway. We have shown previously that EGF receptor activation stimulates gastrin gene expression through a GC-rich element called gERE. This element binds Sp1 family members and raises the possibility that the ras-Erk signal transduction cascade may target this novel EGF responsive element. Moreover, it is known that Erk 2 is capable of phosphorylating other mitogen-inducible transcription factors, e.g., Elk, Sap suggesting that Erk may also inducibly phosphorylate Sp1. To test this hypothesis directly using cotransfection experiments, we show that ras and Erk 2 activation indeed target the gERE element. The Mek 1 kinase inhibitor, PD98059, blocks 50% of EGF-inducible gastrin promoter activity. Pretreatment of the extracts with recombinant Erk2 stimulated Sp1 binding; whereas dephosphorylation reduced but did not eliminate Sp1 binding. Together, these studies demonstrate the novel finding that inducible binding of Sp1 is regulated by its state of phosphorylation. Further, gastrin promoter activation is mediated in part by the ras-Erk signaling cascade that targets Sp1.

Topics: Adenocarcinoma; Base Sequence; Binding Sites; Calcium-Calmodulin-Dependent Protein Kinases; Enzyme Inhibitors; Epidermal Growth Factor; Flavonoids; Gastrins; Gene Expression Regulation, Neoplastic; Genes, ras; Humans; Mitogen-Activated Protein Kinase 1; Oligodeoxyribonucleotides; Phosphorylation; Promoter Regions, Genetic; Signal Transduction; Sp1 Transcription Factor; Stomach Neoplasms; Transcription Factors; Tumor Cells, Cultured

The diagnosis of adenocarcinoid (mucinous/goblet cell carcinoid) is usually unexpected by both clinicians and pathologists. We report here the case of a 74-year-old man with gastric lymphoma (B-cell MALToma) diagnosed by endoscopy, who was found on exploratory laparotomy also to have extensive intraabdominal involvement by adenocarcinoid, arising from the ileum and/or appendix. The patient died two years after diagnosis with bladder outlet and small bowel obstruction due to diffuse metastases. In addition to mucin positivity, immunohistochemical stains demonstrated the tumor to be positive for chromogranin, synaptophysin, serotonin, gastrin, and glucagon. Of histogenetic interest, some individual neoplastic cells appeared to be positive for both mucin and chromogranin, and this was confirmed by the electron microscopic finding of microvilli, intracytoplasmic mucin droplets, and neurosecretory granules involving the same neoplastic cells. This also appears to be the first reported case of adenocarcinoid associated with lymphoma and demonstration of histochemical/immunohistochemical and ultrastructural evidence of cellular components with dual mucinous adenocarcinoma and neuroendocrine features, and the second reported case to have prostatic metastases.

Topics: Adenocarcinoma; Aged; Appendiceal Neoplasms; Biomarkers, Tumor; Carcinoembryonic Antigen; Carmine; Chromogranins; Coloring Agents; Gastrins; Glucagon; Helicobacter Infections; Helicobacter pylori; Humans; Ileal Neoplasms; Immunohistochemistry; Laparotomy; Lymphoma, B-Cell, Marginal Zone; Male; Metaplasia; Microscopy, Electron; Neoplasms, Multiple Primary; Prostatic Neoplasms; Serotonin; Stomach Neoplasms; Synaptophysin

The therapeutic effect of antibodies raised by the immunogen Gastrimmune was compared with both a CCKB/gastrin receptor antagonist, CI-988, and 5-Fluorouracil/leucovorin in a gastric cancer model. The human gastric ascites cell line, MGLVA1asc, produced and secreted progastrin and glycine-extended gastrin as determined by radioimmunoassay and immunocytochemistry. Cells were also stained with an antiserum directed against the human CCKB/gastrin receptor. MGLVAI asc cells were injected i.p. into SCID mice. Antibodies raised by Gastrimmune immunization of rabbits (affinity for G17 of 0.15 nM and GlyG17 of 0.47 nM) were passively infused i.p. and significantly enhanced survival by up to 5 days (p=0.0024 from vehicle controls). The enhancement in survival was not significantly different from that achieved by treatment with 5-Fluorouracil and leucovorin. A CCKB/gastrin receptor antagonist, CI-988, did not affect survival with cells injected at 7.5 x 10(5) cells/mouse but significantly increased the survival of mice injected with a lower cell innoculum of 5 x 10(5) cells/mouse from 30 to 35 days (p=0.0186). At this lower innoculum antibodies raised by Gastrimmune induced complete survival in 2 animals with the remaining dead by day 36 (p=0.0022). Thus, both endocrine and autocrine pathways mediated by precursor and mature gastrin molecules may be jointly operational in the gastric cancer scenario and may be important targets for therapeutic agents.

Topics: Animals; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Ascites; Cancer Vaccines; Diphtheria Toxoid; Fluorouracil; Gastrins; Humans; Leucovorin; Mice; Mice, SCID; Severe Combined Immunodeficiency; Stomach Neoplasms; Tumor Cells, Cultured

The RegIalpha gene (Reg) encodes a secretory protein proposed to regulate islet beta-cell and gastric mucous cell growth. Reg is expressed in rat gastric enterochromaffin-like (ECL) cells. The aim of this study was to examine Reg expression in human corpus and to determine the identity of Reg in ECL cell carcinoid tumors in hypergastrinemic patients.. Reg messenger RNA (mRNA) abundance was quantified by Northern blot in extracts of gastric corpus from patients with and without ECL cell tumors and in AR4-2J cells stimulated by gastrin; cellular origins were determined by immunocytochemistry. Mutations of Reg were determined by reverse-transcription polymerase chain reaction, cloning, and sequencing, and the mutated protein was expressed in HIT-T15 cells.. Reg mRNA abundance was increased approximately threefold in the corpus of hypergastrinemic patients compared with controls, and was enriched in 3 of 7 ECL cell carcinoid tumors but not in non-endocrine cell gastric polyps. In AR4-2J cells, gastrin stimulated Reg mRNA abundance; this was eliminated by the gastrin/cholecystokinin B antagonist L-740,093 (10(-9) mol/L). Immunocytochemistry indicated that Reg was located in both chief cells and ECL cells in human corpus. Mutations of Reg were identified in 3 of 5 patients with ECL cell carcinoid tumors; in 2 cases, mutation of the initiator methionine residue led to exclusion of the protein from the secretory pathway.. Gastrin regulates Reg mRNA abundance in human corpus. Mutations of Reg that prevent secretion are associated with ECL cell carcinoids, suggesting a function as an autocrine or paracrine tumor suppressor.

Topics: Adult; Aged; Aged, 80 and over; Calcium-Binding Proteins; Carcinoid Tumor; Endocrine Gland Neoplasms; Enterochromaffin Cells; Female; Gastric Mucosa; Gastrins; Humans; Lithostathine; Male; Methionine; Middle Aged; Mutation; Nerve Tissue Proteins; Protein Biosynthesis; RNA, Messenger; Stomach Neoplasms; Tissue Distribution

Female inbred cotton rats develop adenocarcinomas in the oxyntic mucosa. Since a female preponderance is typical for enterochromaffin-like (ECL) cell tumors, we examined such tumors for ECL cells. Gastrin plays a decisive role in ECL cell tumorigenesis, so blood gastrin concentration and gastric mucosal pH were measured.. The stomachs from six female cotton rats (6 to 8 months old) were studied histologically, and at euthanasia, gastric mucosal pH was determined. Euthanasia was performed on 15 other female cotton rats of similar age for determination of blood gastrin values by radioimmunoassay (RIA) and gastric mucosal pH. Rats were classified macroscopically to have normal or thick oxyntic mucosa, with or without tumor.. Among the six cotton rats studied histologically, two 6-month-old rats had normal and two others had thick gastric mucosa, whereas two 8-month-old rats had thick mucosa with tumors. The ECL cells were markedly hyperplastic in all rats with thick mucosa, and ECL cells were found in the neoplastic parenchyma. All cotton rats with normal-appearing gastric mucosa had pH <2.5, whereas 14 rats with thick mucosa had pH >3.1 and hypergastrinemia.. Gastrin may play a major role in ECL cell hyperplasia and, perhaps, in adenocarcinoma genesis.

Topics: Adenocarcinoma; Animals; Chromogranin A; Chromogranins; Enterochromaffin Cells; Female; Gastrins; Histidine Decarboxylase; Hydrogen-Ion Concentration; Hyperplasia; Immunoenzyme Techniques; Male; Radioimmunoassay; Rats; Rodent Diseases; Sigmodontinae; Stomach Neoplasms; Synaptophysin

A Mongolian gerbil model was used to clarify whether long-term colonization by Helicobacter pylori is an important risk factor for the development of gastric cancer. Fifty-nine gerbils (3 controls and 56 gerbils inoculated with H. pylori) were killed at various times (average, 23 months) more than 12 months after H. pylori inoculation. In the H. pylori-inoculated group, poorly differentiated adenocarcinoma was observed in the pylorus of 1 gerbil, and carcinoid was observed in the fundus of the stomach in 18 gerbils. No lesions were found in the stomachs of the 3 control gerbils. The results imply that long-term colonization by H. pylori is an important risk factor for the development of gastric adenocarcinoma and carcinoid.

Topics: Adenocarcinoma; Animals; Antibodies, Bacterial; Carcinoid Tumor; Disease Models, Animal; Duodenum; Gastrins; Gerbillinae; Helicobacter Infections; Immunoglobulin G; Intestinal Mucosa; Metaplasia; Stomach Neoplasms; Time

Gastric cancers are a significant cause of morbidity worldwide. Epidemiological studies and animal models show that males have higher incidences of gastric cancers compared with females, suggesting that sex hormones may modulate gastric cancer risk. An animal model of the initiation phase of gastric cancer was used to determine the effects of systemic estrogen administration on morphological progression of preneoplastic lesions and to define cell populations at which estrogens may act. Preneoplastic progression in antral and duodenal mucosa was examined in male rats that received the chemical carcinogen, N-methyl-N'-nitro-nitrosoguanidine (MNNG), during treatment with implants containing 17beta-estradiol or oil vehicle. Histopathological changes in antral and duodenal gland morphology, numbers of proliferating cells and apoptotic bodies, and antral gastrin cell numbers and protein storage levels were determined 4 weeks later. With MNNG treatment, duodenal villous heights were significantly decreased, and epithelial cells displayed histological features of hyperplasia and dysplasia. Antral glands showed epithelial hyperplasia and dysplasia, increased mucosal height, and decreased mucin levels. Antral gastrin storage protein levels were decreased by MNNG. Systemic treatment with 17beta-estradiol significantly reversed MNNG-induced alterations in duodenal gland heights while increasing mucin and gastrin levels in antral glands. Cell proliferation and apoptosis rates were not significantly different between groups. The present results indicate that systemic 17beta-estradiol treatment influences antral and duodenal gland differentiation during the initiation phase of chemical gastroduodenal carcinogenesis in male rats. These results explain, in part, a potential pathway through which protective effects of estrogens on chemical carcinogenesis are mediated in the upper gastrointestinal tract.

Topics: Animals; Apoptosis; Carcinogens; Cell Division; Duodenal Neoplasms; Duodenum; Estradiol; Gastrins; Health Status; Male; Methylnitronitrosoguanidine; Precancerous Conditions; Pyloric Antrum; Rats; Rats, Sprague-Dawley; Stomach Neoplasms

Gastrin is a growth factor for established tumours.. To investigate the therapeutic effect of antibodies, raised against the Gastrimmune immunogen, which neutralise the glycine extended and carboxy amidated forms of gastrin 17 in two human gastric cancer models.. MGLVA1 cells (which have a gastrin autocrine/paracrine phenotype) and ST16 cells (which have an endocrine phenotype) were injected into the peritoneal cavity of SCID mice. Peritoneal tumours, ascites, and cachexia formation occurred, with the monitored endpoint being morbidity.. In MGLVA1 cells, intravenous administration of antibodies raised against Gastrimmune increased the 50% median survived by 25% at three different initial cell seeding concentrations (1 x 10(6)-5 x 10(5) per mouse). In ST16 cells, the effect of Gastrimmune induced antibodies on time to morbidity was greatest at the lowest cell seeding concentration (5 x 10(5) cells/mouse) with the 50% median survival increased by 74% and overall survival achieved in 38% of the mice.. Gastrimmune may have potential therapeutic benefit on gastrin sensitive gastric tumours and may interact with both endocrine and autocrine mediated growth pathways.

Topics: Animals; Autocrine Communication; Cancer Vaccines; Culture Media, Serum-Free; Diphtheria Toxoid; Gastrins; Humans; Immunization, Passive; Luminescent Measurements; Mice; Mice, SCID; Neoplasm Transplantation; Neoplasms, Hormone-Dependent; Paracrine Communication; Reverse Transcriptase Polymerase Chain Reaction; Stomach Neoplasms; Tumor Cells, Cultured

The proximal region of the human gastrin gene promoter contains three GC/GT boxes at positions -140 to -134 bp, -108 to -102 bp and -67 to -61 bp. In this study we have examined the significance of the three elements, and their role in Sp1 and Sp3 mediated gastrin transcription. In AGS cells, mutation of each of the boxes caused a moderate decrease in promoter activity from 33 to 63%, whereas double or triple mutations reduced activity to 3-12%. In Drosophila cells Sp1 activated the promoter, mainly through the distal GC box. Similarly, co-transfection of heterologous promoter constructs revealed that only the distal GC box increased activation by Sp1. The effect of Sp3 was cell-line dependent, since Sp3 inhibited the gastrin promoter activity in AGS cells and caused a synergistic activation of the Sp1 stimulated gastrin promoter in Drosophila cells. Both effects were dependent on the C-terminal DNA binding domain of Sp3. The results indicates that the combined effect of the GC/GT boxes and the ratio between Sp1 and Sp3 are important for gastrin gene expression.

Topics: Adenocarcinoma; Animals; Base Composition; Base Sequence; Chloramphenicol O-Acetyltransferase; Drosophila melanogaster; Gastrins; Genes, Reporter; Humans; Luciferases; Molecular Sequence Data; Promoter Regions, Genetic; Recombinant Fusion Proteins; Stomach Neoplasms; TATA Box; Transcription Factors; Transcription, Genetic; Transfection; Tumor Cells, Cultured

During recent years, gastric ECL cells have attracted much attention, mainly due to the fact that mice and rats were found to develop gastric carcinoids following lifelong treatment with blockers of acid secretion. We present the structure and functions of ECL cells and their influence on physiology and pathology of stomach and duodenum. We describe interactions of enzymes and hormones in histamine-stimulated gastric output.

Topics: Animals; Anti-Ulcer Agents; Chromogranin A; Duodenal Neoplasms; Duodenal Ulcer; Enterochromaffin-like Cells; Gastrins; Histamine; Mice; Pancreatic Hormones; Rats; Stomach Neoplasms; Stomach Ulcer

Gastrin is one of the main factors controlling enterochromaffin-like (ECL) cell endocrine function and growth. Long-standing hypergastrinemia may give rise to ECL cell carcinoids in the gastric corpus in man and in experimental models. We have analysed the expression and function of CCK-B/gastrin receptors in normal ECL cells and in ECL cell tumours (gastric carcinoids) of the African rodent Mastomys natalensis. Hypergastrinemia induced by short-term (5 days) histamine2-receptor blockade (loxtidine) resulted in increased histidine decarboxylase (HDC) mRNA expression in the gastric oxyntic mucosa. This increase was significantly and dose-dependently reversed by selective CCK-B/gastrin receptor blockade (YM022). Long-term (12 months) hypergastrinemia, induced by histamine2-receptor blockade, gave rise to ECL cell carcinoids in the gastric oxyntic mucosa. CCK-B/gastrin receptor mRNA was only slightly elevated while HDC mRNA expression was eight-fold elevated in ECL cell carcinoids and was not influenced by CCK-B/gastrin receptor blockade. Thus CCK-B/gastrin receptor blockade of hypergastrinemic animals reduces the HDC mRNA expression in normal mucosa but not in ECL cell carcinoids. These results demonstrate that HDC mRNA expression in neoplastic ECL cells is not controlled by CCK-B/gastrin receptors.

Topics: Animals; Benzodiazepines; Carcinoid Tumor; Cell Transformation, Neoplastic; Enterochromaffin Cells; Gastric Mucosa; Gastrins; Gene Expression; Histamine H2 Antagonists; Histidine Decarboxylase; Hormone Antagonists; Humans; Muridae; Receptors, Cholecystokinin; RNA, Messenger; RNA, Neoplasm; Stomach Neoplasms; Triazoles

The aims of this study were to illustrate the malignant potential of gastric enterochromaffin-like (ECL) cell carcinoids (ECLomas) associated with hypergastrinemia, and the gradual neoplastic progression of such tumours. In addition, we examined whether the tyramide signal amplification (TSA) technique could visualize immunohistochemical (IHC) neuroendocrine (NE) features in the dedifferentiated neoplastic ECL cells which were not detected by conventional methods.. Conventional histopathological and IHC methods for visualizing ECL cells and cell proliferation were used in addition to the TSA technique.. Our patient was followed for 5 years. During that period, her ECLoma displayed all the signs of classical tumour progression, ultimately with the appearance of metastases in the regional lymph nodes, the liver and the skin. The neoplastic ECL cells became progressively dedifferentiated with an increasing number of Ki-67 immunoreactive (IR) cell nuclei. In addition, there was a substantial decrease in argyrophil and IR NE cells that could be visualized by conventional methods. By applying the TSA technique, however, the number of IR tumour cells increased considerably.. ECLomas secondary to hypergastrinemia should be closely followed for signs of clinical and histopathological tumour progression. Such ECLomas deserve early, active, radical surgical treatment. The TSA technique is a valuable tool for visualizing the characteristic IHC features in dedifferentiated NE cells.

Topics: Aged; Carcinoid Tumor; Cell Differentiation; Chromogranin A; Chromogranins; Enterochromaffin Cells; Female; Gastrins; Gastritis, Atrophic; Histidine Decarboxylase; Humans; Immunohistochemistry; Ki-67 Antigen; Serotonin; Stomach Neoplasms

Helicobacter pylori infection is associated with an increased risk of gastric cancer. In Helicobacter pylori negative patients, factors different from those in Helicobacter pylori positive patients may be involved in gastric carcinogenesis.. Thirty-nine recently diagnosed consecutive patients with gastric cancer were investigated. Gastric biopsies were obtained for detection of Helicobacter pylori (by immunohistochemistry), non-Helicobacter pylori flora (by modified Giemsa and culture) and histological assessment according to the Sydney classification by Haematoxylin-Eosin staining. In serum samples, Helicobacter pylori antibodies were determined by IgG enzyme-linked immunosorbent assay, IgA enzyme-linked immunosorbent assay, and Western blotting. Furthermore, serum gastrin, pepsinogen A and C and plasma chromogranin A were determined.. Helicobacter pylori was detected by immunohistochemistry in 53.8%, by IgG in 56.4%, by IgA in 33.3%, and by Western blotting in 74.4% of the 39 patients. Ten patients (25.6%) were negative by both histology and serology. Non-Helicobacter pylori flora was detected in 27 of the 39 patients (69.2%) with a similar frequency in Helicobacter pylori positive and negative patients. Helicobacter pylori positivity was found significantly more often in diffuse than intestinal type carcinoma patients (p < 0.05). Elevated gastrin levels and antrum-sparing atrophic gastritis were more frequent in Helicobacter pylori negative than in Helicobacter pylori positive patients (p < 0.05).. In 10 out of 39 gastric cancer patients, no evidence of previous or current Helicobacter pylori infection could be demonstrated. Non-Helicobacter pylori was found in 69.2% of patients regardless of the Helicobacter pylori status. Further studies are needed to establish the contribution of non-Helicobacter pylori flora as well as antrum-sparing atrophic gastritis with hypergastrinaemia to the development of gastric cancer.

Topics: Aged; Aged, 80 and over; Antibodies, Bacterial; Chromogranin A; Chromogranins; Female; Gastrins; Helicobacter pylori; Humans; Male; Middle Aged; Pepsinogen A; Pepsinogen C; Prospective Studies; Stomach; Stomach Neoplasms

Numerous epidemiological studies demonstrated the association between Helicobacter pylori (H. pylori) infection and gastric cancer but the mechanism of the involvement of H. pylori in gastric cancerogenesis remains virtually unknown. This study was designed to determine the seropositivity of H. pylori and cytotoxin associated gene A (CagA), serum gastrin and gastric lumen gastrin levels under basal conditions and following stimulation with histamine in gastric cancer patients and controls. 100 gastric cancer patients aging from 21 to 60 years and 300 gender- and age-adjusted controls hospitalized with non-ulcer dyspepsia (NUD) entered this study. 13C-Urea Breath Test (UBT), serum immunoglobulin (IgG) antibodies to H. pylori and CagA were used to assess the H. pylori infection and serum levels of IL-1beta, IL-8 and TNFalpha were measured by enzyme-linked immunosorbent assay (ELISA) to evaluate the degree of gastric inflammation by H. pylori . Gastrin-17 mRNA and gastrin receptors (CCK(B)) mRNA expression in gastric mucosal samples taken by biopsy from the macroscopically intact fundic and antral mucosa as well as from the gastric tumor was determined using RT-PCR. The overall H. pylori seropositivity in gastric cancer patients at age 21-60 years was about 92%, compared, respectively, to 68%, in controls. A summary odds ratio (OR) for gastric cancer in H. pylori infected patients was about 5.0 . The H. pylori CagA seropositivity in gastric cancer patients was about 58.5% compared to 32.4% in controls, giving the summary OR for gastric cancer in CagA positive patients about 8.0. The prevalence of H. pylori- and H. pylori CagA-seropositivity was significantly higher in cancers than in controls, irrespective of the histology of gastric tumor (intestinal, diffuse or mixed type). Median IL-1beta and IL-8 reached significantly higher values in gastric cancer patients (9.31 and 30.8 pg/ml) than in controls (0.21 and 3.12, respectively). In contrast, median serum gastrin in cancers (as total group) was several folds higher (62.6 pM) than in controls (19.3 pM). Also median luminal gastrin concentration in gastric cancer patients was many folds higher (310 pM) than in controls (20 pM). This study shows for the first time that cancer patients are capable of releasing large amounts of gastrin into the gastric lumen to increase luminal hormone concentration to the level that was recently reported to stimulate the growth of H. pylori. There was no any correlation between

Topics: Adult; Antibodies, Bacterial; Antigens, Bacterial; Bacterial Proteins; Female; Gastric Acid; Gastrins; Helicobacter Infections; Helicobacter pylori; Humans; Immunoglobulin G; Male; Middle Aged; Stomach Neoplasms

To investigate the practicability of proglumide to treat gastric cancer.. MKN45 gastric cancer cell line was cultured and the effects on gastrin and gastrin receptor antagonist proglumide proliferative rate, cell dynamic cycle distribution and the concentration of cAMP in the cells were observed in vitro.. Gastrin promoted the proliferation of MKN45 cells and shifted cells from phase G(0)/G(1) to phase S, G(2)/M as well as increased intracellular cAMP, while proglumide blocked these effects.. Gastrin induces the proliferation and synthesis of DNA by its receptor. Proglumide may provide a new approach of non-cytotoxic treatment of gastric cancer.

Topics: Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cyclic AMP; Drug Antagonism; Gastrins; Humans; Proglumide; Stomach Neoplasms

In this study we identified and characterized the receptor related to the modulation of growth of human gastric cancer by gastrin. By performing receptor binding assays on human AGS gastric cancer cells with the selective CCK-B/gastrin receptor antagonist [3H]L-365,260, specific and saturable binding were determined. Binding was dependent on protein concentration, time, temperature, and the presence of protease inhibitors, and was located in the membrane fraction. Gastrin, as well as CCK, stimulated gastric cancer cell growth in a receptor-mediated fashion at a concentration consistent with the binding affinity. Receptor gene expression for the CCK-B/gastrin receptor, but not for the CCK-A receptor, was found by reverse transcription polymerase chain reaction. Receptor binding assays as well as transcriptional and growth studies provide evidence that gastrin-stimulated growth of human gastric cancer is mediated by CCK-B/gastrin-like receptors.

Topics: Benzodiazepinones; Cholecystokinin; Gastric Mucosa; Gastrins; Gene Expression; Growth Substances; Humans; In Vitro Techniques; Molecular Sequence Data; Phenylurea Compounds; Receptors, Cholecystokinin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Stomach Neoplasms; Transcription, Genetic; Tumor Cells, Cultured

Topics: Carcinoid Tumor; Cell Line; Enterochromaffin Cells; Gastrins; Humans; Multiple Endocrine Neoplasia Type 1; Stomach Neoplasms

We present here familial occurrence of two patients with gastric carcinoid. Both patients, a sister and older sister, had type A chronic atrophic gastritis with hypergastrinemia. This is the first case report of familial occurrence of gastric carcinoid associated with type A chronic atrophic gastritis in the world literature. The possible mechanism of familial occurrence in the patients is discussed.

Topics: Adult; Carcinoid Tumor; Chronic Disease; Female; Gastrins; Gastritis, Atrophic; Humans; Pedigree; Stomach Neoplasms

Distinguishing between neuroendocrine carcinoma and adenocarcinoma may be difficult.. In the current prospective study blood and tumor tissue from patients with gastric carcinoma were collected. The tissue was fixed in different ways to allow examination for neuroendocrine markers by multiple methods such as various histochemical and immunohistochemical methods and electron microscopy. Blood and tumor homogenates were examined by radioimmunoassay for specific hormones and general neuroendocrine markers.. Based on examination of general neuroendocrine markers such as chromogranin A (by immunohistochemistry, Northern blot analysis, and tissue concentration), neuron specific enolase (immunohistochemistry) as well as electron microscopy, it was possible to conclude that approximately 10% of the tumors were actually neuroendocrine malignant tumors. Among these tumors, the enterochromaffin-like (ECL) cell was the most preponderant cell of origin (Sevier-Munger positive and serotonin negative immunoreactive tumor cells with secretory granules resembling those observed in normal ECL-cells). As reported previously, tumors of the diffuse type (according to the classification of Laurén) most often were reclassified as neuroendocrine carcinomas.. The current study shows that neuroendocrine and particularly ECL cell-derived tumors are more common in the stomach than previously recognized.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Chromogranin A; Chromogranins; Enterochromaffin Cells; Female; Gastrins; Histamine; Humans; Immunohistochemistry; Male; Middle Aged; Neuroendocrine Tumors; Pancreatic Hormones; Prospective Studies; RNA, Messenger; Stomach Neoplasms

The peptide hormone gastrin is a recognised growth factor for gastrointestinal (GI) tumour cells. Carboxyamidated gastrins bind to the cell surface gastrin/cholecystokinin B (CCK-B) receptor which can be expressed as either a normal or a truncated isoform (delta CCK-B).. To compare gastrin gene expression with delta CCK-B and total CCK-B (both isoforms) gene expression in both GI and non-GI tract derived human tumour cell lines.. Total RNA was extracted and gene expression was assayed by the reverse transcription-polymerase chain reaction followed by Southern blotting and hybridisation with specific oligo probes.. Gastrin was expressed by 5/5 gastric and 7/8 colorectal cell lines. Coexpression of gastrin CCK-B isoform was found in 80% of gastric and 75% of colorectal cell lines. Non-GI cell lines, with the exception of a lymphoblastic leukaemia cell line, showed no coexpression. The truncated receptor, delta CCK-B, was shown in 3/5 gastric and 5/8 colorectal cell lines and was always coexpressed with gastrin.. The truncated gastrin receptor, delta CCK-B, is coexpressed with gastrin in 8/13 GI tumour cell lines. Gastrin and CCK-B receptor isoforms may be involved in maintaining autocrine/paracrine growth pathways in GI cancer cells.

Topics: Blotting, Southern; Colorectal Neoplasms; Gastrins; Gastrointestinal Neoplasms; Humans; Isomerism; Polymerase Chain Reaction; Receptor, Cholecystokinin B; Receptors, Cholecystokinin; RNA, Messenger; Stomach Neoplasms; Tumor Cells, Cultured

In gastric adenocarcinoma the gastrin autocrine-paracrine pathway is activated. As enterochromaffin-like (ECL) cells originate from the same stem as epithelial cells, the aim of this study was to determine if the gastrin autocrine pathway is present in gastric carcinoid.. Samples from ten patients with gastric carcinoid were assessed by immunocytochemistry using primary antibodies directed against gastrin precursors and the gastrin/cholecystokinin B receptor and detected using the avidin-biotin immunoperoxidase system.. A high level of expression of precursor and mature gastrin peptides, together with the gastrin receptor, was seen in all carcinoids screened.. In common with the glandular epithelium of the stomach the gastrin gene is activated during the neoplastic process in ECL cells. This finding may explain why some carcinoids do not regress after surgical procedures that lower serum gastrin. Antigastrin agents may be a useful treatment for carcinoid either in their own right or as an adjunct to surgery.

Topics: Adult; Aged; Carcinoid Tumor; Cholecystokinin; Female; Gastric Acid; Gastrins; Humans; Immunohistochemistry; Male; Middle Aged; Stomach Neoplasms

Chromogranin A (CgA) is a multifunctional acidic protein that in the stomach is expressed predominantly in enterochromaffin-like cells (ECL cells) where it is regulated by gastrin. In order to investigate the transcriptional response of the mouse CgA (mCgA) promoter to gastrin stimulation, we studied a 4.8-kilobase mCgA promoter-luciferase reporter gene construct in transiently transfected AGS-B cells. 5'-Deletion analysis and scanning mutagenesis of mCgA 5'-flanking DNA showed that a Sp1/Egr-1 site spanning -88 to -77 base pairs (bp) and a cyclic AMP-responsive element (CRE) at -71 to -64 bp are essential for gastrin-dependent mCgA transactivation. Gastrin stimulation increased cellular Sp1 protein levels and Sp1-binding to the mCgA -88 to -77 bp element, as well as binding of CREB to its consensus motif at -71 to -64 bp. Gastrin also stimulated CREB Ser-133 phosphorylation, and abundance of cellular CREB protein levels. Overexpression of either Sp1 or phosphorylated CREB transactivated the mCgA promoter dose dependently, while coexpression of both transcription factors resulted in an additive mCgA promoter response. mCgA -92 to -64 bp, comprising the Sp1/Egr-1 site and the CRE motif, conferred gastrin responsiveness to a heterologous thymidine kinase promoter system, and therefore functions as a "true" enhancer element. This report demonstrates that Sp1 and CREB mediate CCK-B/gastrin receptor-dependent gene regulation, and that the effect of gastrin on the CgA gene is brought about by cooperative action of both transcription factors.

Topics: Animals; Base Sequence; Chromogranin A; Chromogranins; Cyclic AMP Response Element-Binding Protein; DNA-Binding Proteins; Early Growth Response Protein 1; Gastrins; Gene Expression Regulation, Neoplastic; Genes, Reporter; Humans; Immediate-Early Proteins; Kinetics; Luciferases; Mice; Molecular Sequence Data; Mutagenesis, Site-Directed; Phosphorylation; Promoter Regions, Genetic; Recombinant Fusion Proteins; Sequence Deletion; Sp1 Transcription Factor; Stomach Neoplasms; Thymidine Kinase; Transcription Factors; Transcriptional Activation; Tumor Cells, Cultured

The tumor suppressor p53 functions at the G1/S-phase checkpoint of the cell cycle to direct cells that have accumulated somatic mutations toward apoptosis and away from mitosis. The p53 gene is commonly mutated in human cancers, but the molecular mechanisms regulating this event are not clear. The African rodent mastomys exhibits a genetic predisposition to develop gastric carcinoids derived from enterochromaffin-like (ECL) cells. The ECL cell transformation can be accelerated by acid inhibition-induced hypergastrinemia. This study evaluates the alteration of p53 during the rapid ECL cell transformation. Hypergastrinemia was generated by the irreversible histamine-2 receptor antagonist loxtidine for 8 weeks (hyperplasia) and 16 weeks (neoplasia). p53 expression was evaluated in fundic mucosa from different stages of transformation by Western blot analysis and immunohistochemistry using monoclonal antibodies against wild-type p53. RT-PCR and molecular sequence analysis of p53 were undertaken with mRNA isolated from purified ECL cells. Overproduction of the wild type of p53 was evident in ECL cells during hypergastrinemia, and the molecular characteristics of p53 were determined in naive and transformed ECL cells. p53 was mutated at the C-terminus in ECLoma induced by hypergastrinemia. Therefore, p53 is altered from overproduction to mutation during the development of hypergastrinemia-induced ECLoma and it may therefore play a role in the cell transformation.

Topics: Amino Acid Sequence; Animals; Blotting, Southern; Blotting, Western; Cell Transformation, Neoplastic; DNA Primers; DNA, Neoplasm; Enterochromaffin-like Cells; Gastrins; Gene Expression Regulation, Neoplastic; Genes, p53; Histamine H2 Antagonists; Immunohistochemistry; Molecular Sequence Data; Muridae; Mutation; Random Allocation; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Stomach Neoplasms; Triazoles; Tumor Suppressor Protein p53

Effects of long term administration of Histamine H2-receptor Antagonist (H2-RA) in the treatment of peptic ulcer was studied for the influence to the risk of causing precancerous changes in gastric mucosa. Serum gastrin. ODC activities, polyamine and PCNA labeling index were biochemically and immunohistologically observed. Rat's mucosae with experimentally induced peptic ulcer treated with long term H2-RA, showed no morphological changes but at 30 weeks of H2-RA, had significantly higher value in PCNA labeling index and in polyamine (spermidine) quantity compared to control H2-RA alone and ulcer alone groups. These results suggest that long term administration of H2-RA, even after healing of the ulcer, may cause the gastric mucosa to possess a milieu in favour of precancerous changes, due to the increased proliferative activity of the cells.

Topics: Animals; Gastric Mucosa; Gastrins; Histamine H2 Antagonists; Male; Ornithine Decarboxylase; Peptic Ulcer; Polyamines; Precancerous Conditions; Rats; Rats, Wistar; Stomach Neoplasms; Triazoles

To assess the potential of gastrin receptor antagonists in the treatment of gastrointestinal cancer, the presence of an autocrine loop involving progastrin-derived peptides has been investigated in two colorectal and one gastric carcinoma cell lines. Progastrin, glycine-extended gastrin and amidated gastrin were detected in cell extracts or conditioned media by radio-immunoassay. Low-affinity binding sites for glycine-extended gastrin and amidated gastrin were present, but high-affinity binding sites were not detected with the appropriate iodinated ligands. In addition, neither glycine-extended gastrin nor amidated gastrin in the concentration range 10pmol/L-10nmol/L stimulated cell proliferation. We conclude that it is unlikely that the carcinoma cell lines LIM 1215, LIM 1839 and LIM 1899 use either amidated or glycine-extended gastrins as extracellular autocrine growth factors.

Topics: Cell Line; Colorectal Neoplasms; Gastrins; Growth Substances; Humans; Protein Precursors; Radioimmunoassay; Receptors, Cholecystokinin; Stomach Neoplasms

In order to observe the regulative effects of pentagastrin (PG) and somatostatin (SS) on the growth of two human gastric cancer cell lines (HGC803 and HGC823) in vitro, we observed the effects of PG and SS on proliferation of human gastric cancer cells by means of MTT. The contents such as gastrin, insulin, and glucagon were determined by radioimmunoassay (RIA), and the hexosamine content was determined by Neuhaus' method. The results showed that the growth of the two human gastric cancer cell lines were obviously promoted by PG. On the contrary, the growth and secretion of gastrin and glucagon were inhibited by SS. In addition, the hexosamine content of human gastric cancer cells was significantly increased by PG (7.58 +/- 0.66 versus 4.20 +/- 0.39 pg/cell, (P < 0.05). But the hexosamine content was decreased by SS (2.62 +/- 0.29 versus 4.20 +/- 0.39 pg/cell, P < 0.05). These findings indicate that the growth of gastric cancer cells is regulated by PG and SS, nevertheless a host of problems need to be elucidated.

Topics: Cell Division; Gastrins; Glucagon; Hexosamines; Humans; Pentagastrin; Somatostatin; Stomach Neoplasms; Tumor Cells, Cultured

To improve the clinical diagnosis and treatment of gastrinoma.. Twelve cases of gastrinoma found in the recent 30 years in our hospital were analyzed.. The results indicated that in addition to the typical symptoms related to gastric acid overproduction, the frequency of certain uncommon features characteristic of the disease was unusually high in our hands i.e., (1) The majority of them (7/12) had serious diarrhea, even resulting in shock. (2) Multiple endocrine neoplasia type I (MEN) was in 3 out of 12 associated in our series. (3) Multiple nodules in the duodenum (3/12) were found and in two patients were shown to be submucosal gastrinoma confirmed by pathology. (4) Multifocal lesions were found in 9 out of 12 patients, and in 7 cases at least two organs were involved. Most gastrinomas were located in the pancreas, stomach and duodenum. (5) As reported by other authors, multiple hormone secretion was common: in five of six patients the tumor secreted more than two hormones. (6) In some cases, tumors were sensitive to chemotherapy.. In our series gastrinoma was found with the feature of multiple lesions and multiple hormone secretion in addition to the typical symptoms related to gastric acid overproduction.

Topics: Adolescent; Adult; Diarrhea; Duodenal Neoplasms; Duodenal Ulcer; Female; Gastrinoma; Gastrins; Humans; Insulinoma; Male; Middle Aged; Multiple Endocrine Neoplasia Type 1; Pancreatic Neoplasms; Somatostatin; Stomach Neoplasms

Topics: Abdominal Pain; Adult; Anemia, Pernicious; Carcinoid Tumor; Diagnosis, Differential; Female; Gastrins; Gastritis, Atrophic; Gastroscopy; Humans; Hyperplasia; Precancerous Conditions; Pyloric Antrum; Stomach Neoplasms

It is not known whether plasma chromogranin analysis could be a complement to histology for detection and grading of gastric fundic mucosal endocrine cell proliferation in hypergastrinemic (type-A) atrophic gastritis.. Gastric biopsy sections (body and antrum) from 43 patients with type-A gastritis (9 with gastric carcinoid) were examined for density and micronodules of argyrophil endocrine cells. Fasting blood samples were analyzed for chromogranin A and B, gastrin, and somatostatin.. All patients with carcinoid and 17 of the 34 without carcinoid had micronodules in the gastric fundic mucosa. The median plasma chromogranin A concentration was 5.7 (3.5-40.0) nmol/l in patients with carcinoid, 4.5 (3.0-9.5) nmol/l in patients with micronodules, and 3.7 (0.8-6.0) nmol/l in patients without micronodules. Overall, chromogranin A concentrations correlated to endocrine cell densities in the fundic mucosa (r = 0.64, P < 0.001) and to gastrin concentrations (r = 0.71, P < 0.001). Plasma somatostatin and chromogranin B concentrations did not differ significantly between the groups.. In type-A gastritis, analysis of plasma chromogranin A may be a useful complement to histology in estimating the endocrine cell mass. Moreover, subclinical type-A gastritis may be a source of error when chromogranin A analysis is used in the search for neuroendocrine neoplasia.

Topics: Aged; Anemia, Pernicious; Biopsy; Carcinoid Tumor; Chromogranin A; Chromogranins; Enterochromaffin Cells; Female; Gastric Mucosa; Gastrins; Gastritis, Atrophic; Humans; Hyperplasia; Male; Stomach Neoplasms

This study evaluated the effect of gastric acid secretion and serum gastrin response on tumor differentiation for early gastric cancer according to patients' age. We investigated the association between serum gastrin levels, gastric acid secretion and the histologic types of 335 early gastric carcinomas limited to the mucosal and submucosal layers in comparison with 450 gastric and 197 duodenal ulcers. The preoperatively examined basal acid output, maximal acid output and peak acid output after administration of tetragastrin and serum gastrin levels before and after ingestion of a test meal were determined. Patients with differentiated cancer and duodenal ulcer showed a significant negative correlation between gastric acid secretion and age, while the former group also had a significant positive correlation between serum gastrin levels and age. On the other hand, patients with undifferentiated cancer did not show any such correlation between gastric acid and age, but showed a significant positive correlation between serum gastrin, integrated gastrin response and age. Patients with gastric ulcer did not show any such correlations. These data suggest that both low acid secretion and endogenous hypergastrinemia, especially in the elderly, may play an important role in differentiated and undifferentiated gastric carcinomas.

Topics: Adenocarcinoma; Adult; Age Factors; Aged; Aged, 80 and over; Duodenal Ulcer; Female; Gastric Acid; Gastric Mucosa; Gastrins; Humans; Male; Middle Aged; Stomach Neoplasms; Stomach Ulcer

Gastrin (G-17) stimulates the growth of certain gastric and colon cancers mostly through gastrin/cholecystokinin (CCK)-B receptors. Glycine-extended gastrin (Gly-G) stimulates growth of a rat pancreatic acinar cell line; however, the effect of Gly-G on human gastric cancers is not known. The purpose of this study was to characterize the trophic effect of G-17 and Gly-G on two human gastric cancer cell lines, AGS and SIIA.. Binding analyses were performed, and cell growth was assessed by counting cells over a time course.. G-17 stimulated growth of both AGS and SIIA cells. In AGS cells, gastrin/CCK-B receptor antagonists inhibited the effect of G-17 and competitively antagonized 125I-G-17 binding, whereas the CCK-preferring (CCK-A) receptor antagonists had no effect. In contrast, CCK-A receptor antagonists inhibited the stimulatory effect of G-17 in SIIA cells, whereas CCK-B receptor antagonists had no effect. Gly-G stimulated the growth of AGS and SIIA cells; neither the CCK-B nor the CCK-A receptor antagonists blocked this effect.. G-17 stimulates proliferation of AGS cells through the CCK-B receptor; however, G-17-mediated growth of SIIA acts through a CCK-A-like receptor. Furthermore, Gly-G stimulates growth of human gastric cancer cell lines, possibly through a receptor other than the CCK-B or CCK-A receptor.

Topics: Cell Division; Gastrins; Humans; Protein Precursors; Receptor, Cholecystokinin A; Receptor, Cholecystokinin B; Receptors, Cholecystokinin; Stomach Neoplasms; Tumor Cells, Cultured

We report a case of a gastric carcinoid tumor in an anemic woman with chronic atrophic gastritis and hypergastrinemia. An antrectomy with excision of a carcinoid tumor was performed; afterwards, gastrinemia was normal. Gastric carcinoids were considered uncommon gastric cancers; however, in recent years they have been studied with increasing interest because, as in chronic atrophic gastritis, it has been suggested that they might be produced by prolonged hypergastrinemia associated with therapeutic use of gastric acid supressors. We discuss the gastrin hypothesis, the different clinical types of gastric carcinoids and its therapeutical management.

Topics: Adult; Carcinoid Tumor; Female; Gastrins; Gastritis; Humans; Stomach Neoplasms

Gastrin stimulates transcription of the human histidine decarboxylase (HDC) gene through binding to the G-protein-coupled cholecystokinin-B/gastrin receptor. We have explored the possibility that mitogen-activated protein kinase cascades play a role in mediating the effects of gastrin on transcription in a gastric cancer (AGS-B) cell line. Gastrin and phorbol 12-myristate 13-acetate (PMA) treatment of AGS-B cells was found to increase the phosphorylation of tyrosine residues of extracellular signal-regulated kinases (ERKs) 1 and 2 and increase ERK activity as determined by the in vitro phosphorylation of myelin basic protein. Reporter gene assays also demonstrated that gastrin and PMA stimulated Elk-1- and c-Myc-dependent transactivation, consistent with gastrin- and PMA-induced activation of ERKs. Overexpression of wild type ERK-1 and ERK-2 or activation of endogenous ERKs using activated MEK-1 (mitogen-activated protein kinase kinase or ERK kinase) overexpression stimulated HDC promoter activity in a dose-dependent fashion. Interruption of the ERK-related pathway using expression vectors for kinase-deficient ERKs or an ERK-specific phosphatase (PAC-1) blocked gastrin- and PMA-stimulated HDC promoter activity. In contrast, inhibition of the Jun kinase pathway using an interfering dominant negative SEK-1 (stress-activated protein kinase/ERK-1) mutant did not inhibit HDC promoter activity. Furthermore, whereas gastrin stimulated phosphorylation of Shc proteins and association with Grb2, activation of the HDC promoter was not influenced by expression of dominant negative Ras (N15 or N17) proteins. However, gastrin stimulated Raf-1 kinase activity, and activation of the HDC promoter was blocked by coexpression of a dominant negative Raf-1 construct. Overall, these data demonstrate that gastrin regulates HDC transcription in a Rafdependent, Ras-independent fashion predominantly through activation of the ERK-related pathway.

Topics: Base Sequence; Calcium-Calmodulin-Dependent Protein Kinases; Gastrins; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Genes, Reporter; Histidine Decarboxylase; Humans; JNK Mitogen-Activated Protein Kinases; Luciferases; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinases; Myelin Basic Protein; Phosphorylation; Promoter Regions, Genetic; Recombinant Fusion Proteins; Signal Transduction; Stomach Neoplasms; Tetradecanoylphorbol Acetate; Transfection

Topics: Aged; Contrast Media; Duodenal Neoplasms; Gastrinoma; Gastrins; Humans; Image Processing, Computer-Assisted; Intubation, Gastrointestinal; Male; Pyloric Antrum; Receptors, Somatostatin; Stomach Neoplasms; Tomography, Emission-Computed, Single-Photon; Tomography, X-Ray Computed; Zollinger-Ellison Syndrome

A 48-year-old male with type A atrophic gastritis developed multiple gastric carcinoids and a pituitary adenoma. Laboratory tests revealed high levels of serum gastrin and growth hormone (GH). He underwent subtotal gastrectomy, resulting in a return of the previously elevated gastrin level to normal. Serum GH concentration remained high. Three months after the surgery, the pituitary tumor, composed greatly of GH-immunoreactive cells, was partially removed. Since hypergastrinemia plays a pivotal role in gastric carcinoid formation and induces GH-releasing factor (GHRH) release resulting in GH-producing pituitary tumor formation, GH-producing pituitary adenoma might be a clinical manifestation in type A gastritis.

Topics: Adenoma; Carcinoid Tumor; Follow-Up Studies; Gastrectomy; Gastrins; Gastritis, Atrophic; Gastroscopy; Growth Hormone; Growth Hormone-Releasing Hormone; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Neoplasms, Multiple Primary; Pituitary Neoplasms; Stomach Neoplasms; Tomography, X-Ray Computed

The enterochromaffin-like cell (ECL) cells of the stomach are principally regulated by gastrin via a gastrin/CCK(B) receptor (G[R]) which modulates both histamine secretion and cell proliferation. In the African rodent (mastomys) hypergastrinemia generated by the histamine-2 receptor antagonist (loxtidine) results in ECL cell hyperplasia and neoplasia at 8 and 16 weeks respectively. The expression, structure and function of the G(R) during transformation is however unknown. We utilized a pure (approximately 90%) preparation of ECL cells to evaluate alterations in the G(R) utilizing immunocytochemistry, Western blot analysis, reverse transcription polymerase chain reaction (RT-PCR), 5-bromo-2-deoxyuridine uptake and phosphorylation site analysis. Although the expression of ECL cell G(R) was upregulated at both mRNA (PT-PCR) and protein (Western analysis) level, its affinity to gastrin was decreased in the hyperplastic phase and lost during transformation. The coding sequence of the G(R) of mastomys tumor ECL cells was identical to that of normal ECL cells, parietal cells and the brain. However, the mRNA sequence of the third introcytoplasmic loop of the G(R) was significantly different to other species. In addition, the G(R) exhibited phosphorylation site on serine residue(s). We have thus noted a direct correlation between hypergastrinemia and G(R) alteration and function during ECL cell transformation. It is possible that the unique mastomys gastrin receptor mediated ECL cell transformation involves the novel phosphorylation sites and a divergence in the introcytoplasmic domain.

Topics: Animals; Blotting, Western; Cell Transformation, Neoplastic; Enterochromaffin Cells; Female; Gastrins; Gene Expression Regulation, Neoplastic; Histamine H2 Antagonists; Immunohistochemistry; Male; Muridae; Phosphorylation; Phosphoserine; Phosphotyrosine; Polymerase Chain Reaction; Receptors, Cholecystokinin; RNA, Messenger; Stomach Neoplasms; Triazoles

Helicobacter pylori infection exerts variable effects on gastric acid secretion. It may increase acid secretion, decrease acid secretion or produce no overall change. The effect of the infection on acid secretion depends upon the relative extent to which the Helicobacter pylori gastritis affects the antral and body mucosa of the stomach. When there is antral predominant, body-sparing gastritis, there is increased gastrin release and this is accompanied by increased acid secretion. When there is a significant body gastritis, acid secretion is reduced and subjects may be completely achlorhydric. The majority of subjects have both antral gastritis and body gastritis and this results in no overall change in gastric acid secretion. There is now increasing evidence that the alteration which Helicobacter pylori infection exerts upon gastric acid secretion is a pivotal factor in determining the clinical outcome of the infection. Subjects in whom the infection produces acid hypersecretion develop duodenal ulcer disease due to the increased duodenal acid load. In subjects in whom the infection induces marked hypochlorhydria, there is an increased risk of gastric cancer. The hypochlorhydria probably plays an important role in the carcinogenic process as high intragastric pH markedly raises intragastric nitrite levels, profoundly lowers gastric juice ascorbic acid and allows colonization by nitrosating bacteria. The reason for the different functional responses to Helicobacter pylori infection is unclear but may be related to the host's pre-morbid acid secretory status.

Topics: Duodenal Ulcer; Gastric Acid; Gastrins; Gastritis; Helicobacter Infections; Helicobacter pylori; Humans; Stomach; Stomach Neoplasms

Topics: Adult; Carcinoid Tumor; Gastrins; Humans; Male; Neoplasms, Multiple Primary; Pancreatic Diseases; Stomach Neoplasms

This study aimed to estimate the prevalence and type of chronic gastritis in an asymptomatic working population and to determine whether a combination of serum pepsinogen levels and Helicobacter pylori serology could be used to identify a subgroup with atrophic gastritis at elevated risk of gastric carcinoma. A 10% subsample of 544 male volunteer factory workers aged 18-63 years and participating in a larger study underwent endoscopy and biopsy. Of these men, 29 were seropositive for Helicobacter pylori; all but three (89.7%) had chronic gastritis. Serum pepsinogen A levels increased with progression from a corpus predominant pattern of gastritis through pangastritis to an antral predominant pattern. Nine subjects had corpus atrophy, which was in most cases accompanied by fasting hypochlorhydria and hypergastrinaemia. A combination of pepsinogen A below 80 ng ml-1 and Helicobaceter pylori seropositivity detected corpus atrophy with sensitivity 88.9% and specificity 92.3%. A second screening stage, using a pepsinogen A/C ratio of below 2.5 as a cut-off, resulted in a reduction in numbers requiring further investigation but with some loss of sensitivity (77.8%). Application of this two-stage screening programme to the original sample of 544 workers would have resulted in 11 (2.2%) men being selected for follow-up, excluding 25 (5.1%) false negatives. Our results suggest that a combination of serum pepsinogen levels and Helicobacter pylori serology could be useful as a biomarker strategy for detection of individuals at increased risk of gastric carcinoma and for non-invasive investigation of the natural history of Helicobacter pylori gastritis.

Topics: Adolescent; Adult; Biomarkers; Gastrins; Gastritis, Atrophic; Helicobacter Infections; Helicobacter pylori; Humans; Male; Middle Aged; Occupational Diseases; Pepsinogens; Prevalence; Risk Factors; Stomach Neoplasms

Transcriptional regulation of the human histidine decarboxylase (HDC) gene by gastrin and the phorbol ester phorbol 12-myristate 13-acetate (PMA) was studied using transient transfection of human HDC promoter-luciferase constructs in a human gastric carcinoma cell line (AGS-B) that expresses the human cholecystokinin-B/gastrin receptor. The transcriptional activity of the human HDC promoter was stimulated 3-4-fold by gastrin and 13-fold by PMA, effects that could be blocked by down-regulation or antagonism of protein kinase C. 5'- and 3'-deletion analysis demonstrated that the sequence responsible for gastrin- and PMA-stimulated transactivation (gastrin response element (GAS-RE)) was located in a region (+2 to +24) downstream of the transcriptional start site (+1) in the human HDC promoter and contained a palindrome (5'-CCCTTTAAATAAAGGG-3'). When ligated upstream of the herpes simplex virus 1 thymidine kinase promoter, a single copy of the GAS-RE was sufficient to confer responsiveness to gastrin and PMA. Electrophoretic mobility shift assays with specific competitors and factor-specific antibody supershifts showed that the labeled GAS-RE bound a novel nuclear factor(s). In addition, both gastrin and PMA increased binding of this factor to the GAS-RE. Hence, the palindromic GAS-RE site is sufficient to explain the gastrin/PMA responsiveness of the human HDC promoter and appears to bind a novel transcription factor.

Topics: Base Sequence; Cell Line; Cell Nucleus; Cloning, Molecular; DNA Primers; Female; Gastrins; Gene Expression Regulation, Enzymologic; Genomic Library; HeLa Cells; Histidine Decarboxylase; Humans; Kinetics; Luciferases; Molecular Sequence Data; Placenta; Polymerase Chain Reaction; Pregnancy; Promoter Regions, Genetic; Protein Kinase C; Recombinant Proteins; Regulatory Sequences, Nucleic Acid; Sequence Deletion; Stomach Neoplasms; Tetradecanoylphorbol Acetate; Transcription, Genetic; Transcriptional Activation; Transfection; Tumor Cells, Cultured

The genesis of human gastric carcinoma is ill understood but is invariably related to achlorhydria. Gastrin secretion is negatively regulated by luminal acid and hypergastrinaemia is thus associated with low acid states which may be natural (atrophic gastritis) or owing to acid inhibitory therapy. Apart from its acid secretory activity, gastrin is trophic to the mucosa, via stimulation of the fundic enterochromaffin-like (ECL) cells to secrete histamine. In conditions of elevated gastrin levels, ECL cell hyperplasia and even neoplasia have been noted. The relationship between low acid, hypergastrinaemia, ECL cell hyperplasia, and neoplasia may be of relevance since ECL cells secrete histamine and TGF alpha which are both recognised mitogens. We studied the rodent mastomys, which spontaneously develop gastric carcinoid tumours, which can be generated in 4 months under conditions of drug-induced acid inhibition and inhibited by octreotide administration. A pure (90-95%) cell preparation was used to evaluate ECL cell physiology and trophic regulation. A gastrin/CCKB receptor responsible for histamine secretion and DNA synthesis was identified, cloned and sequenced. Octreotide lowers plasma gastrin levels, decreases ECL cell neoplasia and, in vitro, inhibits ECL cell DNA synthesis. H1 receptor antagonists inhibited DNA synthesis in vitro and ECL neoplasia in vivo without altering gastrin levels. Hypergastrinaemia increased TGF alpha/EGF receptor and TGF alpha production and TGF alpha massively stimulated ECL cell DNA synthesis. Since ECL cells produce both histamine and TGF alpha and regulate parietal cells which produce TGF alpha, it is possible that achlorhydria-generated ECL cell dysfunction may play an initiative role in the pathobiology of gastric adenocarcinoma. The long-term clinical consequences of drug-induced sustained acid inhibition are worthy of further consideration.

Topics: Animals; Base Sequence; Carcinoid Tumor; Cell Transformation, Neoplastic; DNA; DNA, Neoplasm; Enterochromaffin Cells; Gastrins; Histamine Release; Molecular Sequence Data; Polymerase Chain Reaction; Rats; Receptors, Cholecystokinin; Stomach Neoplasms; Transforming Growth Factor alpha; Tumor Cells, Cultured

A total of 14 gastric biopsy specimens from patients with microcarcinoidosis were analysed by immunohistochemical methods to evaluate the pattern of endocrine cell hyperplasia and dysplasia. All the patients had type A gastritis (autoimmune gastritis). Nonantral proliferations of gastric endocrine cells were classified according to Solcia et al. All 14 cases had hyperplasia and 13 (92.9%) of them, dysplasia of gastric endocrine cells; 9 (64.3%) of the 14 were found to have showed a coexisting invasive gastric carcinoid at the time of diagnosis of microcarcinoidosis. The patients with invasive carcinoids had higher degrees and more complex forms of endocrine dysplasia (precarcinoid lesions). The average size of the foci of the microcarcinoidosis in gastric biopsies was 0.14 +/- 0.09 cm in the patients without invasive carcinoid, as against to 0.5 +/- 0.24 cm in the group of patients with associated invasive carcinoid. Microcarcinoid gastric biopsies about 0.5 cm in size, are suggestive of adjacent invasive carcinoid. However, even frankly invasive ECL carcinoids seem to be clinically less dangerous than was thought until recently.

Topics: Adult; Aged; Aged, 80 and over; Biopsy; Carcinoid Tumor; Endocrine Glands; Female; Gastrins; Humans; Hyperplasia; Immunohistochemistry; Male; Middle Aged; Stomach; Stomach Neoplasms

A now 54-year-old woman was 32 years ago found to have immune thrombocytopenia and 3 years ago ANA-positive and HBsAg-negative hepatitis with cirrhotic metaplasia. Numerous small asymptomatic carcinoids with marked hypergastrinaemia (1626 ng/l) were also first found 3 years ago. No gastrinoma could be found. Severe arthralgia was the main symptom on admission.. Gastroscopy revealed a polypoid carcinoid, 1 cm in diameter. There was total achlorhydria. No pernicious anaemia or carcinoid syndrome was found.. Total gastrectomy with construction of a jejunal substitute stomach was performed. Histology showed typical chronic-atrophic gastritis type A, all stages of an argyrophilic endocrine cell hyperplasia, as well as microcarcinoidosis and multicentric carcinoid, in part with submucosal infiltration and lymph node metastases. Immunohistology revealed immune reaction for the global endocrine marker. No specific hormones were demonstrable in the carcinoid cells. The postoperative course was without complications. Serum gastrin levels have since been normal.. The case confirms the possibility of an achlorhydria-hypergastrinaemia-carcinoid sequence. Now new stage-related therapeutic guidelines for this disease are needed.

Topics: Achlorhydria; Autoimmune Diseases; Carcinoid Tumor; Female; Follow-Up Studies; Gastrectomy; Gastrins; Gastritis, Atrophic; Gastroenterostomy; Humans; Jejunum; Lymphatic Metastasis; Middle Aged; Stomach; Stomach Neoplasms; Time Factors

Histamine is an important stimulator of gastric acid secretion. In experimental animals, inhibition of acid secretion by long term histamine2 receptor blockade causes hypergastrinemia, proliferation of enterochromaffin-like (ECL) cells, and formation of histamine-producing gastric carcinoids. The aim of this study was to examine the role of gastrin in histamine synthesis and metabolism of the oxyntic mucosa of normal, hyperplastic, and carcinoid-bearing Mastomys natalensis. Administration of exogenous gastrin to normal animals increased histidine decarboxylase (HDC) messenger RNA (mRNA) expression in the oxyntic mucosa within 30 min, indicating that gastrin stimulates histamine synthesis by regulating HDC mRNA abundance. Endogenous hypergastrinemia, induced by short term histamine2 receptor blockade (loxtidine) for 3-29 days, did not induce tumors, but enhanced the expression of HDC mRNA (2- to 4-fold elevated) and histamine contents (2-fold elevated) in the oxyntic mucosa. Long term histamine2 receptor blockade (7-21 months) resulted in sustained hypergastrinemia and ECL tumor formation. Tumor-bearing animals had a 4-fold increase in HDC mRNA expression and histamine contents of the oxyntic mucosa. Urinary excretion of the histamine metabolite methyl-imidazole-acetic acid was 2-fold elevated. Tumor-bearing animals recovering from histamine2 receptor blockade were normogastrinemic and had normal levels of HDC mRNA and histamine in the oxyntic mucosa as well as normal excretion of methyl-imidazole-acetic acid. The results indicate that ECL cell carcinoids developing during hypergastrinemia are well differentiated tumors that respond to high gastrin levels with increased histamine synthesis and secretion.

Topics: Animals; Carcinoid Tumor; Female; Gastric Mucosa; Gastrins; Histamine H2 Antagonists; Histamine Release; Histidine Decarboxylase; Male; Muridae; Parietal Cells, Gastric; RNA, Messenger; Stomach Neoplasms; Time Factors; Tissue Distribution; Triazoles

The effect of vagotomy on the development of ECL cell tumours was analyzed during drug-induced hypergastrinemia in Mastomys natalensis, a rodent prone to develop ECL cell tumours. Untreated animals were compared with animals receiving the histamine2-receptor blocker loxtidine (LOX) and with animals subjected to unilateral subdiaphragmatic vagotomy prior to loxtidine treatment (VAG+LOX). Loxtidine (2g/l) was administered in drinking water for 48 weeks to allow multiple ECL cell carcinoids to develop. Plasma gastrin levels were increased in LOX animals (94 +/- 31 pmol/l) and in VAG+LOX animals (181 +/- 59 pmol/l) compared to controls (45 +/- 4 pmol/l). Corpus weight and oxyntic mucosal thickness was almost doubled in all loxtidine-treated animals and the density of mucosal endocrine cells was increased by 65% in the LOX group and by 135% in VAG+LOX animals. No significant differences in mucosal thickness and endocrine cell density were seen when denervated and intact parts of the stomach were compared. In the VAG+LOX animals endocrine cell neoplasia was seen in 60% and dysplasia in 40% of animals compared to 40% neoplasia, 45% dysplasia and 15% hyperplasia in LOX animals. The frequency of neoplastic and dysplastic lesions did not differ between denervated and intact parts of the stomach. Untreated animals showed no neoplastic or dysplastic lesions. It is concluded that unilateral vagotomy has no protective effect on the development of ECL-cell tumours in Mastomys during hypergastrinemia, as opposed to previous studies in the rat.

Topics: Animals; Cell Count; Cell Division; Chromogranins; Enterochromaffin Cells; Female; Gastric Acid; Gastric Mucosa; Gastrins; Immunohistochemistry; Male; Muridae; Organ Size; Parietal Cells, Gastric; Stomach Neoplasms; Vagotomy

The brain-gut hormones, cholecystokinin (CCK) and gastrin, regulate the growth of gastrointestinal mucosa and tumor cells. In this study, reverse transcription-polymerase chain reaction (RT-PCR) was used to evaluate messenger RNA expression for CCK, gastrin, CCK-A receptor, and CCK-B/gastrin receptor in surgical specimens of gastric cancers and in normal antrum and body mucosa of the stomach. The CCK mRNA expression was detectable in 4/14 (29%) samples of gastric cancer and in 3/12 (25%) samples of antral mucosa. However, the gastrin mRNA expression was not detectable in any gastric cancer samples, although it was detectable in all the samples of antral mucosa. The CCK-A receptor mRNA expression was detectable in 5/14 (36%) samples of gastric cancer and in 7/12 (58%) body mucosa. Three cases out of 14 (21%) of gastric cancer expressed both CCK gene and CCK-A receptor gene. The CCK-B receptor mRNA expression was detectable in only 1/14 (7%) samples of gastric cancer, although it was detectable in 10/12 (83%) body mucosa of the stomach. These findings may suggest a greater role for CCK and CCK-A receptor than for gastrin and CCK-B receptor in gastric cancers.

Topics: Cholecystokinin; Gastrins; Gene Expression; Humans; Polymerase Chain Reaction; Radioimmunoassay; Receptors, Cholecystokinin; RNA, Messenger; Stomach Neoplasms

A patient with long-standing Zollinger-Ellison syndrome, treated for 14 years with antisecretory agents, underwent computed tomography and upper gastrointestinal examination because of upper gastrointestinal bleeding. Radiologic and pathologic examinations showed multiple nodular masses arising from the wall of the stomach that were determined to be mucosal carcinoid tumors. A gastrin-producing islet cell tumor of the pancreatic head was also present. Gastric carcinoid tumors occurred as a consequence of chronic hypergastrinemia.

Topics: Carcinoid Tumor; Gastrins; Humans; Male; Middle Aged; Stomach Neoplasms; Tomography, X-Ray Computed; Zollinger-Ellison Syndrome

Gastric carcinoids evolved from enterochromaffin-like (ECL) cell hyperplasia are usually associated with high pH and hypergastrinemia. The Mastomys species exhibits a genetic propensity to gastric carcinoid formation that can be accelerated by acid inhibition-induced hypergastrinemia. Although gastrin is critical in the initiation of the ECL cell transformation, the role of other growth factors involved in the evolution of the tumor autonomy has not been established. The aim of this study was to evaluate the role of transforming growth factor (TGF) alpha in the regulation of ECL cell transformation.. Mastomys were orally administered an irreversible H2-receptor antagonist loxtidine for 0, 8, and 16 weeks, and ECL cell transformation was monitored by assessing gastrin levels, mucosal histamine content, and chromogranin immunoreactivity. The ECL cells were purified, and cell proliferation at each stage in response to gastrin and TGF alpha was measured by bromodeoxyuridine uptake. TGF-alpha expression was evaluated by radioimmunoassay and Northern blot, and epidermal growth factor (EGF) receptor expression was determined by Western blot, immunoprecipitation, and immunocytochemistry.. Although the response to gastrin decreased during hypergastrinemia, the proliferative effect of TGF-alpha on ECL cells was specifically amplified during the development of hyperplasia. TGF-alpha and EGF receptor expression increased steadily in the transformed cells.. During low acid-induced hypergastrinemia, the expression of TGF-alpha and EGF receptor may constitute an autocrine regulatory mechanism in ECL cell tumor transformation.

Topics: Animals; Carcinoid Tumor; Cell Division; Cell Transformation, Neoplastic; Cells, Cultured; Enterochromaffin Cells; Epidermal Growth Factor; ErbB Receptors; Gastrins; Histamine; Muridae; Stomach Neoplasms; Transforming Growth Factor alpha

The present work analyzes the serie levels of pepsinogen I (PG I) and gastrin in relation to the histopathological findings with the optical microscope (OM) and electron microscope (EM) of different gastric mucosa biopsies obtained through fibrogastroscopy. 45 patients were studied (19 men and 26 women) with an average age of 63 with different clinical diagnoses documented later by fibrogastroscopy (peptic ulcer, neoplasia etc.), whose previous consent, two biopsies were taken at an antrum level and two biopsies at a fundic-body area level, analyzed later by OM and EM. The anatomopathological criteria followed in order to classify the condition of the mucosa was Whitehead's classification. The PG I and gastrin determination was carried out with RIA against a control group of 25 healthy individuals. Our study allows us to conclude that the normal or high serie concentration of PG I reflects a functional integrity of the fundic-body area, and low levels imply the presence of atrophic chronic gastritis at a fundic-body level. Thus a low level of PG I is a reliable marker of the atrophic condition of the mucosa and it can be considered as a precancerous factor.

Topics: Adult; Aged; Biomarkers; Biopsy; Chronic Disease; Female; Gastrins; Gastritis; Humans; Male; Middle Aged; Pepsinogens; Stomach Neoplasms

Long term administration of butachlor to Sprague-Dawley rats in a previous bioassay, resulted in the induction of gastric neoplasms which occurred only in the highest dose group (3000 ppm in the diet), primarily in females and specifically in the fundic region. The tumors were a composite of highly undifferentiated enterochromaffin-like (ECL) cells and mucus producing cells with morphologic characteristics unlike those previously described in the rat stomach. Mucosal atrophy of marked intensity was a consistent feature of the gastric mucosa in animals from the highest dose group. An additional long term study was conducted in female Sprague-Dawley rats at dietary levels of 0, 100, 1000 and 3000 ppm to explore the mechanism(s) involved in the formation of these neoplasms. Cell proliferation was evaluated in both fundic and pyloric regions of the stomachs of rats at multiple time periods from 14 days to 26 months. Mucosal thickness was determined in the fundic region at the same time intervals as were used for cell proliferation studies. Gastric pH and gastric acid production were measured after approximately 21 months of exposure. Serum gastrin levels were analyzed at 14, 60, and 120 days and at 6, 18 and 20 months. Cholecystokinin (CCK)/gastrin receptor binding studies were conducted on samples of four tumors and pooled fundic mucosa from five animals in the control group. Cell proliferation was increased in both the neck and base regions of the fundic mucosa at nearly all time points measured from 14 days to 26 months. The magnitude of the changes in the base region were substantially greater than those in the neck region. Fundic mucosal thickness was decreased beginning at the 30-day time point and continued at all intervals, being less than one half that of controls at 20 and 26 months. Gastric pH in rats from the highest dose was elevated to nearly twice control levels at 21 months. Gastric acid secretion was dramatically decreased in animals from the 3000 ppm group and was moderately decreased in the 1000 ppm group at 21 months. Hypergastrinemia was observed at the 3000 ppm level only, beginning at 120 days with progression to extremely high levels by 18 months. CCK/gastrin receptor binding was demonstrated in all tumors studied, at levels comparable to or higher than that of the pooled control sample. All changes involved only the fundic region, the site of tumor formation. Tumors occurred only in animals from the 3000 ppm level, the only level at w

Topics: Acetanilides; Animal Feed; Animals; Carcinogens; Cell Division; Female; Gastric Acid; Gastric Mucosa; Gastrins; Male; Rats; Rats, Sprague-Dawley; Receptors, Cholecystokinin; Stomach Neoplasms

Studies of transgenic mice have shown that transcriptional control of the gastrin gene exhibits significant species differences. Transfection of the human gastrin promoter in murine cells have depicted proximal Sp1, E-box and CACC elements as the major determinants of transcription. We have examined cis-regulatory elements of the human promoter on a human gastrin expressing cell line and find that a distal -135 to -142 Sp1 element is necessary for maximal activity. Alignment of the mouse and human promoters shows that the proximal human Sp1 and CACC elements are not conserved, whereas the E-box element is retained. The distal Sp1 element is present in mouse but exhibits a C to T transition in the core that is likely to reduce binding affinity of Sp1. We conclude that gastrin gene transcription is regulated by distinct elements in man and rodents.

Topics: Adenocarcinoma; Animals; Base Sequence; Cloning, Molecular; DNA; Gastrins; Humans; Mice; Molecular Sequence Data; Promoter Regions, Genetic; Sequence Alignment; Sequence Analysis, DNA; Sequence Deletion; Sp1 Transcription Factor; Stomach Neoplasms; Transcription, Genetic; Tumor Cells, Cultured

The introduction of sensitive radioimmunoassays for gastrin has led to the earlier and more accurate diagnosis of gastrinomas and, as methods for tumour localization both pre- and intraoperatively have improved, the emphasis of surgery has changed from control of gastric acid secretion to tumour removal. We present three cases of sporadic gastrinoma who underwent exploratory laparotomy. In two cases, gastrinomas were discovered and excised resulting in cure for one patient. The third case underwent a negative laparotomy. The changes in serum gastrin levels taken during and immediately after surgery were related to the success or otherwise of tumour removal in each of the three cases. As in parathyroid surgery, with the development of rapid radioimmunoassays, the intraoperative measurement of declining serum gastrin levels will help in the early definition of surgical success supplementing frozen section and clinical judgement and improving patient management.

Topics: Adult; Duodenal Neoplasms; Female; Gastrins; Humans; Intraoperative Care; Laparotomy; Middle Aged; Preoperative Care; Radioimmunoassay; Stomach Neoplasms; Zollinger-Ellison Syndrome

Although an association is suggested between gastric cancer and prior infection with Helicobacter pylori (HP), the role of HP in gastric carcinogenesis remains obscure. HP has potent urease activity and produces ammonia, a factor causing HP-related gastroduodenal mucosal lesions. In this study, rats were examined in an effort to determine effects of ammonia on gastric carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). After pretreatment with MNNG (83 mg/l) for 24 weeks, a solution of either 0.01% ammonia or plain tap water was administered to the animals as drinking water for an additional 24 weeks. The administration of the 0.01% ammonia solution significantly increased the incidence and number of cancers in the glandular stomach. The numbers of cases in which these cancers penetrated the muscle layer or deeper and of low-grade differentiated adenocarcinomas were significantly higher in rats receiving the ammonia solution. Continuing administration of ammonia accelerated cell proliferation in the gastric mucosa, but had no effect on the serum gastrin level. Therefore, gastric ammonia, which stimulates mucosal cell proliferation, appears to be an important promoter in carcinogenesis in rats and possibly in the HP-related gastric carcinogenesis in humans.

Topics: Ammonia; Animals; Carcinogens; Cell Division; Gastric Mucosa; Gastrins; Male; Methylnitronitrosoguanidine; Rats; Rats, Sprague-Dawley; Stomach Neoplasms

A 41-year-old woman with a chronic atrophic gastritis after endoscopic investigation diagnosed a carcinoid at the corpus of the stomach. There were more lesions in the mucosa of the stomach in the form of dysplasias. The labor investigation indicated an hypergastrinaemia. We performed a resection of the basis of the carcinoid. It has shown to be histologically tumor-free as the rest of the stomach. A gastrectomy was not necessary. After resection the patient was under therapy with vitamin B-12. The level of gastrin in blood was normal under this treatment. Two years later the patient remained symptom-free. Regular endoscopic investigations show a stagnation of the growth of the dysplastic lesions of the mucosa of the stomach.

Topics: Adult; Biomarkers, Tumor; Carcinoid Tumor; Chromogranins; Diagnosis, Differential; Female; Gastric Mucosa; Gastrins; Gastritis, Atrophic; Gastroscopy; Humans; Stomach Neoplasms; Synaptophysin

A rapid induction of enterochromaffinlike (ECL) cell tumours has been shown in Praomys (Mastomys) natalensis subjected to histamine2-receptor blockade. In the present study the reversibility of ECL cell proliferation induced by acid inhibition was investigated. Short-term treatment (8 weeks) with the histamine2-receptor antagonist loxtidine caused a moderate hypergastrinemia, accompanied by a minor increase in histamine contents and a 2-fold increased volume density of the endocrine cells in gastric oxyntic mucosa. Eight weeks after withdrawal of treatment the volume density of endocrine cells was normalised as were the tissue levels of histamine, indicating a total reversibility of ECL cell hyperplasia. Long-term treatment (24 weeks) caused severe changes in the endocrine cell population of the oxyntic mucosa with neoplasia (5/21), dysplasia (11/21) and nodular hyperplasia (5/21). The endocrine cell density increased twofold and tissue histamine levels fourfold. 24 weeks after cessation of treatment, the endocrine cell density had decreased to 136% of controls, while histamine concentrations were normalised. The frequency of invasive carcinoids after recovery (4/23) differed only slightly from that seen after treatment for 24 weeks (5/21). Dysplastic lesions were only seen in 1/23 and hyperplastic lesions were of less severe type after recovery. The results demonstrate that ECL cell hyperplasia and dysplasia, induced by acid inhibition, are reversible after cessation of treatment. However, ECL cell tumours did not disappear, within the given observation period. One may therefore speculate that ECL cell proliferation is no longer reversible once the neoplastic (transformed) phenotype has developed.

Topics: Animals; Carcinoid Tumor; Cell Count; Cell Division; Cell Transformation, Neoplastic; Enterochromaffin Cells; Female; Gastrins; Histamine; Histamine H2 Antagonists; Hyperplasia; Male; Muridae; Parietal Cells, Gastric; Stomach Neoplasms; Triazoles

This study was carried out to develop a scoring system for the diagnosis of gastric adenocarcinoma (GAC). A total of 686 subjects, 150 patients with GAC, 182 with gastric ulcer, 127 with duodenal ulcer, and 227 subjects with negative findings, were enrolled. Analysis of the likelihood ratio (LR) showed that patients with advanced age, ulcer in the stomach, low serum levels of pepsinogen I (PGI), low PGI x gastrin values, and low PGI/gastrin ratio were likely to have GAC. Of these indicators, the serum PGI level had the greatest weight, with a LR of 7.59 for the group with a level < 30 ng/ml. A scoring system combining serum PGI level, Helicobacter pylori seropositivity, and gastric ulcer status was derived, using a logistic regression model. This scoring system was found to be better than any one-parameter criterion for diagnosing GAC after evaluation by the area under the receiver operating characteristic curve (0.84; 95% confidence interval, 0.81-0.88) or by specificity-fixed sensitivity (sensitivity 0.82 at specificity 0.72, sensitivity 0.87 at specificity 0.66, sensitivity 0.96 at specificity 0.44). This scoring system may be potentially useful as a new model for the noninvasive diagnosis of GAC in the future.

Topics: Adenocarcinoma; Adolescent; Adult; Aged; Aged, 80 and over; Female; Gastrins; Helicobacter Infections; Helicobacter pylori; Humans; Male; Middle Aged; Pepsinogens; Radioimmunoassay; Retrospective Studies; Sensitivity and Specificity; Serologic Tests; Stomach Neoplasms

To document our experience with gastric carcinoids over the past decade and to identify lesion frequency and the existence of a relationship to low acid states.. Retrospective case series.. Tertiary care referral center.. A consecutive sample of 16 patients with gastric carcinoids was evaluated over the last decade. Only two cases were recorded in the prior decade. Ages ranged from 30 to 93 years (mean, 65.9 years). There were eight men and eight women. Three patients were unavailable for follow-up.. Therapy included total gastrectomy (n = 4), subtotal gastrectomy (n = 3), endoscopic polypectomy (n = 3), and endoscopic surveillance (n = 6).. Pathobiological tumor characteristics and survival.. All carcinoids were of gastric fundic origin. None of the patients exhibited the carcinoid syndrome. Chronic atrophic gastritis was the most frequently observed comorbid pathologic condition (63%). Half of the patients had multiple polypi. Mean follow-up was 4.7 years (n = 13). There were 10 survivors. The only related death occurred in a patient with a solitary tumor.. Diagnosis of the complex and ill-defined entity of gastric carcinoid is increasing. This may be due to an increased awareness and increased upper gastrointestinal endoscopy rate rather than an increase in real incidence. Criteria for prediction of malignant progression are not available. Multiple gastric carcinoids associated with hypergastrinemia predominantly display nonaggressive behavior. Conservative gastric surgery may be appropriate therapy for such patients.

Topics: Adult; Aged; Aged, 80 and over; Carcinoid Tumor; Comorbidity; Connecticut; Female; Follow-Up Studies; Gastrectomy; Gastric Acid; Gastric Fundus; Gastrins; Gastritis, Atrophic; Gastroscopy; Humans; Incidence; Male; Middle Aged; Polyps; Retrospective Studies; Stomach Neoplasms; Survival Rate

Gastric mucosal blood flow, secretion of mucin, and renewal of the gastric mucosal cells are considered to be defensive factors against gastric mucosal injuries. These factors are regulated by the nervous system and neuropeptides. Gastrectomy may affect this regulation and induce gastric mucosal changes, such as atrophic gastritis and carcinoma. The effects of denervation of the gastric mucosa on tumorigenesis of the remnant stomach were investigated.. Using male Wistar rats, four groups of Billroth I (B-I)gastrectomy, Billroth II (B-II) gastrectomy, and those with denervation were conducted. Subdiaphragmatic truncal vagotomy was performed in the denervated group. Thirty weeks after the operations, histologic examination and periodic acid-Schiff--Alcian blue (PAS-AB) staining of the gastric mucosa, analysis of cell kinetics of the gastric mucosa by immunohistochemistry of proliferating cell nuclear antigen, and measurement of intragastric pH, intragastric bile acid concentration, and serum gastrin levels were performed. No carcinogenic agents were given.. The B-I group showed no remarkable gastric mucosal changes, but B-I with denervation showed a significant increase in the development of tumor (67%) and carcinoma (42%). In the B-II groups, the denervation induced a significant increase in tumorigenesis, from 22% to 58%. Analysis of cell kinetics revealed a significant increase of labeling index in those groups that developed tumors. PAS-AB staining showed a decrease of PAS positive mucin but an increase of acidic mucin-producing cells in the denervated groups, suggesting an increase in the number of immature cells that are more susceptible to atrophic gastritis and carcinoma. There was no close relationship between tumorigenesis and intragastric pH, intragastric bile acid concentration, or serum gastrin levels.. After gastrectomy, not only duodenogastric reflux, but also the denervation of the gastric mucosa play an important role in the etiology of gastric remnant cancer.

Topics: Animals; Bile Acids and Salts; Cell Division; Denervation; Gastrectomy; Gastric Mucosa; Gastric Stump; Gastrins; Hydrogen-Ion Concentration; Male; Nuclear Proteins; Rats; Rats, Wistar; Stomach Neoplasms

A 48-year-old woman with type II diabetes developed fatigue, arthralgia and myalgia. A few weeks later she was found to have hepatomegaly. The erythrocyte sedimentation rate was raised (53/93 mm), as were liver enzyme activities (GOT 186 U/l; GPT 240 U/l; gamma-GT 199 U/l), the gamma-globulin levels (40.7%;IgG 4470 mg/dl, IgA 698 mg/dl, IgM 245 mg/dl), antinuclear antibodies and antibodies against double-strand DNA, smooth muscles and actin. Laparoscopy revealed small-nodular liver cirrhosis. The autoimmune hepatitis was treated with prednisolone (initially 60 mg daily, then reduced to 10 mg daily) and azathioprine (initially 100 mg daily, reduced to 50 mg daily). The symptoms markedly improved. But one year later, during follow-up examination, gastric polyps were found, excised and histologically found to be carcinoid. The gastrin level was raised to 765 pg/ml. Another year later the liver cirrhosis had advanced further and the type A gastritis was still present, but there was no sign of carcinoid recurrence.

Topics: Autoimmune Diseases; Azathioprine; Carcinoid Tumor; Cholangiopancreatography, Endoscopic Retrograde; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Endoscopy, Digestive System; Female; Follow-Up Studies; Gastrins; Gastritis; Hepatitis; Humans; Liver Cirrhosis; Middle Aged; Prednisolone; Stomach Neoplasms

Topics: Animals; Carcinogenicity Tests; Carcinogens; Carcinoid Tumor; Gastric Mucosa; Gastrins; Liver; Liver Neoplasms, Experimental; Mice; Rats; Risk Assessment; Stomach; Stomach Neoplasms

Double immunofluorescence and in situ hybridizations performed on adjacent thin sections show that a population of normal antropyloric cells of the human stomach expresses both gastrin and somatostatin mRNA's and the corresponding peptides. Such cells were present in both adult and fetal antropyloric mucosa and were situated in the regenerative (isthmus) region of the antropyloric tubes. It is, hence, likely that these cells represent immature endocrine cells that yet have to be committed to either the gastrin or somatostatin lineage. Cells coexpressing gastrin and somatostatin were also detected in pancreatic endocrine tumours. The presence of gastrin-somatostatin cells during development and in tumours suggests that gastrin and somatostatin cells may differentiate from such multipotent precursor cells.

Topics: Adult; Cell Differentiation; Cells, Cultured; Fluorescent Antibody Technique, Direct; Gastric Mucosa; Gastrins; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; In Situ Hybridization; Pancreatic Neoplasms; Somatostatin; Stomach Neoplasms; Tumor Cells, Cultured

To determine the relationship between gastric secretion and gastric carcinoma, we investigated gastric acid secretion and the fasting serum levels of pepsinogen I and gastrin in 50 Japanese patients with early gastric carcinoma. After the histological and macroscopic type of carcinoma had been determined, results were compared with findings in 50 Japanese control subjects whose gastric mucosa was endoscopically normal. The maximum gastric acid secretion and fasting levels of serum pepsinogen I were significantly lower in intestinal type gastric carcinoma than in diffuse type carcinoma and in the controls. They were also significantly lower in the non-ulcerative (elevated or flat) type than in the ulcerative (depressed) type of carcinoma. The serum gastrin levels in patients with early gastric carcinoma of either the intestinal or diffuse type were higher than those in the control subjects, though the difference was not significant. Gastric acid secretion and serum pepsinogen I levels were related with both the histological and macroscopic types of gastric carcinoma. These findings suggest that the serum pepsinogen I level might be useful as a maker for early gastric carcinoma of the intestinal type.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers; Female; Gastric Acid; Gastrins; Humans; Male; Middle Aged; Pepsinogens; Stomach Neoplasms

To evaluate the possible relationship between Helicobacter pylori infection and gastric carcinoma, and its precursor lesion, intestinal metaplasia, in a Japanese population.. H. pylori infection was identified by the presence of anti-H. pylori immunoglobulin (Ig)G. The frequency of H. pylori infection was compared in 109 patients with gastric carcinoma, the same number of patients with atrophic gastritis and asymptomatic controls matched for age, sex and place of birth. To study the relation between H. pylori and intestinal metaplasia, sera and gastric antral and corpus mucosal biopsies were obtained from 58 asymptomatic controls, 92 patients with chronic gastritis and 80 patients with peptic ulcer.. The presence of IgG antibody to H. pylori was significantly more frequent in those with gastric carcinoma than in asymptomatic controls (87.2 versus 74.3%; odds ratio 2.4; 95% confidence interval 1.2-4.8). The positive rates of H. pylori IgG antibody were 80.7% in patients with atrophic gastritis. Mean serum gastrin and pepsinogen II levels in H. pylori-positive patients were higher than those in H. pylori-negative patients. Serum gastrin and pepsinogen I levels were significantly higher in controls than gastric carcinoma patients (P < 0.01 and P < 0.05, respectively). Serum pepsinogen I:II ratios were significantly lower in controls than in gastric carcinoma patients (P < 0.01). Intestinal metaplasia was strongly associated with H. pylori infection, and was only found in patients with IgG antibodies to H. pylori.. These results suggest that H. pylori infection is associated with the development of gastric cancer by providing a suitable environment for carcinogenesis of the gastric mucosa, such as gastric atrophy and intestinal metaplasia.

Topics: Enzyme-Linked Immunosorbent Assay; Female; Gastrins; Gastritis, Atrophic; Helicobacter Infections; Helicobacter pylori; Humans; Immunoglobulin G; Intestines; Japan; Male; Metaplasia; Pepsinogens; Stomach Neoplasms

To determine serum concentration of gastrin and pepsinogens (PGs) as markers for the gastric mucosal status and to elucidate the prevalence of serum Helicobacter pylori (H pylori) IgG antibodies and parietal cell autoantibodies (PCAs) in patients with gastric polyps.. The subjects in this study were composed of 36 patients with fundic glandular polyps (FGP), 25 patients with foveolar hyperplastic polyps (FHP), and 27 asymptomatic healthy volunteers (controls). Serum concentrations of gastrin and PGs were determined by radioinmmunoassay. H. pylori IgG antibodies were measured through an enzyme-linked immunosorbent assay. PCAs were detected by an indirect immunofluorescence technique using cryostat sections of rat gastric mucosa.. There were no significant differences between FGP patients and controls in serum concentrations of gastrin, PG I and PG II. FHP patients showed significantly higher serum gastrin, lower PG I, higher PG II levels and, as a consequence, far lower PG I/PG II ratio compared with controls. The prevalence of H pylori infection was much higher in FHP patients (84.0%), whereas lower in FGP patients (19.44%) than that in controls (40.7%) was positive in 24.0% of FHP patients, 2.78% of FGP patients and 4% of controls.. These results suggest that FHP often develops in a gastric mucosa associated with H pylori infection, while FGP does not appear to be related to H pylori infection.

Topics: Antibodies, Bacterial; Autoantibodies; Biomarkers; Female; Gastrins; Helicobacter Infections; Helicobacter pylori; Humans; Immunoglobulin G; Male; Middle Aged; Parietal Cells, Gastric; Pepsinogens; Polyps; Stomach Neoplasms

The occurrence of H. pylori infection and the levels of fasting serum gastrin (SEGA) were examined in 97 patients with different morphological types of endoscopically diagnosed gastric polyps. According to the histology of the polyps the series was divided into three groups: inflammatory polyps (43 cases), polyps with foveolar hyperplasia (25 cases), and hyperplastic polyps including adenomas (29 cases). The prevalence of H. pylori infection was significantly lower in patients with hyperplastic polyps (45%) and foveolar hyperplasia (48%) than in the group with inflammatory polyps (81%). SEGA levels were higher in patients with hyperplastic polyps (mean +/- sd: 335 +/- 298 pmol/l) and foveolar hyperplasia (183 +/- 216) than in patients with inflammatory polyps (89 +/- 127). Signs of so-called "autoimmune" gastric, i.e. corpus atrophy and presence of parietal cell antibodies, were commonly found in patients with hyperplastic polyps and foveolar hyperplasia, but rarely in patients with inflammatory polyps. These results suggest that the polyps with hyperplastic changes (hyperplastic polyps and foveolar hyperplasia) are in some of the cases closely related to autoimmune gastritis. The presence of corpus atrophy, hypoacidity and various types of metaplasia, which characterizes autoimmune gastritis, could explain the low prevalence of H. pylori and the high SEGA levels found in these patients.

Topics: Adenoma; Aged; Female; Gastrins; Gastroscopy; Helicobacter Infections; Helicobacter pylori; Humans; Hyperplasia; Male; Middle Aged; Polyps; Stomach Neoplasms

Previously, we have shown that a significant proportion of human gastric carcinomas of the diffuse type may be neuroendocrine tumors derived from the enterochromaffinlike (ECL) cell. The growth of the ECL cell is specifically regulated by gastrin, suggesting an important role of gastrin in human gastric carcinogenesis. However, patients with antral-resected stomachs have reduced plasma gastrin and despite that an increased risk of gastric cancer. Recently, it has been shown that gastrin has a negative trophic effect on the oxyntic D-cell of the rat. The present study evaluates whether gastric stump carcinomas are D-cell derived. Twenty gastric stump carcinomas that had developed from 20 to 53 years after antral resection were examined for neuroendocrine differentiation by neuron-specific enolase immunohistochemistry and for D-cell origin by somatostatin immunohistochemistry. Half the tumors were classified as gastric carcinomas of the intestinal type, while the other half initially was classified as gastric carcinomas of the diffuse type. One of these latter tumors could, however, be reclassified as carcinoid tumor by appearance in hematoxylin erythrosin saffron-stained sections as well as by neuron-specific enolase positivity. Interestingly, this tumor was also positive for somatostatin, suggesting D-cell origin. Three other tumors were positive for neuron-specific enolase, but they were negative for somatostatin. Nevertheless, this study suggests that some gastric stump carcinomas may be malignant neuroendocrine tumors derived from neuroendocrine cells and possibly from D-cells. Furthermore, this study may indicate an important role for hormones and neuroendocrine cells in human gastric carcinogenesis.

Topics: Aged; Aged, 80 and over; Enterochromaffin Cells; Female; Gastric Mucosa; Gastric Stump; Gastrins; Humans; Immunohistochemistry; Male; Middle Aged; Phosphopyruvate Hydratase; Somatostatin; Stomach Neoplasms

Gastric cancer remains a major cause of mortality and will remain so for the lifetime of current clinicians. Many cancers are diagnosed at a stage when current therapy cannot provide the hope of cure. A method for early detection of gastric cancer which can be widely applied is needed. The serum levels of pepsinogen A and gastrin-17 have been shown to vary in the presence of pathologic conditions of the gastric mucosa and may provide such a tool.. Serum samples were obtained from 432 patients undergoing endoscopy for undiagnosed dyspepsia. The levels of pepsinogen I and gastrin-17 were estimated by radioimmunoassay and compared with the final diagnosis. Discriminant analysis was performed to assess the value of the peptides predicting the presence of gastric cancer and the high-risk mucosal changes.. Abnormal levels of gastrin-17 or pepsinogen A were found in 60% of patients with gastric cancer and 60% of those with one of the high-risk mucosal changes, the latter figure rising to 75% when the changes were in the upper third of the stomach. Discriminant analysis showed the log of gastrin-17 and log of pepsinogen A to be the best predictors of the high-risk mucosal changes, gastric cancer, and benign disease.. These results confirm gastrin-17 and pepsinogen A as markers of pathologic gastric conditions and suggest that these peptides are potential screening tools worthy of further assessment.

Topics: Adult; Biomarkers; Dyspepsia; Gastric Mucosa; Gastrins; Gastroscopy; Humans; Mass Screening; Pepsinogens; Radioimmunoassay; Sensitivity and Specificity; Stomach Neoplasms

Topics: Animals; Blotting, Northern; Carcinogens; Carcinoid Tumor; Chromaffin System; Gastric Mucosa; Gastrins; Histamine H2 Antagonists; Muridae; Receptors, Cholecystokinin; Reference Values; Stomach; Stomach Neoplasms; Triazoles

Topics: Carcinoid Tumor; Esophagitis, Peptic; Gastrins; Humans; Omeprazole; Stomach Neoplasms

Profound and sustained inhibition of gastric acid secretion has been associated with development of carcinoid tumors of the fundic enterochromaffin-like (ECL) cells in rodents. While ECL cell hyperplasia has been recognized in humans, the development of carcinoid tumors is rare and often confined to patients under treatment for gastrinoma related to the multiple endocrine neoplasia type I (MEN1) syndrome. The Mastomys was utilized as a model for the rapid induction of ECLomas by insurmountable acid secretory blockade induced by the pharmacologically irreversible H2-receptor antagonist, loxtidine. Loxtidine-induced ECL cell hyperplasia and neoplasia were compared in the absence of presence of cyproheptadine (0.5 mg/kg), an H1-receptor antagonist. Loxtidine administration resulted in a significant increase in ECL cell hyperplasia and neoplasia as well as an increase in ECL cell number, mucosal thickness, plasma gastrin levels, and stomach weight. Cyproheptadine ameliorated loxtidine-induced ECL cell hyperplasia and neoplasia and significantly decreased loxtidine-stimulated increases in ECL cell number. Nevertheless, cyproheptadine failed to alter the loxtidine-induced increase in plasma gastrin, stomach weight or mucosal height. The results indicate that cyproheptadine, an H1-receptor antagonist, inhibits loxtidine-induced ECL cell hyperplasia independent of any effects on serum gastrin.

Topics: Animals; Carcinoid Tumor; Cell Count; Cyproheptadine; Enterochromaffin Cells; Gastric Acid; Gastric Fundus; Gastrins; Growth Substances; Histamine; Muridae; Stomach Neoplasms

Topics: Aged; Anemia, Pernicious; Carcinoid Tumor; Female; Gastrectomy; Gastrins; Gastroscopy; Humans; Stomach Neoplasms

Although widely reported on, the clinical diversity and eventual varied outcome of patients with extrapancreatic gastrinomas remain a medical mystery. In an attempt to help clarify conflicting management of extrapancreatic gastrinomas, we reviewed our experience with these unique tumors.. Retrospective analysis with long-term follow-up (mean, 8 years).. Tertiary care referral center.. From January 1958 through January 1993, we identified and operated on 23 patients with extrapancreatic gastrinomas (duodenum, n = 18; stomach, n = 3; nodal, n = 2). The 12 men and 11 women (none with multiple endocrine neoplasia type I syndrome) ranged in age from 12 to 68 years (mean, 47 years). Preoperatively, all patients were symptomatic with peptic ulcer disease (duodenal [n = 18, 78%], jejunal [n = 4, 17%]) and/or diarrhea (n = 17, 74%).. Preoperatively, tumor localization was successful in only three patients (13%). Surgical management included tumor excision only in 14 patients (61%), partial gastroduodenectomy in six (27%), total gastrectomy in one (4%), limited enterectomy in one (4%), and tumor biopsy alone in one (4%). Seven patients had evidence of lymphatic metastases at the time of operation, including a single patient with hepatic metastases (malignancy rate, 30%). Postoperatively, complications developed in seven patients (30%): wound infection in two, ileus in two, pulmonary sepsis in one, intra-abdominal abscess in one, and diabetic ketoacidosis in one. The postoperative mortality rate was 4%.. Emphasis was placed on rendering patients eugastrinemic.. Long-term follow-up (mean, 8 years) of all patients revealed that 11 patients (48%) were eugastrinemic, asymptomatic, and not receiving gastric acid-reducing medication. Sixteen patients remain alive and well. Of the six now decreased patients who had been participating in long-term follow-up (mean survival, 14 years), death was due to atherosclerotic coronary artery disease in four and tumor progression in two.. Following surgical excision, patients with extrapancreatic gastrinomas have a favorable outcome, with nearly half being cured.

Topics: Adolescent; Adult; Aged; Child; Duodenal Neoplasms; Female; Follow-Up Studies; Gastrinoma; Gastrins; Humans; Lymphatic Metastasis; Male; Middle Aged; Postoperative Complications; Reoperation; Retrospective Studies; Stomach Neoplasms; Surgical Procedures, Operative; Survival Rate; Time Factors; Treatment Outcome

In the rat, hypergastrinaemia induced by drug treatment with omeprazole or potent H2-receptor antagonists leads to the development of gastric enterochromaffin-like cell carcinoids. In man, gastric carcinoids induced by hypergastrinaemia have been described only in patients with chronic atrophic gastritis type A and in patients with the multiple endocrine neoplasia syndrome type 1. This patient with Zollinger-Ellison syndrome without gastric mucosal atrophy and without evidence of the multiple endocrine neoplasia syndrome developed an argyrophil gastric carcinoid tumour. This observation indicates that hypergastrinaemia in the sporadic Zollinger-Ellison-syndrome may induce gastric carcinoids.

Topics: Adult; Carcinoid Tumor; Female; Gastric Mucosa; Gastrins; Humans; Stomach Neoplasms; Zollinger-Ellison Syndrome

Enterochromaffinlike (ECL) cell carcinoids recently observed in rats stimulated new interest in gastric endocrine tumors arising in humans.. Paraffin-embedded sections of 55 endocrine tumor cases were stained with H&E, mucin tests were performed, and immunoperoxidase was used for detecting endocrine markers; 23 cases were also investigated ultrastructurally.. Forty-five argyrophil carcinoids, 9 neuroendocrine carcinomas, and 1 gastrinoma were identified. Three clinicopathologic subtypes of carcinoids were characterized: (1) twenty-eight cases, none metastatic, arose in a background of body-fundus atrophic gastritis and hypergastrinemia; (2) seven cases, 2 locally metastatic, were associated with hypertrophic gastropathy and hypergastrinemia due to multiple endocrine neoplasia/Zollinger-Ellison syndrome; and (3) ten were sporadic cases, 7 of which were deeply invasive, 6 metastatic, and 5 histologically atypical. All carcinoids showed histochemical and ultrastructural patterns of ECL cells. The 9 neuroendocrine carcinomas, all deeply invasive and metastatic, were composed of anaplastic, small- to intermediate-sized cells with high mitotic index and focal necrosis.. Gastrin-promoted carcinoids represent a benign or low grade tumor disease, whereas sporadic carcinoids and neuroendocrine carcinomas are life-threatening neoplasms, independent of gastrin promotion.

Topics: Adult; Aged; Antigens, Neoplasm; Biomarkers; Biomarkers, Tumor; Carcinoid Tumor; Chromogranin A; Chromogranins; Female; Gastrins; Glycoprotein Hormones, alpha Subunit; Humans; Immunoenzyme Techniques; Immunohistochemistry; Male; Membrane Glycoproteins; Microscopy, Electron; Middle Aged; Mucin-1; Multiple Endocrine Neoplasia; Neoplasm Invasiveness; Neoplasm Metastasis; Pancreatic Polypeptide; Phosphopyruvate Hydratase; Serotonin; Somatostatin; Stomach Neoplasms; Thiolester Hydrolases; Ubiquitin Thiolesterase

Examination of gastrin-immunoreactive G-cells, somatostatin-immunoreactive D-cells, enterochromaffin cells and 5-hydroxytryptamine-immunoreactive (5-HT-immunoreactive) cells of the completely mapped histologic antrum (70 to 100 tissue blocks) was done in 20 normal stomachs of persons between 17 and 94 years of age (from forensic autopsy). Results were compared with those of nine patients between 48 and 76 years of age with total gastrectomy for carcinoma of the proximal part of the stomach. Cell counts and morphometric examinations were performed. Results were summarized for the proximal (I), middle (II) and distal (III) one-third of the antrum and for the major (A) and minor (B) curvature side. In normal stomachs, the G-cell count was 2.52 percent of the total gland cell count in AI; 4.25 percent in AII and 4.77 percent in AIII. In BI, the numbers were 2.5 percent, in BII, 3.73 percent and 4.06 percent in BIII. The D-cell count was 0.47 percent in AI, 0.62 percent in AII and 0.58 percent in AIII. The numbers were 0.44 percent in BI, 0.51 percent in BII and 0.51 percent in BIII. In the antrum of the stomach with carcinoma, the G-cells revealed a non-significant 20 to 70 percent lower cell count, while the D-cell count was reduced insignificantly by as much as 35 percent in all areas. The 5-HT-immunoreactive cell count in normal stomachs is 0.25 percent in AI of the total gland cells, 0.32 percent in AII and 0.39 percent in AIII. In B, it shows numerically no difference to that of A. Contrary to the cell count in normal stomachs, the carcinoma antrum revealed a 200 to 400 percent increase in 5-HT-immunoreactive cell count, highly significant in every area of the antrum. Because 5-HT is known as a growth stimulant, especially for tumors, an increase in 5-HT-immunoreactive cells may be a factor that contributes to the initial histologic changes observed during the early phase of gastric tumor.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Gastric Mucosa; Gastrins; Humans; Immunoenzyme Techniques; Middle Aged; Pyloric Antrum; Reference Values; Serotonin; Somatostatin; Stomach Neoplasms

The influence of Helicobacter pylori infection on serum levels of pepsinogen I and gastrin in gastric carcinoma was investigated by simultaneous determination of serum pepsinogen I, gastrin, and IgG antibodies against Helicobacter pylori in 100 patients with gastric carcinoma, and in another 100 age- and sex-matched healthy controls. Serum pepsinogen I level was significantly lower in gastric carcinoma than in controls (55.5 +/- 28.1 vs. 76.9 +/- 25.1 ng/ml, p < 0.005), but there was no difference in serum gastrin between them (63.2 +/- 30.2 vs. 57.4 +/- 28.5 pg/ml, p = 0.16). Helicobacter pylori infection caused a significant increase in serum PGI level in advanced, intestinal type, and non-cardia gastric carcinoma. The serum gastrin level was affected by neither Helicobacter pylori infection nor any of the tumor characteristics. It is concluded that pepsinogen I, rather than gastrin, in the serum is greatly influenced by Helicobacter pylori infection and tumor characteristics in gastric carcinoma.

Topics: Adult; Aged; Aged, 80 and over; Female; Gastrins; Helicobacter Infections; Helicobacter pylori; Humans; Male; Middle Aged; Pepsinogens; Stomach Neoplasms

A 63-year-old woman was diagnosed as autoimmune gastritis by the presence of serum antibody against alpha-subunit of gastric H+,K(+)-ATPase. The patient did not have pernicious anemia, but showed achlorhydria, marked hypergastrinemia, enterochromaffin-like cell hyperplasia and an extremely high histidine decarboxylase activity in the gastric fundic mucosa. Intragastric acidification by infusion of hydrochloric acid via a nasogastric tube induced a transient reduction of serum gastrin level and fundic mucosal histidine decarboxylase activity. A marked increase in fundic mucosal histidine decarboxylase activity as well as hypergastrinemia appears to be the pathophysiologic response to achlorhydria caused by autoimmunity against gastric H+,K(+)-ATPase.

Topics: Achlorhydria; Autoimmune Diseases; Enterochromaffin Cells; Female; Gastric Fundus; Gastric Mucosa; Gastrins; Gastritis; Graves Disease; H(+)-K(+)-Exchanging ATPase; Histidine Decarboxylase; Humans; Hyperplasia; Middle Aged; Parietal Cells, Gastric; Polyps; Stomach Neoplasms

Gastrin has been shown to promote the growth of some colonic tumor cell lines. To evaluate the involvement of this hormone in the proliferation of gastric tumors, we studied the effects of gastrin/CCK-receptor antagonists (L365,260 and L364,718), proglumide and C terminal-specific gastrin antibodies on the human gastric adenocarcinoma cell line HGT-1. L365,260, but not L364,718, dose-dependently inhibited cell proliferation (72% after 4 days at 10 nM) and [3H]thymidine incorporation (68% after 2 days at 10 nM) in serum-free medium. No cytotoxic effects of proglumide or L365,260 on this cell line were detected. Proglumide inhibited cell proliferation in serum-free medium (40% and 66.5% after 2 and 4 days of treatment; IC50 = 1.4 mM) and in 5% fetal calf serum (FCS)-supplemented medium (30% and 22% after 2 and 4 days of treatment; IC50 = 3.25 mM). [3H]Thymidine incorporation was also inhibited by proglumide in serum-free medium (IC50 = 2.3 mM) and 5% FCS-supplemented medium (IC50 = 3.35 mM). Gastrin did not induce cell proliferation or increase [3H]thymidine incorporation and no high-affinity gastrin binding sites were observed. However, C terminal-specific gastrin antibodies, even at low concentration, caused a dramatic decrease in both cell number (IC50 = 1:4000 antiserum dilution) and [3H]thymidine incorporation (IC50 = 1:400 antiserum dilution) in the HGT-1 cell line. In addition, immunofluorescence analysis revealed that these antibodies specifically bind HGT-1 cells and radioimmunoassay analysis confirms the presence of gastrin/CCK-like peptide in cell extracts.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adenocarcinoma; Antibodies; Benzodiazepinones; Cell Division; Devazepide; Gastrins; Growth Substances; Humans; Neoplasm Proteins; Phenylurea Compounds; Proglumide; Receptors, Cholecystokinin; RNA, Messenger; RNA, Neoplasm; Stomach Neoplasms; Tumor Cells, Cultured

Topics: Carcinoid Tumor; Dyspepsia; Gastrins; Humans; Kidney Failure, Chronic; Male; Middle Aged; Ranitidine; Self Administration; Stomach Neoplasms

A solitary pedunculated gastric polyp in the gastric fundus was removed from an asymptomatic 36-year-old woman with normal gastric acid secretion and a normal serum gastrin level. This lesion exhibited distinctive histological features including prominent proliferation of pseudopyloric glands, fundic glands, foveolar epithelium and a fibromuscular stroma. Moreover, its surface was entirely covered by a layer of normal gastric epithelium. Biopsies of the background mucosa taken from the gastric fundus revealed only mild superficial gastritis. A gastric gland heterotopia was diagnosed because of its unique morphology.

Topics: Adult; Choristoma; Female; Gastric Acid; Gastric Fundus; Gastric Mucosa; Gastrins; Humans; Polyps; Stomach Neoplasms

We determined the maximum secretion of gastric acid and the fasting serum levels of pepsinogen I and gastrin in Japanese patients with gastric hyperplastic polyps or polypoid-type early gastric carcinoma, comparing those findings with observations in control subjects. Both the maximum acid secretion and fasting levels of serum pepsinogen I were significantly lower in the patients with gastric hyperplastic polyps or polypoid-type early gastric carcinoma than in the controls. Fasting serum gastrin levels were significantly higher in the patients with gastric hyperplastic polyps than in the other two groups of subjects. These data demonstrated that the combination of hypochlorhydria, a low level of pepsinogen I, and hypergastrinemia (type-A gastritis) was common in the patients with gastric hyperplastic polyps, whereas hypochlorhydria and a low pepsinogen I without hypergastrinemia (type-B gastritis) were common in those with polypoid-type early gastric carcinoma.

Topics: Aged; Female; Gastric Acid; Gastrins; Humans; Hyperplasia; Japan; Male; Middle Aged; Pepsinogens; Polyps; Stomach Neoplasms

To determine the risk of gastric remnant cancer according to the type of surgical reconstruction, the distal two-thirds of the glandular stomach was resected in male Wistar rats, followed by gastroduodenostomy (Billroth I anastomosis) or gastrojejunostomy (Billroth II anastomosis). No carcinogens were given and the animals were killed 50 weeks after operation. No cancers developed in 22 rats undergoing Billroth I gastrectomy, but five of 24 with Billroth II anastomosis had adenocarcinoma (P < 0.05). All carcinomas were confined to the stoma. Animals with Billroth II anastomosis had a more advanced grade of mucosal atrophy at the stoma, with a higher incidence of cystic dilatation, submucosal adenocystic proliferation and pseudopyloric metaplasia (P < 0.05). Cell kinetics in the stomal mucosa after Billroth II gastrectomy showed an increased cell count in the proliferative zone, longer duration of S phase and increased cell cycle time (P < 0.05). These results suggest that Billroth II gastrectomy carries a greater risk of cancer than the Billroth I procedure.

Topics: Anastomosis, Surgical; Animals; Cell Division; Duodenum; Gastrectomy; Gastrins; Jejunum; Male; Rats; Rats, Wistar; Stomach; Stomach Neoplasms

A gastric antral tumor histologically classified as a yolk sac carcinoma was studied immunohistochemically. The tumor contained immunoreactive alpha-fetoprotein and gastrin. This is the first yolk sac carcinoma in which neuroendocrine differentiation was demonstrated immunohistochemically.

Topics: Aged; Aged, 80 and over; Dysgerminoma; Gastrins; Humans; Immunohistochemistry; Male; Stomach Neoplasms

Topics: Cell Transformation, Neoplastic; Enterochromaffin Cells; Gastrins; Humans; Stomach Neoplasms

Topics: Adenocarcinoma; Carcinoid Tumor; Gastric Acid; Gastrins; Helicobacter Infections; Helicobacter pylori; Humans; Peptic Ulcer; Stomach Neoplasms

To assess the value of gastroscopic cancer surveillance of patients with pernicious anaemia, 56 patients were re-endoscoped and biopsied after three years. In addition, changes in the density of fundic mucosal endocrine cells were evaluated morphometrically. Two cases (3.6%) of early gastric cancer and two cases of small gastric carcinoid tumours (3.6%) were detected in addition to the five carcinoids that had been found at the initial endoscopic screening. Nodular argyrophil cell hyperplasia and morphometric density of argyrophil cells were not stable phenomena: nodular hyperplasias regressed in five patients, remained similar in six, and progressed to a small carcinoid tumour in one. Serum gastrin concentrations did not correlate well with changes in the endocrine cell density. Regular endoscopic surveillance for gastric cancer may be beneficial and realistic in young patients with pernicious anaemia while the importance of fundic endocrine cell hyperplasia and that of small gastric carcinoids need further study.

Topics: Adenocarcinoma; Adult; Aged; Anemia, Pernicious; Carcinoid Tumor; Female; Follow-Up Studies; Gastric Fundus; Gastric Mucosa; Gastrins; Gastroscopy; Humans; Hyperplasia; Male; Middle Aged; Stomach; Stomach Neoplasms

Recently, we identified the specific binding site for gastrin on the gastric carcinoid tumor of Mastomys (Praomys) natalensis. In this study, precise characterization of the gastrin binding site on these tumors was performed. Both 125I-human gastrin I (gastrin) and 125I-CCK-8 bound specifically to the cell membrane, and Scatchard analysis revealed a high affinity binding site for each ligand with similar Kd and Bmax values. The specific binding of both 125I-gastrin and 125I-CCK-8 was displaced in a concentration-dependent manner by various related peptides with a relative potency order of CCK-8 > or = gastrin < des(SO3)CCK-8. In addition, L364,718 as well as L365,260 displaced the binding of both ligands with similar potencies. Furthermore, not only gastrin but also CCK-8 increased [Ca2+]i in these tumor cells, the action of both being inhibited by L364,718 as well as by L365,260 (10(-7) M). These results suggest that the carcinoid tumor of Mastomys possesses a high affinity gastrin/CCK binding site coupled to the increase of [Ca2+]i.

Topics: Animals; Carcinoid Tumor; Female; Gastrins; Humans; Kinetics; Male; Muridae; Neoplasm Transplantation; Receptors, Cholecystokinin; Sincalide; Stomach Neoplasms

Topics: Adenocarcinoma; Animals; Antigens, Viral, Tumor; Carcinoma; Gastrinoma; Gastrins; Genetic Engineering; Hyperplasia; Liver Neoplasms; Mice; Mice, Transgenic; Pancreatic Neoplasms; Pyloric Antrum; Stomach Neoplasms

Hypergastrinemia has been claimed to cause first hyperplasia and then dysplasia/neoplasia of enterochromaffin-like (ECL) cells in rat stomach. The growth is thought to reflect an accelerated self replication rate of mature ECL cells. The cytokinetics and the histidine decarboxylase (HDC) activity of the ECL cells were investigated during sustained hypergastrinemia.. Hypergastrinemia was evoked by omeprazole (400 mumol.kg-1 x day-1 orally) for up to 1 year. Immunocytochemistry for histamine was used to determine the ECL cell density and combined with [H3]-thymidine autoradiography to establish the labeling index (LI), i.e., the proportion of the ECL cells that has incorporated [H3]thymidine.. The ECL cell density increased progressively for 10-20 weeks in response to the hypergastrinemia and remained at a plateau for the remainder of the study. The hyperplasia was diffuse with additional micronodules at 52 weeks. The ECL cell Ll was maximally elevated after 1-2 weeks and declined to control values after 10-20 weeks of treatment. In contrast, the HDC activity remained elevated for the duration of the study.. The ECL cell hyperplasia reflects the transiently elevated ECL cell Ll during the early phase but is not associated with an accelerated rate of mitosis during the 10-52 weeks period. Even though with time gastrin seems to loose its ability to sustain a high ECL cell Ll it retains its ability to maintain a high HDC activity.

Topics: Animals; Carcinoid Tumor; Cell Division; Enterochromaffin Cells; Female; Gastric Mucosa; Gastrins; Histidine Decarboxylase; Hyperplasia; Kinetics; Male; Rats; Rats, Sprague-Dawley; Stem Cells; Stomach Neoplasms

Pronounced inhibition of acid secretion appears to induce an intragastric environment suitable for N-nitrosamine formation, hyper-gastrinemia, ECL cell hyperplasia and carcinoid tumor formation. Development of gastric cancer, however, has not been obvious in clinical and experimental studies, but oncongenicity studies indicate an increased risk of gastric cancer with long-term use of proton pump inhibitors in subjects with hyperplastic or other, changes in the gastric mucosa. The findings suggest that proton pump inhibitors should be used only for short term treatment.

Topics: Adenosine Triphosphatases; Animals; Depression, Chemical; Gastric Acid; Gastrins; H(+)-K(+)-Exchanging ATPase; Humans; Nitrosamines; Omeprazole; Stomach; Stomach Neoplasms; Stomach Ulcer; Time Factors

One hundred and twenty-eight cases of gastric carcinoma were examined with immunohistochemical technic for carcinoembryonic antigen (CEA), human chorionic gonadotropin (HCG), serotonin, gastrin and lysozyme. CEA were observed in 105 cases. Twenty-four cases were positive for HCG, 53 cases for serotonin, 31 cases for gastrin, 89 cases for lysozyme. Sixty-nine cases exhibited more than two hormones or one hormone and lysozyme simultaneously in different cells of the same tumor. Ultrastructurally, sometimes three types of secretory granules were noticed. The electron dense granules in the lysozyme-containing tumor cells were similar to those of Paneth's cells in intestinal metaplasia. The positive rates of the above three hormones, lysozyme and multi-marker expression in diffuse type carcinoma were higher than those in intestinal type, and 42/44 cases of the diffuse type carcinoma were histologically undifferentiated carcinomas or signet-ring cell carcinomas. Lymph node metastasis occurred more frequently in those carcinomas with hormone or lysozyme positivity. These findings suggest that these neoplastic endocrine cells and Paneth's cells have originated from multipotential differentiation of neoplastic stem cells in the stomach, reflecting the state of the gene activity in the tumor cells.

Topics: Adenocarcinoma; Adenocarcinoma, Mucinous; Carcinoembryonic Antigen; Carcinoma; Chorionic Gonadotropin; Gastrins; Humans; Immunohistochemistry; Lymphatic Metastasis; Muramidase; Neoplasm Staging; Serotonin; Stomach Neoplasms

The efficacy of octreotide in the regulation of endocrine tumor secretion and symptomatology has been well documented. Its effects on neuroendocrine tumor generation and cell proliferation are less well understood. The purpose of this study was to determine if blockade of somatostatin receptors by octreotide would alter gastrin levels and influence enterochromaffin-like (ECL) cell proliferation.. The well-established gastric ECLoma model of the rodent, mastomys, was used. Animals received loxtidine (1 mg/kg/day), an irreversible H2 blocker, and subcutaneous slow release, octreotide pellet implants (150 or 300 micrograms/kg/day) or placebo pellets for a 4-month period.. Control parameters for gastric mucosal thickness, plasma gastrin level, ECL cell density, and bromodeoxyuridine-positive cells were 517 +/- 20 microns, 46.1 +/- 11.4 pmol/L, 7.4 +/- 0.9 cells/visual field, and 13.8 +/- 2.6 cells/visual field, respectively. After loxtidine-placebo treatment all values were significantly increased (p < 0.05; 883 +/- 70 microns, 192.8 +/- 10.6 pmol/L, 97 +/- 16.2 cells/visual field, and 51.7 +/- 19.2 cells/visual field, respectively). High dose octreotide significantly inhibited all parameters (668 +/- 3.5 microns, 66.2 +/- 20.5 pmol/L, 37.0 +/- 8.0 cells/visual field, and 10.9 +/- 2.2 cells/visual field; p < 0.05). Low dose octreotide failed to significantly inhibit ECL cell density mucosal thickness, or cell proliferation.. Irreversible H2 receptor blockade results in hypergastrinemia and ECL cell tumor generation. Hypergastrinemia, ECL cell hyperplasia, and cell proliferation are significantly inhibited by in vivo blockade of somatostatin receptors by administration of octreotide.

Topics: Animals; Bromodeoxyuridine; Cell Count; Cell Division; Enterochromaffin Cells; Female; Gastrins; Histamine H2 Antagonists; Hyperplasia; Male; Muridae; Octreotide; Stomach; Stomach Neoplasms; Triazoles

Ordinary histological investigation has suggested that heterotopic pancreas of the stomach may have two types of histogenesis; one is development from immigrated fetal pancreas tissue, and the other is development from primitive gastric mucosal epithelium following penetration into the submucosa with subsequent erroneous differentiation into pancreas tissue. It is suspected that type-I lesions include the majority of cases caused by immigration from fetal pancreas, and that some type-II cases arise through erroneous differentiation of primitive gastric mucosal epithelium. With regard to immunohistochemical findings, cells positive for pancreatic polypeptide and amylase were much more numerous in the acini of type-I cases compared with type-II cases. Positive cells were found not infrequently in the acini of type-II cases after staining for pancreatic polypeptide, insulin, glucagon, somatostatin, serotonin, and gastrin. On the other hand, a small number of cells in islets were not infrequently positive for alpha 1-antitrypsin, alpha 1-antichymotrypsin, and amylase. It is considered that in the heterotopic pancreas, ductal cells have the potential to differentiate into acinar cells and islet cells, as is the cases in the orthotopic pancreas.

Topics: Amylases; Choristoma; Gastrins; Humans; Immunohistochemistry; Pancreas; Pancreatic Hormones; Serine Proteinase Inhibitors; Serotonin; Somatostatin; Stomach Neoplasms

An infant presented with hematemesis and gastric outlet obstruction. Preoperative diagnosis of duodenal duplication cyst was based on a collaboration of radiological studies. At exploration the patient was found to have a gastric polyp that had intussuscepted into the duodenum leading to obstruction and hypergastrinemia secondary to gastric mucosa in the duodenal alkaline environment.

Topics: Gastric Outlet Obstruction; Gastrins; Hematemesis; Humans; Hyperplasia; Infant; Male; Polyps; Stomach Neoplasms

So far, no cells have been found to synthesize both of the homologous hormones, cholecystokinin and gastrin. Northern analysis and reverse transcription PCR showed, that the human gastric carcinoma cell line (AGS) expresses both a gastrin mRNA of 0.7 kb and a cholecystokinin transcript of 0.8 kb. A library of sequence-specific radioimmunoassays, cleavage with processing-like enzymes and chromatography subsequently revealed that the gastrin mRNA was translated into progastrin that was constitutively secreted into the medium (45 +/- 3 pmol/l). Neither procholecystokinin nor any of its processing products were detectable in cells and media. The results suggest that differentiation into gastrin- or cholecystokinin-producing cells may be regulated at the translational level. The gastric cell line, AGS, provides a model for studies of translational regulation of cell differentiation.

Topics: Blotting, Northern; Cell Line; Cholecystokinin; Gastrins; Humans; Immune Sera; Oligodeoxyribonucleotides; Polymerase Chain Reaction; Protein Biosynthesis; RNA, Messenger; Stomach Neoplasms; Transcription, Genetic

The effects of the opioid receptor agonists methionine-enkephalin (Met-ENK) and leucine-enkephalin (Leu-ENK) on gastric carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine were investigated in Wistar rats. After 25 weeks of oral treatment with the carcinogen, the rats received subcutaneous injections of Met-ENK (20 micrograms/kg) or Leu-ENK (20 micrograms/kg) once every 2 days. The prolonged administrations of Met-ENK and Leu-ENK significantly increased the incidence of gastric cancers in week 52. Treatments with these opioid receptor agonists significantly increased the labeling index of the antral mucosa. These findings indicate that opioids enhance gastric carcinogenesis and suggest that their effects may be related to their influence on increasing proliferation of the antral epithelial cells.

Topics: Animals; Carcinoma; Cell Division; Drug Synergism; Enkephalin, Leucine; Enkephalin, Methionine; Gastric Mucosa; Gastrins; Hydrogen-Ion Concentration; Male; Methylnitronitrosoguanidine; Rats; Rats, Inbred Strains; Stomach Neoplasms

We report here the cDNA cloning of a putative gastrin receptor from enterochromaffin-like (ECL) carcinoid tumor of Mastomys natalensis. For this study, we used the polymerase chain reaction technique to amplify transmembrane domain sequences related to rat pancreatic cholecystokinin (CCK)-A receptor from the ECL tumor cDNA library. The amino acid sequence deduced from the cloned cDNA showed 85.7% and 49.0% identity to canine parietal cell gastrin receptor and rat pancreatic CCK-A receptor, respectively. Ligand binding studies using COS-7 cells transfected with the cDNA showed the same binding specificity for gastrin and CCK-8 as the gastrin receptor on the Mastomys carcinoid tumor membrane. Both gastrin and CCK-8 elevated free cytosolic calcium concentration in COS-7 cells expressing the cloned receptor. RNA blot analysis revealed the expression of the gastrin receptor in both Mastomys stomach and brain.

Topics: Amino Acid Sequence; Animals; Base Sequence; Calcium; Carcinoid Tumor; Cloning, Molecular; DNA; Dogs; Female; Gastrins; Molecular Sequence Data; Muridae; Pancreas; Parietal Cells, Gastric; Rats; Receptors, Cholecystokinin; Sequence Homology, Nucleic Acid; Sincalide; Stomach Neoplasms; Transfection

The effects of vaso-active intestinal peptide (VIP) on gastric carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) were investigated in Wistar rats given VIP every other day for 27 weeks after oral administration of MNNG for 25 weeks. In week 52, administration of VIP caused a significant increase in the incidence of gastric cancers, but did not influence their histological appearance. VIP significantly increased the labeling indices of the antral mucosa. Our findings indicate that VIP enhances gastric carcinogenesis, and that this effect may be related to its effect in increasing cell proliferation of the antral epithelial cells.

Topics: Animals; Drug Synergism; Gastric Juice; Gastrins; Hyperplasia; Male; Methylnitronitrosoguanidine; Rats; Rats, Inbred Strains; Stomach; Stomach Neoplasms; Vasoactive Intestinal Peptide

In rats, hypergastrinemia due to achlorhydria produced by antisecretory drugs or resection of the gastric fundus leads to enterochromaffinlike (ECL) cell hyperplasia and gastric carcinoids. In humans, achlorhydria due to pernicious anemia may also lead to ECL cell hyperplasia and multicentric gastric carcinoids in as many as 5% of cases. To examine the apparent gastrin dependence of gastric ECL carcinoids, three patients were studied (2 men aged 59 and 73 years; 1 woman aged 45 years) who had pernicious anemia, serum gastrin concentrations of greater than 1000 ng/L (greater than 1000 pg/mL), and multicentric gastric carcinoids. Antrectomy resulted in normalization of serum gastrin levels within 8 hours and disappearance of carcinoids in 6-16 weeks. In each of the three patients, a focus of microcarcinoid was found at 12-18 months. Further follow-up in each of the three patients 21-30 months after antrectomy again showed no carcinoids or ECL cell hyperplasia. It is concluded that multicentric ECL gastric carcinoids in patients with pernicious anemia and achlorhydria appear to be gastrin dependent and disappear after normalization of serum gastrin by antrectomy. Antrectomy rather than total gastrectomy may be the most appropriate treatment for this condition.

Topics: Aged; Anemia, Pernicious; Carcinoid Tumor; Enterochromaffin Cells; Female; Gastrins; Gastroscopy; Humans; Hyperplasia; Male; Middle Aged; Pyloric Antrum; Stomach Neoplasms

The effects of the dopamine agonist 2-bromo-alpha-ergocryptine methanesulfonate (bromocriptine) on the incidence, number and histology of gastric cancer induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) were investigated in Wistar rats. Rats were given 1 or 2 mg kg-1 body weight of bromocriptine subcutaneously every other day in depot form after 25 weeks of oral treatment with MNNG. Prolonged administration of bromocriptine at both dosages every other day resulted in a significant increase in the incidence and number of gastric cancers of the glandular stomach by week 52. Bromocriptine treatment did not influence the histological type of gastric cancer, but caused a significant increase in the labelling index of epithelial cells of the antrum. These findings indicate that the dopamine agonist bromocriptine promotes gastric carcinogenesis, and that this effect may be related to its effect in increasing proliferation of epithelial cells in the antral mucosa.

Topics: Adenocarcinoma; Animals; Bromocriptine; Dopamine; Epinephrine; Gastric Mucosa; Gastrins; Hydrogen-Ion Concentration; Male; Methylnitronitrosoguanidine; Neoplasms, Experimental; Norepinephrine; Rats; Rats, Inbred Strains; Stomach Neoplasms

A synthetic DNA template has been constructed that is suitable for the quantitation of mRNAs encoding gastrin, transforming growth factor alpha (TGF alpha), cholecystokinin, and the 78-kDa gastrin-binding protein. The template was used to measure levels of gastrin and TGF alpha mRNA in 7 colonic and 2 gastric carcinoma cell lines by the polymerase chain reaction. All lines produced detectable gastrin and TGF alpha mRNA with amounts varying between 2.1 and 540 molecules of gastrin mRNA/10(3) cells and 1.1 and 28 molecules of TGF alpha mRNA/10(3) cells. These results are consistent with the hypothesis that both gastrin and TGF alpha act as autocrine growth factors in colon carcinoma cell lines.

Topics: 3T3 Cells; Animals; Base Sequence; CHO Cells; Colonic Neoplasms; Cricetinae; Gastrins; Humans; Mice; Molecular Sequence Data; Polymerase Chain Reaction; RNA, Messenger; RNA, Neoplasm; Stomach Neoplasms; Transforming Growth Factor alpha; Tumor Cells, Cultured

The effect of gamma-butyrolactone (GBL) on inhibition by baclofen of gastric carcinogenesis was investigated in Wistar rats. In week 52, baclofen significantly decreased the incidence of gastric cancers. Concomitant treatment with GBL significantly increased gastric acid secretion but had no influence on the inhibition by baclofen of gastric carcinogenesis. This finding suggest that GBL significantly increased the sensitivity of gamma-aminobutyric acid (GABA) receptor to GABA mimetics in gastric acid secretion but not in the inhibitory effect of gastric carcinogenesis.

Topics: 4-Butyrolactone; Animals; Baclofen; DNA; Gastric Juice; Gastrins; Hydrogen-Ion Concentration; Male; Methylnitronitrosoguanidine; Rats; Rats, Inbred Strains; Secretory Rate; Stomach Neoplasms

Gastrin is known as a trophic factor for some stomach and colorectal cancer cells; however, the roles of gastrin receptors and the intracellular signal transduction pathways by which gastrin regulates cell growth are still unknown. The authors examined the effect of synthetic human gastrin-17 on growth of human stomach cancer cells (the parent line, AGS-P, and two different clones, AGS-10 and AGS-12), which were established (and have been maintained) in our laboratory. Gastrin stimulated growth of AGS-P and AGS-10 cells, which have gastrin receptors, in a dose-dependent fashion. A highly selective gastrin receptor antagonist, JMV 320, inhibited the growth-stimulatory effect of gastrin on AGS-P cells in a dose-dependent fashion. Concentrations of gastrin (10(-8) to 10(-6) M), which stimulated growth of AGS-P cells, did not affect either cyclic adenosine monophosphate production or phosphatidylinositol hydrolysis. Gastrin (10(-11) to 10(-5) M) mobilized calcium from the intracellular organelles to increases intracellular calcium level in AGS-P cells. The AGS-12 clone has no gastrin receptors, and gastrin did not affect growth or mobilization of intracellular calcium in these cells. Our findings indicate that gastrin stimulates growth of AGS cells through a mechanism that involves binding to specific gastrin receptors that are linked to the system for mobilization of intracellular calcium.

Topics: Amino Acid Sequence; Calcium; Gastrins; Hormones; Humans; In Vitro Techniques; Molecular Sequence Data; Receptors, Cholecystokinin; Sincalide; Stomach Neoplasms; Tumor Cells, Cultured

The effects of combined administration of bombesin and the ornithine decarboxylase (ODC) inhibitor 1,3-diaminopropane (DAP) on the incidence and number of gastric tumors induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), the ODC activity of the gastric wall and the labelling index of the gastric mucosa were investigated in inbred Wistar rats. Rats were given drinking water containing MNNG (50 micrograms/ml) for 25 weeks and then drinking water containing DAP (2.5 g/l) and/or injections of 40 micrograms/kg body weight of bombesin in depot form every other day. Administration of bombesin alone resulted in significant increases in the incidence of gastric cancers, the ODC activity of the antral portion of the gastric wall and the labelling index of the antral mucosa. Administration of DAP with bombesin significantly reduced enhancement by the latter of gastric carcinogenesis, ODC activity of the antral portion of the gastric wall and the labelling index of the antral mucosa. Our results suggest that ODC inhibition attenuated the enhancement of gastric carcinogenesis by bombesin, and that this enhancement by bombesin was mediated by polyamine biosynthesis.

Topics: Adenocarcinoma; Animals; Bombesin; Diamines; Drug Interactions; Drug Synergism; Gastric Mucosa; Gastrins; Hydrogen-Ion Concentration; Male; Methylnitronitrosoguanidine; Ornithine Decarboxylase Inhibitors; Rats; Rats, Inbred Strains; Stomach; Stomach Neoplasms

The regulation of gastrin secretion from antral G-cells is of major importance in the physiologic control of acid secretion. Gastrin secretion is highly dependent upon gastric intraluminal pH and is inhibited significantly by a pH of less than 3.0. Acute gastric alkalinization greater than pH 6.0 with antisecretory agents such as H2-receptor antagonists or H+/K+ ATPase inhibitors has little impact on fasting serum gastrin levels but promotes an enhanced sustained rise in meal-stimulated gastrin release. Courses of standard therapy with both H2-antagonists and H+/K+ inhibitors cause a significant rise in 24 h integrated plasma gastrin levels that is inversely correlated to the 24-h integrated gastric acidity. The rise in fasting or integrated plasma gastrin levels observed in patients treated with H2-antagonists is small and of unclear clinical significance. Therapy with antisecretory agents leads to earlier ulcer relapse than with other agents. A variety of factors have been proposed to explain the earlier ulcer relapse rate, including secondary hypergastrinemia with rebound acid hypersecretion after discontinuation of the drug. Secondary hypergastrinemia may also lead to tolerance to prolonged courses of H2-antagonists therapy with a decrease in acid inhibition. This may contribute to break-through ulcer recurrence during maintenance H2-antagonist therapy. However, the relative importance of hypergastrinemia and tolerance to H2-antagonists compared with other factors such as baseline gastric acid secretion, smoking status, nonsteroidal anti-inflammatory drug use, and Helicobacter pylori status is difficult to assess.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adenosine Triphosphatases; Carcinoid Tumor; Gastrins; H(+)-K(+)-Exchanging ATPase; Histamine H2 Antagonists; Humans; Peptic Ulcer; Stomach Neoplasms

A histologic and immunohistochemical study was carried out in 23 unselected nonantral gastric carcinoids and their precursor lesions classified according to Solcia et al. None of the patients showed Zollinger-Ellison syndrome. Two variants of carcinoids showing distinctive pathologic and pathogenetic characteristics were identified on the basis of presence or absence of associated chronic atrophic gastritis type A (A-CAG). Chronic atrophic gastritis type A was found in 19 cases showing either single or multiple neoplasms, tumor extension limited to the mucosa or submucosa, consistent endocrine cell precursor changes in extratumoral mucosa, and consistent hypergastrinemia and/or G cell hyperplasia. Associated precursor lesions were only hyperplastic in all but two cases with single carcinoids whereas they were also dysplastic in all but one case with multiple carcinoids. The four tumors arising in nonatrophic mucosa were all single, more aggressive, and not associated with extratumoral endocrine cell proliferations or with signs of gastrin hypersecretion. Tumor cells were diffusely immunoreactive for chromogranin A and synaptophysin but usually negative for chromogranin B or HISL-19. Scattered serotonin cells were found in ten carcinoids. They were more frequent in infiltrating than in intramucosal tumors as were the less represented pancreatic polypeptide cells whereas the reverse was found for alpha-subunit-containing cells. These results are of relevance for tumor pathogenesis and may provide the rationale for a less aggressive therapeutic approach in the patients.

Topics: Adolescent; Adult; Aged; Carcinoid Tumor; Chromogranin A; Chromogranins; Female; Gastric Mucosa; Gastrins; Glycoprotein Hormones, alpha Subunit; Humans; Hyperplasia; Immunohistochemistry; Male; Membrane Proteins; Middle Aged; Neoplasms, Multiple Primary; Nerve Tissue Proteins; Pancreatic Polypeptide; Precancerous Conditions; Serotonin; Stomach Neoplasms; Synaptophysin

Gastrin may play a role in gastric carcinogenesis, as indicated by an increased frequency of gastric carcinomas in patients with pernicious anaemia and the fact some human gastric cancer cell lines carry the gastrin receptor. Recently, it has been shown that the acid-stimulatory effect of gastrin may be solely mediated by histamine release from the enterochromaffin-like (ECL) cell, on which gastrin has a specific trophic effect. We therefore found it of interest to examine human gastric carcinomas for the presence of ECL tumour cells by using silver staining and chromogranin immunohistochemistry. We found evidence of ECL cell-derived tumour cells in 40% of the diffuse gastric carcinomas but no such tumour cells in the intestinal type of gastric carcinoma. This may suggest that diffuse gastric carcinomas, like malignant gastric tumours of the mastomys, are in fact malignant ECLomas.

Topics: Carcinoma; Enterochromaffin Cells; Gastric Mucosa; Gastrins; Humans; Receptors, Cholecystokinin; Staining and Labeling; Stomach; Stomach Neoplasms

To evaluate the characteristics of the gastric mucosa in women with fundic glandular polyps, we examined gastric acid secretion, fasting serum levels of pepsinogen I and gastrin, and gastric histology in 11 female patients with fundic polyps, and compared the results with 30 female controls without endoscopic abnormalities and 50 female patients with gastric foveolar hyperplastic polyps. No significant difference was found in gastric and secretion and fasting serum levels of pepsinogen I and gastrin between the patients with fundic glandular polyps and the control subjects. Histological examination showed that atrophic gastritis was generally not found in the patients with fundic glandular polyps. In contrast, gastric acid secretion and fasting serum levels of pepsinogen I were significantly lower and serum gastrin levels were significantly higher in the patients with foveolar hyperplastic polyps than in the other two groups. Also, patients with foveolar hyperplastic polyps had a higher prevalence and further advanced atrophic gastritis in the fundus than did the other two groups. Our investigations demonstrated that fundic glandular polyps arise from gastric mucosa without atrophic gastritis, whereas foveolar hyperplastic polyps develop from mucosa affected by atrophic gastritis, especially type A gastritis.

Topics: Female; Gastric Acid; Gastric Mucosa; Gastrins; Gastritis, Atrophic; Humans; Middle Aged; Pepsinogens; Polyps; Stomach Neoplasms

Being pepsinogen A (PGA) levels generally reduced and pepsinogen C (PGC) increased in gastric cancer patients, PGA/PGC ratio has been proposed as a useful marker of the tumour. We tested PGA, PGC and Gastrin (G) levels in patients with gastric cancer (39) and, as a control, in patients with epithelial dysplasia (21), chronic atrophic gastritis (57), gastric ulcer (11) or subjects lacking major or minor endoscopic and microscopic changes at gastroscopy (48). PGA and PGA/PGC levels were significantly reduced in gastric cancer patients (p less than 0.005 and p less than 0.0001 respectively with analysis of variance). Gastrin levels were also reduced in the same patients (p less than 0.005). We therefore adopted an index number (PGA x Gastrin) which was also dramatically reduced in gastric cancer (p less than 0.005); using an arbitrarily chosen cut-off, the "marker" showed very high sensitivity (76%), specificity (96%) and overall accuracy (74%, by Youden J test). We therefore suggest the use of the index number PGA x G in the diagnosis of gastric cancer, as the most useful gastrin presently available, to our knowledge.

Topics: Biomarkers, Tumor; Chronic Disease; Gastrins; Gastritis, Atrophic; Humans; Mathematics; Pepsinogens; Sensitivity and Specificity; Stomach Neoplasms; Stomach Ulcer

The possibilities to screen atrophic corpus gastritis with serum pepsinogen I (S-PGI) and serum gastrin (S-gastrin) concentrations have been studied in 774 subjects: 71 index subjects selected from a general population at random, 353 of their first-degree relatives, 276 first-degree relatives of patients with gastric cancer, 53 patients with pernicious anaemia, and 21 of their relatives. Discrimination function analysis was calculated from members of random and gastric carcinoma families. S-PGI less than 30 ng/ml had a high sensitivity for severe diffuse atrophic corpus gastritis (SDAG) alone (89.5%) and SDAG + severe patchy atrophic corpus gastritis (SPAG) (89.1%). Respective figures for specificity were 91.5% and 94.8%. The discriminatory power of S-PGI less than 30 ng/ml and S-PGI less than 25 ng/ml was of the same order. The sensitivity of low S-PGI decreased sharply in detection of slighter forms of atrophic corpus gastritis. The sensitivity of S-gastrin greater than 100 pmol/l to discriminate SDAG was 57.9% and SDAG+SPAG 58.7%. Respective figures for specificity were 90.2% and 92.2%. Diffuse and patchy atrophic changes behaved similarly regarding S-PGI and S-gastrin mean concentrations. Accordingly, the biopsy specimen with the severest atrophic changes indicates the degree of atrophy, which associates closely with the changes in S-PGI and S-gastrin. In conclusion, severe atrophic (diffuse or patchy) corpus gastritis may be screened from a general population with high sensitivity and specificity by low S-PGI less than 30 ng/ml, whereas an increased level of S-gastrin is too insensitive for this.

Topics: Aged; Anemia, Pernicious; Female; Gastric Mucosa; Gastrins; Gastritis, Atrophic; Humans; Male; Middle Aged; Pepsinogens; Predictive Value of Tests; Sensitivity and Specificity; Stomach Neoplasms

Serum pepsinogen I (S-PGI) and serum gastrin (S-gastrin) were examined in the screening of three types of atrophic gastritis with inherent high risk of gastric cancer: in 102 cases with severe atrophic corpus gastritis (SACG), in 5 cases with severe atrophic antrum gastritis (SAAG), and in 15 cases with severe atrophic pangastritis (SAPG) (atrophy both in corpus and in antrum) found among 916 subjects from three family series (265 from gastric cancer families, 425 from randomly selected control families and 226 from pernicious anaemia families). There is no way to screen directly atrophic gastritis restricted to the antral mucosa. In pangastritis atrophy of antral glands causes a failure of the hypergastrinemic reaction of achlorhydria. The combination of S-PGI less than 25 micrograms/l + S-gastrin less than 200 pmol/l detected 80.0% of our cases with SAPG, and only 17 subjects of 794 (2.1%) were false positives i.e. who had not advanced atrophic gastritis. The risk of gastric cancer may be significantly higher in SAPG than in SACG. The estimated prevalence of SAPG was 3% in random-family members over 60 years. The combination of S-PGI and S-gastrin is recommended when the cost/benefit ratio in the screening program of gastric cancer is considered and people from a general population are selected for endoscopic studies.

Topics: Anemia, Pernicious; Gastric Mucosa; Gastrins; Gastritis, Atrophic; Humans; Middle Aged; Pepsinogens; Risk Factors; Stomach Neoplasms

Topics: Carcinoma; Gastrins; Humans; Stomach Neoplasms

Topics: Animals; Carcinoid Tumor; Female; Gastrins; Humans; Neoplasms, Hormone-Dependent; Rats; Stomach; Stomach Neoplasms; Zollinger-Ellison Syndrome

Epidermal growth factor receptors and insulin like growth factor-I receptors were co-expressed on two gastric and three colorectal tumour cell lines. Previous studies have shown that gastrin receptors were also expressed at a low level or two of these cell lines. Both TGF alpha and IGF-I promoted cell growth in all of the cell lines tested. The cell doubling time of a colorectal cell line was reduced from 48 to 30-34 h. Furthermore the effects of the growth factors were additive. Each growth factor also increased the response of the cells to gastrin, but a combination of both growth factors and gastrin did not further increase growth.

Topics: Cell Division; Colonic Neoplasms; Drug Synergism; Drug Therapy, Combination; ErbB Receptors; Gastrins; Humans; Insulin-Like Growth Factor I; Mitogens; Receptors, Cell Surface; Receptors, Somatomedin; Stomach Neoplasms; Transforming Growth Factor alpha; Tumor Cells, Cultured

Topics: Carcinoid Tumor; Gastrectomy; Gastric Mucosa; Gastrins; Humans; Neoplasm Staging; Prognosis; Stomach Neoplasms

Mastomys is a rodent with a high incidence of spontaneous carcinoids in the acid-producing part of the stomach. The present study was conducted to examine whether hypergastrinemia could promote tumor formation in this species. Mastomys, 4 months of age, were treated for 5 months with omeprazole subcutaneously, 100 mumol/kg body weight daily, and compared with mastomys given the vehicle only. The plasma gastrin concentration and the number of antral gastrin cells were increased in the omeprazole-treated group. The hypergastrinemia was associated with elevated histidine decarboxylase activity and histamine content in the oxyntic mucosa and with a trophic effect on the oxyntic mucosa and the enterochromaffin-like cells. However, no carcinoid tumors were observed, possibly because the strain of mastomys studied does not produce carcinoids spontaneously.

Topics: Animals; Carcinoid Tumor; Enterochromaffin Cells; Female; Gastric Mucosa; Gastrins; Histamine; Histidine Decarboxylase; Injections, Subcutaneous; Male; Muridae; Omeprazole; Radioimmunoassay; Stomach Neoplasms; Time Factors

Topics: Age Factors; Carcinoid Tumor; Esophagitis, Peptic; Female; Gastrins; Humans; Male; Middle Aged; Omeprazole; Peptic Ulcer; Risk Factors; Sex Factors; Stomach Neoplasms

The susceptibility to cancer in the vagotomized stomach which was assigned either to selective vagotomy (SV) or selective proximal vagotomy (SPV) was studied by gastric carcinoma model of male Wistar rat on N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) administration. Predilection for cancer of the remnant stomach was also studied. Four groups of the rats submitted to either one of the SV, SPV, antrectomy (Billroth-I reconstruction) or control (simple laparotomy) group, were prepared. The techniques of SV and SPV in rat was originally developed. MNNG in drinking water was given as carcinogen. Gastric acid output, gastric stasis, serum gastrin levels together with the number and the invasiveness of the atypical glands those were recognized in the glandular stomach of rats were examined. The results were as follows: (1) the reduction rate of gastric acid output was the most conspicuous at antrectomy group followed by SV and SPV groups, (2) gastric stasis was observed in almost the same degree in SV and SPV groups, (3) serum gastrin level was the highest in SV group followed by SPV, control and antrectomy groups in this order and (4) the susceptibility to malignancy was significantly high at SV group but not high at SPV and antrectomy group as compared with control group.

Topics: Animals; Gastrectomy; Gastric Acid; Gastric Emptying; Gastrins; Male; Methylnitronitrosoguanidine; Pyloric Antrum; Rats; Stomach; Stomach Neoplasms; Vagotomy; Vagotomy, Proximal Gastric

Topics: Achlorhydria; Animals; Carcinoid Tumor; Gastrins; Humans; Omeprazole; Rats; Stomach Neoplasms

Studies in the rat have shown that partial gastric corpectomy, in which about 75% of the acid-producing oxyntic mucosa was removed, leads to markedly reduced acid secretion and a feedback increase in the plasma gastrin levels. Ten weeks after operation, the gastric enterochromaffin (ECL)-like cell density in the remaining part of the oxyntic mucosa had increased significantly. In the present study, the effects on the gastric ECL cells of lifelong persistent hypergastrinemia induced by partial (75%) corpectomy have been investigated. Seventy-five partially corpectomized rats and 40 control rats were investigated for plasma gastrin and oxyntic mucosal changes in a 124-week study. The partially corpectomized rats showed increased plasma gastrin levels after the operation; the mean increase compared with the controls was almost 10-fold during the entire study. The remaining oxyntic mucosa of the partially corpectomized rats differed from that of control rats in two respects, showing first general hypertrophy and second a marked hyperplasia of argyrophil ECL cells. The degree and incidence of these changes increased towards the end of the study, i.e., in the aging rats. An age-related increase in ECL-cell density occurred spontaneously also in the control rats but to a lesser extent than in the partially corpectomized group. ECL-cell carcinoids were found in the oxyntic mucosa of 26 of the 75 partially corpectomized rats. The first carcinoid was found 78 weeks after the beginning of the study. Six rats with carcinoids (23%) were found before week 104 (2 years) and the remainder, 20 (77%), were discovered later. No carcinoid tumor was found in the control rats. It is concluded that lifelong hypergastrinemia induced by partial corpectomy leads to the development of ECL-cell carcinoids in the oxyntic mucosa of some rats towards the end of their life span. This observation strongly supports the hypothesis that the gastric ECL-cell carcinoids found in rats treated with antisecretory drugs are caused by long-standing hypergastrinemia developing secondary to inhibition of gastric acid secretion.

Topics: Animals; Body Weight; Carcinoid Tumor; Enterochromaffin Cells; Feedback; Female; Gastric Mucosa; Gastrins; Hyperplasia; Hypertrophy; Parietal Cells, Gastric; Rats; Rats, Inbred Strains; Stomach; Stomach Neoplasms; Time Factors

The effects of sulpiride on cysteamine inhibition of gastric carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and on the BUdR labelling index of gastric mucosa were investigated in inbred Wistar rats. After 25 weeks of oral treatment with MNNG, rats received one of the following alternate-day injections: cysteamine (2 doses), cysteamine (2 doses) plus sulpiride or sulpiride. At week 52, prolonged administration of cysteamine significantly reduced the incidence of adenocarcinomas of the glandular stomach. Cysteamine at low dose had no effect on the incidence of gastric cancers, but a combination of low-dose cysteamine and sulpiride caused a significantly greater reduction in the incidence of gastric cancers. Administration of sulpiride alone had no influence on gastric carcinogenesis. The labelling index of the antral mucosa was significantly lower in rats treated with high but not low doses of cysteamine. However, a combination of low-dose cysteamine and sulpiride significantly decreased the labelling index of the antral mucosa. Our findings indicate that cysteamine suppressed gastric carcinogenesis and that sulpiride enhanced this inhibition. Because sulpiride is a dopamine antagonist, these findings also indicate that dopamine may play an important role in cysteamine inhibition of gastric carcinogenesis.

Topics: Animals; Cysteamine; Dose-Response Relationship, Drug; Drug Synergism; Gastric Acid; Gastric Mucosa; Gastrins; Methylnitronitrosoguanidine; Rats; Rats, Inbred Strains; Stomach Neoplasms; Sulpiride

A 51 year-old woman with vomitus, intermittent epigastric pain and heartburn had chronic sideropenic anemia. Gastroscopy revealed a subcardial, submucosal tumor. The tumor was removed totally by endoscopic polypectomy. Histologically it was identified as a carcinoid. The endocrinologic examination showed hypergastrinemia caused by chronic atrophic gastritis. The association of this gastric carcinoid with chronic atrophic gastritis type A, hypergastrinemia, hyperplasia of the gastrin-producing antral cells and micronodular hyperplasia of endocrine cells in the gastric fundus, confirms the hypothesis about the pathogenesis of these extremely rare gastric tumors.

Topics: Carcinoid Tumor; Chronic Disease; Female; Gastrins; Gastritis, Atrophic; Gastroscopy; Humans; Middle Aged; Stomach; Stomach Neoplasms

Specific binding sites for human gastrin I (gastrin) were identified in a crude membrane preparation from the gastric carcinoid tumor of Mastomys (Praomys) natalensis. The binding of 125I-gastrin to the carcinoid tumor membrane was saturable, and Scatchard analysis of the data revealed a single class of binding site with a dissociation constant of 139.2 pM and a maximal binding capacity of 23.5 fmol/mg protein. Gastrin and CCK8 equipotently and dose-dependently displaced the binding of 125I-gastrin to the membrane. GTP but not ATP decreased 125I-gastrin binding to the membrane, and removal of Mg2+ attenuated this inhibitory action of GTP. The GTP-induced reduction of 125I-gastrin binding was found to be due to a decrease in binding affinity without a change in binding capacity. These results clearly indicate the presence of specific binding sites for gastrin, probably coupled to guanine nucleotide-binding protein, in the carcinoid tumor membrane of Mastomys, and suggest that gastrin has possible biological actions on these tumors.

Topics: Adenosine Triphosphate; Animals; Carcinoid Tumor; Cell Membrane; Female; Gastrins; Guanosine Triphosphate; Humans; Kinetics; Muridae; Receptors, Cholecystokinin; Stomach Neoplasms

Flow cytometry and immunohistochemical analyses of the human gastric adenocarcinoma cell line MKN45G identified an intracellular peptide recognized by an anti-gastrin-17 (G17) antiserum but not by an anti-cholecystokinin-specific antiserum. Staining was not associated with the parental line MKN45, of which MKN45G is a clonal variant. The MKN45G cell line had elevated in vitro growth in serum-free medium in which the proliferation of MKN45G cells but not MKN45 cells was reduced to 58% of the control value by treatment with a rabbit anti-G17 antiserum. This inhibition of proliferation was reversed by preabsorbing the antiserum with excess G17. Disaggregated primary human gastric and colorectal tumors were screened for gastrin immunoreactivity by flow cytometry, and 6 of 28 colorectal and 8 of 22 gastric tumors had greater than 20% positively staining cells.

Topics: Adenocarcinoma; Animals; Antibodies; Carcinoembryonic Antigen; Cell Division; Cholecystokinin; Colorectal Neoplasms; Flow Cytometry; Gastrins; Gastrointestinal Neoplasms; Humans; Immunohistochemistry; Intracellular Fluid; Rabbits; Stomach Neoplasms; Tumor Cells, Cultured

Elevated plasma gastrin levels have been found in patients with colorectal cancer. We measured fasting serum gastrin levels in control subjects (n = 12), patients with gastric cancer (n = 43), and patients with carcinoma of the esophagus (n = 55). Serum gastrin levels were significantly higher in patients with gastric cancer compared to normal controls (P less than 0.005) and those with esophageal cancer (P less than 0.05). This information may add to our understanding of the pathogenesis of gastric cancer.

Topics: Carcinoma, Squamous Cell; Esophageal Neoplasms; Gastrins; Humans; Pepsinogens; Stomach Neoplasms

The effect of tyrosine methyl ester (TME) on the incidence, number, and histological types of gastric cancers induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) was investigated in male Wistar rats. Rats were subcutaneously given TME, 512 mg/kg body weight, every other day after 20 weeks of oral treatment with MNNG. Prolonged alternate-day administration of TME caused a significant increase in the incidence and number of gastric cancers of the glandular stomach by week 52. However, it did not affect the histology of the cancers. TME also caused a significant increase in tissue norepinephrine concentrations in the antral portion of the gastric wall and in the labelling indices of the antral epithelial cells. However, TME had no influence on the serum gastrin level and antral pH. These findings indicate that TME enhances gastric carcinogenesis, and this may be related to its effects on increasing norepinephrine levels in the gastric wall and stimulating proliferation of the antral epithelial cells.

Topics: Adenocarcinoma; Animals; Catecholamines; Drug Synergism; Epinephrine; Gastric Acidity Determination; Gastric Mucosa; Gastrins; Male; Methylnitronitrosoguanidine; Muscle, Smooth; Norepinephrine; Rats; Rats, Inbred Strains; Stomach; Stomach Neoplasms; Tyrosine

To elucidate the biological and clinicopathological significance of endocrine differentiation in gastric adenocarcinoma, an immunohistochemical study was made of 127 cases with ascertained five-year survivals, and of 45 recent cases of bromodeoxyuridine (BrdU) labeling. Endocrine differentiated cancer cells were demonstrated in 37 out of the 127 cases (29.1%) evaluated by chromogranin A (CGA) immunoreactivity, and all CGA-positive tumors were classified as advanced gastric cancer. Analysis of retrospective five-year survival rates revealed the adenocarcinomas with endocrine differentiation to have had significantly longer survival times than those without endocrine immunoreactivity in stage II, but not in stages III or IV. Double immunolabeling for CGA and BrdU in the other 45 adenocarcinoma cases showed only a single CGA-positive cancer cell with BrdU incorporation among a total of 454 CGA-positive cells examined. There was no significant difference between the labeling indices of the general cancer population and the cancer cells adjacent to CGA-positive cells. In conclusion, endocrine differentiation of gastric cancer is not uncommon, particularly in advancing cancer, and it would be a useful marker for a better prognosis in stage II. Probably, endocrine differentiated cancer cells are almost dormant with virtually no DNA synthesizing activity, and their paracrine effect is most unlikely to work in vivo.

Topics: Adenocarcinoma; Bromodeoxyuridine; Cell Differentiation; Cell Division; Chromogranin A; Chromogranins; Gastrins; Glicentin; Glucagon; Glucagon-Like Peptides; Glycoprotein Hormones, alpha Subunit; Hormones; Humans; Immunohistochemistry; Lymph Nodes; Lymphatic Metastasis; Peptide Fragments; Protein Precursors; Serotonin; Somatostatin; Stomach Neoplasms

The immunoreactive gastrin (IRG) and somatostatin (IRS) contents in gastric mucosa were measured from the same biopsy specimen of the same patients with duodenal ulcer (DU) at the active stage and healing stage, and compared to those of patients with fundic gland polyposis (FP) and endoscopically normal subjects whose gastric mucosa had only slight atrophic change (Control). The IRS in both the antrum and the gastric body of DU were significantly lower than those of the other two groups, and those showed no difference between the two stages. In all groups, there was a significant positive relation between the IRG and IRS in the antrum. In DU, particularly at the active stage, the relative decrease of the IRS against the IRG was prominent compared to the other two groups. In FP, which has similar background gastric mucosa and ability of acid output to those of DU, it was found that somatostatin was secreted sufficient to control gastrin secretion and acid output. Whereas in DU, secretion of somatostatin was reduced and, particularly at the active stage, it was considered that somatostatin, which could control increased gastrin secretion and increased acid output, was not secreted.

Topics: Adult; Duodenal Ulcer; Female; Gastric Fundus; Gastric Mucosa; Gastrins; Humans; Male; Polyps; Radioimmunoassay; Somatostatin; Stomach Neoplasms

1,351 specimens resected surgically from 100 patients with gastric carcinoma were studied with PAP immunoperoxidase and ultrastructural method. The tumor cells were found positive for gastrin, serotonin, somatostatin and argyrophil particles in 19 patients. Among them the gastrin-secreting tumor cells consisted of 50% of the total in 4 cases, representing a separate new subtype, neuro-endocrine (NE) gastric carcinoma. Of the 100 cases, 16 (32%) contained NE cells among 50 undifferentiated type, while only 3 cases (6%) contained NE cells among the remaining 50 cases, the well-differentiated type. These results suggest that the appearance of NE tumor cells is closely correlated with the degree of differentiation of cancer, and confirms theoretically the heterogenicity of gastric carcinoma, and further supports the concept that exocrine and endocrine type gastric cancer cells are isogenous, i.e., from the endodermal stem cells.

Topics: Adenocarcinoma, Mucinous; Adult; Aged; Female; Gastrins; Humans; Immunohistochemistry; Male; Middle Aged; Serotonin; Somatostatin; Stomach Neoplasms

Neuroendocrine cell (carcinoid) tumours have been reported in the acid-secreting part of the stomach of rodents after long-term administration of a range of potent chemically diverse antisecretory agents. Although evidence shows a link between the sequence of acid suppression, hypergastrinaemia, and neuroendocrine cell hyperplasia, other factors are also thought to be involved in neoplastic transformation. Prolonged hypochlorhydria or achlorhydria resulting in bacterial colonization of the stomach may allow the generation of carcinogenic substances. Other as yet unidentified trophic factors may be involved in tumour formation. In view of the potential risks associated with these agents, there must be concern about the possible consequences in man of marked suppression of acid. It seems wise to limit the use of these more potent agents to situations in which conventional therapy has failed and to short-term treatment.

Topics: Animals; Carcinoid Tumor; Female; Gastric Acid; Gastric Mucosa; Gastrins; Histamine H2 Antagonists; Humans; Hyperplasia; Male; Mice; Omeprazole; Rats; Stomach Neoplasms; Time Factors; Triazoles

The effect of enprostil and the somatostatin analogue SMS 201 995 on the growth of a clonal variant of the human gastric adenocarcinoma cell line, MKN45, was studied. The derived cell line grew twice as fast as MKN45 when grown as a xenograft line in nude mice. However, it did not respond trophically to gastrin either in vitro or in vivo (unlike MKN45) although it possessed the same number of gastrin receptors as the parental line. Gastrin production by the cell line during in vitro culture was twice that of MKN45; thus, the cell line was denoted MKN45G. When MKN45G was grown as xenografts in nude mice (n = 10/group), enprostil (20 micrograms/kg/day) significantly inhibited tumour growth when administered continuously by an osmotic mini-pump from day 1 to day 7 of a 20-day experiment, and induced tumour regression when administered from day 7 to day 14. Enprostil reduced postprandial serum gastrin levels when administered from day 7 to day 14 and prevented gastrin release by MKN45 in vitro. SMS 201 995 at doses of 25 and 240 micrograms/kg/day induced tumour regression when administered from day 1 to day 7 and the former dose reduced post-prandial serum gastrin levels at day 5. Gastrin release by MKN45G was not affected by SMS 201 995 in vitro, thus its effect may not be mediated directly via gastrin, requiring interaction between other hormones or growth factors in the in vivo situation.

Topics: Adenocarcinoma; Animals; Cell Line; Drug Evaluation, Preclinical; Enprostil; Female; Gastrins; Humans; Male; Mice; Mice, Nude; Middle Aged; Neoplasm Transplantation; Octreotide; Prostaglandins E, Synthetic; Receptors, Gastrointestinal Hormone; Stomach Neoplasms; Time Factors; Tumor Cells, Cultured

The effects of combined administration of tetragastrin and the ornithine decarboxylase inhibitor 1,3-diaminopropane (DAP) on the incidence and number of gastric cancers induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), and the BUdR labelling indices of the fundic and antral mucosae, were investigated in inbred Wistar rats. Rats were given drinking water containing 2.5 g/l of DAP ad libitum and received alternate-day injections of 1 mg/kg body weight of tetragastrin in depot form after 25 weeks of oral treatment with MNNG. At week 52, prolonged administration of tetragastrin alone resulted in a significant reduction in the incidence and number of gastric cancers and a significant increase or decrease in the labelling indices of the fundic and antral mucosae, respectively. Concomitant administration of tetragastrin and DAP had no effect on the inhibition by tetragastrin of gastric carcinogenesis. With this treatment, the labelling index was significantly reduced in the fundic mucosa but not in the antral mucosa. These results suggest that ODC inhibitor does not attenuate tetragastrin inhibition of gastric carcinogenesis, and that anti-trophic action of tetragastrin on antral mucosa may be related to tetragastrin inhibition of gastric carcinogenesis.

Topics: Animals; Diamines; DNA; Eflornithine; Gastrins; Hydrogen-Ion Concentration; Male; Methylnitronitrosoguanidine; Ornithine Decarboxylase Inhibitors; Rats; Rats, Inbred Strains; Stomach Neoplasms; Tetragastrin

Multifocal gastric carcinoid tumors occasionally develop in patients with pernicious anemia, associated with hyperplasia of endocrine cells in the atrophic and metaplastic gastric body mucosa. This constellation of findings probably requires a trophic drive from hypergastrinemia associated with antral G cell hyperplasia, a consequence of achlorhydria in these patients. We report a case in which antrectomy was performed on such a patient in order to abrogate the trophic stimulus. Antrectomy was followed by resolution of hypergastrinemia and a decrease in the size of polyps endoscopically. Nine months later, the gastric remnant was resected. Using morphometric techniques, endocrine cells in the initial antrectomy specimen (which included body mucosa at the resection line) were compared with those in the subsequently removed gastric body. Antrectomy resulted in striking decreases in number (137 versus 34/mm2; P = 0.0001) and size (93 versus 56 microns2; P = 0.0001) of endocrine cells of body mucosa. The findings suggest that antrectomy may be useful in the management of endocrine cell hyperplasia, and possibly also associated carcinoid tumors, in pernicious anemia.

Topics: Anemia, Pernicious; Carcinoid Tumor; Female; Gastric Mucosa; Gastrins; Humans; Hyperplasia; Middle Aged; Pyloric Antrum; Reproducibility of Results; Stomach Neoplasms

A patient with pernicious anemia, atrophic non-antral gastritis, hypergastrinemia, and widespread hyperplasia of enterochromaffin-like cells and manifest enterochromaffin-like cell carcinoma was followed up during 39 months, including 15 months after gastric resection. In this case normalization of gastrin levels did not prevent the development of multiple gastric carcinoids in the fundic mucosa, suggesting that factors other than gastrin are of importance in the pathogenesis.

Topics: Anemia, Pernicious; Carcinoid Tumor; Follow-Up Studies; Gastrectomy; Gastric Mucosa; Gastrins; Gastritis, Atrophic; Humans; Hyperplasia; Male; Middle Aged; Stomach Neoplasms

The results of rehabilitative treatment received at health resort by 200 gastric cancer patients were studied. In 85 of them, radioimmunoassay was used to measure serum CEA, ferritin and gastrin levels in the course of treatment. CEA and ferritin concentrations in remission patients (12.6 +/- 5.7 ng/ml and 94,6 +/- 15.3 ng/ml, respectively) differed from those in cases of relapse (69.2 +/- 7.1 ng/ml and 361.4 +/- 46.8 ng/ml). It is suggested that serum markers levels be used as criteria of response to treatment and prognosis.

Topics: Adult; Biomarkers, Tumor; Carcinoembryonic Antigen; Ferritins; Gastrins; Health Resorts; Humans; Middle Aged; Postoperative Care; Prognosis; Stomach Neoplasms; Time Factors

The effects of the organic calcium channel blocker verapamil and the inorganic calcium channel blocker MgCl2 on gastric carcinogenesis, on caerulein enhancement of gastric carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine, and on the labeling index of gastric mucosa were investigated in inbred Wistar rats. After 25 weeks of treatment with N-methyl-N'-nitro-N-nitrosoguanidine (50 micrograms/ml p.o.), rats received one of the following alternate-day injections: caerulein (2 micrograms/kg body weight, s.c.), MgCl2 (150 mg/kg, s.c.), verapamil (20 mg/kg body weight, i.p.), caerulein (2 micrograms/kg body weight, s.c.) plus MgCl2 (150 mg/kg body weight, s.c.), or caerulein (2 micrograms/kg body weight, s.c.) plus verapamil (20 mg/kg body weight, i.p.). At Week 52, prolonged administration of caerulein had significantly increased the incidence and number of adenocarcinomas in the glandular stomach and the incidence of gastric cancers that penetrated through or beyond the muscle layer. Concomitant administration of MgCl2 significantly attenuated the enhancing effect of caerulein on gastric carcinogenesis. Combined administration of caerulein and verapamil did not affect the incidence and number of gastric cancers but significantly reduced the incidence of cancers penetrating through or beyond the muscle layer. Administration of MgCl2 or verapamil alone had no influence on gastric carcinogenesis. Rats treated with caerulein had a significantly elevated labeling index of the antral mucosa which was significantly decreased by concomitant administration of MgCl2 and/or of verapamil, as compared with the labeling index observed after treatment with caerulein alone. Either MgCl2 or verapamil alone had no influence on the labeling index of the antral mucosa. These findings indicate that caerulein enhances gastric carcinogenesis and that MgCl2 and verapamil attenuate this enhancement. These findings also indicate that calcium may play an important role in caerulein enhancement of gastric carcinogenesis.

Topics: Adenocarcinoma; Animals; Calcium Channel Blockers; Ceruletide; DNA; Gastric Juice; Gastrins; Hydrogen-Ion Concentration; Magnesium Chloride; Male; Methylnitronitrosoguanidine; Rats; Rats, Inbred Strains; Stomach Neoplasms; Verapamil

The Mastomys (Praomys natalensis) species are a unique natural model in which the bioactivity of gastric carcinoids may be studied. Several investigators have previously demonstrated that these tumors contain large amounts of histamine. In this study we investigated the presence of peptides associated with the neoplasm. The levels and location of gastrin, gastric inhibitory peptide (GIP), neurotensin, peptide YY (PYY), pancreatic polypeptide (PP), glucagon, bombesin, vasoactive intestinal peptide (VIP) and somatostatin (SRIF) were investigated by radioimmunoassay and immunocytochemistry. In addition the distribution of these peptides were evaluated in the gastrointestinal tract of young and old animals to investigate possible age-related changes. PYY and enteroglucagon (EG) were significantly (P less than 0.001) elevated in both tumor tissue (676 +/- 152, 551 +/- 164 pmol/g) and plasma (620 +/- 160, 500 +/- 147 pmol/l) of tumor-bearing animals. Immunocytochemistry revealed PYY- and EG-like immunoreactivity in 20-30% of tumor cells. A significant decrease (P less than 0.05) in bombesin was noted in older animals, but no changes in gastric tissue content of PYY or EG could be detected between young and old animals. Gastrin was not detected in tumors and there were no significant changes in tissue or plasma levels with age. Small bowel concentrations of VIP and PYY were higher in the older mastomys (P less than 0.05). In contrast, colonic levels of bombesin, VIP, somatostatin and PYY were significantly lower (P less than 0.05) in older mastomys compared with young. The age-related changes in several peptides may reflect an adaptive response to acid hypersecretion. The multi-hormonal character of these neoplasms suggests that these tumors develop from a pluripotential stem cell.

Topics: Age Factors; Animals; Bombesin; Carcinoid Tumor; Gastric Inhibitory Polypeptide; Gastrins; Immunohistochemistry; Muridae; Neoplasm Proteins; Neurotensin; Pancreatic Polypeptide; Peptide YY; Peptides; Radioimmunoassay; Stomach Neoplasms; Vasoactive Intestinal Peptide

7 gastrinomes and 1 gastrin-producer complex carcinoma-carcinoid tumor were examined by light and electron microscopical-method and by immunohistochemical method. In six cases, the tumor was in the pancreas or in the wall of duodenum; in two cases its localisation was of extra-gastroenteropancreatic (liver, lymph node). All patients developed Zollinger-Ellison syndrome, three patients bled and one had diarrhea. One patient had other tumors, besides gastrinome, which were characteristic of MEN-I syndrome. By immunohistochemical methods all tumors proved to be gastrin and neuron-specific-enolase positive. In four cases somatostatin positivity, in some cases glucagon, pancreatic polypeptide, S-100 protein, keratin and carcinoembryonal antigen positivity were detected. Relation could not be detected between other polypeptide hormones, produced besides gastrin, and biological behaviour of tumor and clinical symptoms.

Topics: Carcinoid Tumor; Carcinoma; Duodenal Neoplasms; Gastrins; Humans; Pancreatic Neoplasms; Stomach Neoplasms; Zollinger-Ellison Syndrome

The hypothesis that a gastrin-like peptide is acting as an autocrine growth factor in gastric and colonic carcinoma cell lines requires that the cells should synthesize a gastrin-like mRNA. Although no gastrin mRNA was observed in the gastric line Okajima or the colonic lines HCT 116 or LIM 1215 by Northern blotting, gastrin mRNA was detected by application of the polymerase chain reaction. Two products were observed corresponding to mRNA with and without a 130 bp intron. The sequences of both products were identical to the sequences predicted from the normal human gastrin gene.

Topics: Base Sequence; Blotting, Northern; Cloning, Molecular; Colonic Neoplasms; DNA; DNA Replication; Gastrins; Humans; Molecular Sequence Data; Oligonucleotide Probes; Polymerase Chain Reaction; RNA, Messenger; Stomach Neoplasms; Tumor Cells, Cultured

The effect of oral administration of L-phenylalanine on the incidence and histology of gastric adenocarcinomas induced by N-methyl-N'-nitro-N-nitrosoguanidine was investigated in inbred Wistar rats. Oral administration of 6% phenylalanine after 25 weeks of treatment with the carcinogen significantly reduced the incidence and number of adenocarcinomas of the glandular stomach at experimental week 52. Oral administration of high dose phenylalanine significantly increased the basal serum gastrin level and significantly decreased the norepinephrine concentration in the antral portion of the gastric wall, as well as the labelling indices of antral mucosa. These findings indicate that orally administered phenylalanine inhibits the development of gastric cancers.

Topics: Adenocarcinoma; Administration, Oral; Animals; Gastric Mucosa; Gastrins; Hydrogen-Ion Concentration; Incidence; Male; Methylnitronitrosoguanidine; Norepinephrine; Phenylalanine; Rats; Rats, Inbred Strains; Stomach Neoplasms

The effect of bromocriptine on inhibition by cysteamine of gastric carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine was investigated in inbred Wistar rats. After 25 weeks of p.o. treatment with N-methyl-N'-nitro-N-nitrosoguanidine, rats were given injections every other day: cysteamine (50 mg/kg body weight); cysteamine (50 mg/kg body weight) plus bromocriptine (0.5 or 0.25 mg/kg body weight); or bromocriptine (0.5 or 0.25 mg/kg body weight). In week 52, the group treated with cysteamine showed a significantly decreased incidence of gastric cancers. Concomitant treatment with bromocriptine at 0.5 but not at 0.25 mg/kg body weight significantly attenuated the inhibitory effect of cysteamine on gastric carcinogenesis. Administration of bromocriptine alone at either dosage had no influence on gastric carcinogenesis. The labeling index of the antral mucosa was significantly reduced in rats treated with cysteamine and significantly higher in those treated concomitantly with bromocriptine at 0.5 mg/kg body weight than in those treated with cysteamine alone. These findings indicate that cysteamine suppressed gastric carcinogenesis and that bromocriptine at high dosage attenuated this inhibition. These findings also suggest that dopamine is involved in the mechanism of inhibition of gastric carcinogenesis by cysteamine.

Topics: Animals; Bromocriptine; Cysteamine; Drug Interactions; Gastric Acid; Gastric Mucosa; Gastrins; Male; Methylnitronitrosoguanidine; Mitotic Index; Norepinephrine; Rats; Rats, Inbred Strains; Reference Values; Stomach Neoplasms

Topics: Achlorhydria; Aged; Carcinoid Tumor; Gastrins; Humans; Male; Stomach; Stomach Neoplasms

Long-term administration of some long-acting inhibitors of gastric acid secretion has been associated with the development of gastric enterochromaffin-like (ECL)-cell carcinoids in the rat. It has been argued that short-acting, surmountable histamine H2-receptor blockers such as ranitidine do not cause carcinoids. In this study, female rats (n = 100) were treated for 2 years with the histamine H2-receptor blocker ranitidine, 2 g/kg/day in the diet. Specimens from the stomachs of all rats, including 50 controls, were stained for argyrophil cells. Plasma gastrin and ranitidine levels were measured in separate groups of rats at different times during the study. The mean plasma level of ranitidine was 37.5 mumol/l, measured at midnight when the maximal level after food intake was expected. The resulting acid inhibition was associated with an approximately 3-fold increase in plasma gastrin which persisted throughout the whole period of the study. The ranitidine treatment resulted in a pronounced hyperplasia of gastric ECL cells. In 19 rats carcinoids were found, 4 of which were micro-invasive. No carcinoids were found in the control animals. The results provide further support for the gastrin mechanism, i.e. that the development of ECL-cell carcinoids in the rat gastric mucosa is a consequence of prolonged hypergastrinaemia and is not a unique effect of any individual acid-inhibiting drug.

Topics: Animals; Carcinoid Tumor; Enterochromaffin Cells; Female; Gastric Mucosa; Gastrins; Ranitidine; Rats; Rats, Inbred Strains; Stomach Neoplasms; Time Factors

The effects of 6-hydroxydopamine (6-OHDA) on gastric carcinogenesis, on inhibition by tetragastrin of gastric carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine, and on the tissue catecholamine concentrations of the gastric wall and the labeling index of the gastric mucosa were investigated in inbred Wistar rats. Rats received s.c. injections of tetragastrin (1 mg/kg of body weight every other day) in depot form, i.p. injections of 6-OHDA (42 mg/kg twice within 24 h and 105 mg/kg every 2 wk), or injections of both compounds after 25 wk of p.o. treatment with N-methyl-N'-nitro-N-nitrosoguanidine (100 micrograms/ml). At Wk 52, prolonged administration of tetragastrin or 6-OHDA had significantly reduced the incidence and the number of adenocarcinomas. Combined administration of tetragastrin and 6-OHDA significantly enhanced the inhibitory effects of tetragastrin or 6-OHDA on gastric carcinogenesis. Administration of 6-OHDA but not tetragastrin, caused a significant decrease in norepinephrine concentrations in the antral portion of the gastric wall. Rats treated with tetragastrin or 6-OHDA had a significantly lower labelling index of the antral mucosa, and this index was significantly decreased by combined administration of tetragastrin and 6-OHDA, as compared with labeling indices observed after treatment with tetragastrin or 6-OHDA alone. These findings indicate that 6-OHDA exerts a protective effect against gastric carcinogenesis and enhances the inhibitory effect of tetragastrin on gastric carcinogenesis. This effect of 6-OHDA may be related to its ability to inhibit cell proliferation of the antral mucosa.

Topics: Animals; Catecholamines; Cell Division; Ganglia, Sympathetic; Gastrins; Hydroxydopamines; Male; Methylnitronitrosoguanidine; Organ Size; Oxidopamine; Rats; Rats, Inbred Strains; Stomach Neoplasms; Sympathetic Nervous System; Tetragastrin

Oral administration of ciprofibrate, a potent hypolipidemic compound, to rats for 2 or more weeks at doses of 20 mg/kg/day or more resulted in hypertrophy and increased eosinophilia of the oxyntic cells in the gastric mucosa. Ultrastructural evaluation revealed small secretory canaliculi with small microvilli in these cells, changes consistent with the inhibition of acid secretion. After longer administration (e.g., greater than 2 months at 20 mg/kg/day), hyperplasia of the neuroendocrine cells (in particular, the enterochromaffin-like cells) was present in the fundic mucosa of the stomach. After life-time (2-year) administration at 10 mg/kg/day, neuroendocrine cell hyperplasia was accompanied by formation of malignant carcinoid tumors in the fundus of 5 of 59 male and 1 of 60 female rats. In contrast, administration of ciprofibrate to mice at 20 mg/kg/day for 2 months was not associated with oxyntic or neuroendocrine cell changes, a finding consistent with the lack of gastric carcinoid tumors in a 2-year mouse study. Similarly, no significant changes were induced in the marmoset stomach by doses as high as 100 mg/kg/day for 6 months. These findings are consistent with the hypothesis that the formation of gastric carcinoid tumors following ciprofibrate administration is a phenomenon that occurs specifically in those species such as the rat where this compound has significant gastric antisecretory activity.

Topics: Animals; Callitrichinae; Carcinoid Tumor; Clofibrate; Clofibric Acid; Fibric Acids; Gastric Mucosa; Gastrins; Hypolipidemic Agents; Male; Mice; Microscopy, Electron; Rats; Rats, Inbred F344; Stomach Neoplasms

The effects of nialamide, a monoamine oxidase inhibitor, on the incidence, number, and histology of gastric cancers induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) were investigated in male Wistar rats. Rats were given subcutaneously 50 mg/kg body weight of nialamide in depot form every other day after 25 weeks of oral treatment with MNNG. Prolonged alternate-day administration of nialamide caused a significant increase in the incidence and number of gastric cancers of the glandular stomach in week 52. However, it did not affect the histology of the cancers. Nialamide also caused a significant increase in tissue norepinephrine concentrations in the gastric wall and in the labeling indices of the gastric mucosae. However, nialamide had no influence on serum gastrin levels in the fasting state and after re-feeding. These findings indicate that nialamide promotes gastric carcinogenesis and that this may be related to its effects in increasing norepinephrine in the gastric wall and stimulating proliferation of gastric epithelial cells.

Topics: Adenocarcinoma; Animals; Gastric Fundus; Gastric Mucosa; Gastrins; Male; Methylnitronitrosoguanidine; Nialamide; Norepinephrine; Pyloric Antrum; Rats; Rats, Inbred Strains; Stomach Neoplasms

Three hundred and one gastric cancer patients have been examined preoperatively to investigate their gastric acid secretions after stimulation by tetragastrin, and serum gastrin stimulation by a test meal, as well as for skin reactions and an evaluation of their serum glycoproteins. The results have indicated that their gastric secretions and serum gastrin response were found to be reduced, according to the advancement of their cancer, and that the gastric acid secretion of patients with signet ring cell carcinoma was higher than that of patients with other histological carcinomas. Gastric acid secretions of patients with an ulcerated type of cancer, that is, type IIc and type III in an early cancer stage and type IIc of an advanced Borrmann V type, was higher than in patients with other types, and there were significant correlationships between gastric secretions and PHA skin test and gastric secretions and the IAP and the sialic acid.

Topics: Adenocarcinoma, Mucinous; Adult; Aged; Aged, 80 and over; Female; Gastric Acid; Gastrins; Glycoproteins; Humans; Immunity, Cellular; Male; Middle Aged; Skin Tests; Stomach Neoplasms

Gastric acid secretions and serum gastrin levels have been examined in 128 patients with early gastric cancer and in 98 gastric ulcer patients. Gastric cancer patients were found to have lower acid secretions than did gastric ulcer patients, and those with elevated types of a differentiated adenocarcinoma had lower acid secretions than did those with depressed types of an undifferentiated adenocarcinoma. Gastric acid secretions in patients with both a gastric ulcer and cancer were found to decrease with aging. However, the serum gastrin levels were found to be decreased in patients with a gastric ulcer and to be increased in patients with a gastric cancer. Incidences of a differentiated adenocarcinoma increased with aging. From these observations, it has been speculated that the carcinogenesis of a differentiated adenocarcinoma may be related to increasing endogenous gastrin levels and decreasing gastric acid secretions. These results suggest that a continuous check of the serum gastrin levels might be a good marker for cancer detection and that gastrin antibodies might be useful for treatment.

Topics: Adenocarcinoma; Adenocarcinoma, Mucinous; Adenocarcinoma, Papillary; Adult; Aged; Aging; Biomarkers, Tumor; Female; Gastric Acid; Gastric Mucosa; Gastrins; Humans; Male; Middle Aged; Stomach Neoplasms; Stomach Ulcer

Gastrin and somatostatin-like immunoreactivity (SLI) levels were studied by means of radioimmunoassay in peripheral venous blood of healthy volunteers and patients suffering from gastric adenocarcinoma or duodenal and gastric ulcers. Gastrin and SLI levels were also evaluated in patients in blood drawn from gastric veins during surgery. The elevations of gastrin and SLI levels were found in patients with gastric cancer as compared with healthy people and patients suffering from ulcers. The impairment of the negative feedback between gastrin and somatostatin secretions in patients with gastric cancer was suggested.

Topics: Adenocarcinoma; Adult; Aged; Female; Gastrins; Humans; Male; Middle Aged; Radioimmunoassay; Somatostatin; Stomach Neoplasms; Stomach Ulcer

The effects of somatostatin on the incidence, number, and histological type of gastric cancers induced by N-methyl-N'-nitro-N-nitrosoguanidine were investigated in Wistar rats. Rats received alternate-day s.c. injections of 100 or 200 micrograms/kg body weight of somatostatin in depot form after 25 weeks of p.o. treatment with the carcinogen. Prolonged administration of somatostatin at both dosages significantly increased the incidence and number of gastric cancers of the glandular stomach in Week 52. Furthermore, somatostatin at 200 micrograms/kg caused a significant increase in the incidence of gastric cancers penetrating the muscle layer or deeper layers. However, somatostatin at both dosages did not influence their histological appearance. Histologically, somatostatin at both dosages significantly elevated the labeling index of gastric cancers but not of the antral mucosa and significantly reduced the gastrin levels. These findings indicate that somatostatin enhances gastric carcinogenesis after N-methyl-N'-nitro-N-nitrosoguanidine treatment and that this effect may be related to its effect in increasing proliferation of gastric cancers and decreasing serum gastrin level.

Topics: Animals; Carcinoma; Cell Division; Gastric Mucosa; Gastrins; Hydrogen-Ion Concentration; Male; Methylnitronitrosoguanidine; Neoplasms, Experimental; Rats; Rats, Inbred Strains; Somatostatin; Stomach Neoplasms

Sixty patients with surgically correctable hypergastrinemia were treated between 1960 and 1988. Provocative testing was used when available to select appropriate operations. Sources of hypergastrinemia included antral G cell hyperplasia (AGCH) (17), pancreatic gastrinomas (14), duodenal gastrinomas (11), multiple gastrinomas in patients with type I multiple endocrine neoplasia (MEN I) (five), lymph node gastrinomas (four), and the source not found in nine patients. Eugastrinemia was achieved by resection in 17 of 17 patients with AGCH, nine of 11 patients with duodenal gastrinomas, three of four patients with lymph node gastrinomas, zero of 14 patients with pancreatic gastrinomas, zero of five patients with MEN I, and zero of nine patients in whom the source was not found. Hepatic metastases developed in 11 patients with pancreatic gastrinomas, two patients with MEN I, one patient with duodenal gastrinomas, and one patient with lymph node gastrinomas. One patient in whom the source of the hypergastrinemia was not found developed hepatic metastases, and seven required total gastrectomy. This experience suggests the following: (1) that patients with AGCH, duodenal gastrinomas, or lymph node gastrinomas can usually be rendered eugastrinemic by resection; (2) that patients with pancreatic gastrinomas, whether sporadic or familial (MEN I), are rarely cured by resection and frequently develop hepatic metastases; and (3) that patients in whom the source of the hypergastrinemia is not identified and removed frequently require total gastrectomy, but antroduodenectomy should be considered because it may uncover an occult duodenal microneurogastrinoma or may correct AGCH.

Topics: Biomarkers, Tumor; Duodenal Neoplasms; Eating; Female; Follow-Up Studies; Gastrinoma; Gastrins; Humans; Hyperplasia; Male; Middle Aged; Multiple Endocrine Neoplasia; Pancreatic Neoplasms; Prognosis; Secretin; Stomach; Stomach Neoplasms

Topics: Duodenal Ulcer; Gastrins; Humans; Liver Cirrhosis; Postoperative Period; Prognosis; Stomach Neoplasms

We report a case of gastric enterochromaffin-like carcinoid tumour associated with fundic chronic atrophic gastritis and hypergastrinaemia of antral origin. The clinical and pathological features of this association are reviewed. The probable causal relationship between these argyrophil carcinoids and hypergastrinaemia is also discussed.

Topics: Adult; Carcinoid Tumor; Female; Gastrins; Gastritis; Humans; Stomach Neoplasms

A series of 31 colorectal and 13 gastric primary human tumours were screened for their growth response to human gastrin-17 in vitro, as assessed by 75Se-seleno-methionine incorporation. Fifty-five percent of colorectal and 69% of gastric tumours showed a significant trophic response to the hormone. The responses were achieved at physiological gastrin concentrations (post-prandial circulating gastrin levels) in 35% of colorectal and 55% of gastric tumours. Lymphocytes from tumour-associated lymph nodes showed no response to the hormone and "normal" mucosal cells (obtained from the resection margin of the surgical specimen) showed lower mean levels of 75Se-seleno-methionine uptake (colorectal: 110%; gastric: 119%, expressed as a percentage of the control) when compared to tumours (colorectal: 151%; gastric: 147%). The small number of well differentiated and/or Dukes' stage A colorectal tumours examined were gastrin-responsive, but all the responsive gastric tumours were poorly differentiated. With respect to ploidy, 89% of diploid and 67% of aneuploid colorectal tumours responded trophically to gastrin. Patients with colorectal or gastric tumours may benefit from treatment with gastrin antagonists.

Topics: Animals; Colorectal Neoplasms; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Fibroblasts; Gastric Mucosa; Gastrins; Humans; Lymph Nodes; Lymphocytes; Mice; Ploidies; Selenomethionine; Stomach Neoplasms; Tumor Cells, Cultured

Two colorectal (HT29, LoVo) and one gastric (MKN45) human tumour cell lines were examined for their in vitro trophic response to human gastrin-17. MKN45 and HT29 responded by increased 75Se selenomethionine uptake to exogenous gastrin (139 +/- 5.5% and 123 +/- 3% of control values respectively) whereas LoVo showed no significant response to this hormone. When these same cell lines were grown as xenografts in nude mice, similar responses were seen to exogenously administered human gastrin-17 (10 micrograms mouse-1 day-1, subcutaneous injection). MKN45 xenografts showed a greater response to continuously administered gastrin (osmotic mini-pumps, (10 micrograms mouse-1 day-1) when compared to the same dose given via a subcutaneous bolus injection. The hormone-treated xenografts had a two-fold increase in tumour cross-sectional area and growth rate when compared to saline-treated controls. Dose-response studies revealed that 0.4 micrograms gastrin mouse-1 day-1 appeared to be the minimally effective dose. As gastric and colorectal tumour cells show a trophic response to gastrin, antagonists of the gastrin receptor may prevent this effect causing tumour stasis. The gastric tumour cell line, MKN45, is gastrin-responsive and would be an ideal model for screening potent receptor antagonists.

Topics: Adenocarcinoma; Animals; Cell Division; Cell Line; Colorectal Neoplasms; Gastrins; Hormones; Humans; Mice; Mice, Nude; Neoplasm Transplantation; Stomach Neoplasms; Tumor Cells, Cultured

To assess the functional and morphological characteristics of the gastric mucosa of patients with fundic hyperplastic polyps (FP), the determination of gastric acid secretion, serum gastrin levels, serum pepsinogen 1 (PG1) levels and histological examination were undertaken in 24 patients with FP, 34 with foveolar hyperplastic polyps (HP) and 62 controls, who had no gastric lesions. The following were the results of our investigation. 1) There were no differences between the patients with FP and the controls as to gastric acid secretion, serum gastrin levels, and serum PG1 levels. On the other hand, hypochlorhydria, hypergastrinemia and hypopepsinogenemia were common in those with HP. 2) Histological examination using gastric biopsy specimens showed almost normal gastric mucosa in patients with FP. However, severe atrophic gastritis of the fundus was common in patients with HP. 3) It was shown that there were definite differences between the patients with FP and those with HP with regard to the gastric function and morphology, although both types of gastric polyp were histologically classified as hyperplastic.

Topics: Adolescent; Adult; Female; Gastric Acid; Gastric Fundus; Gastric Mucosa; Gastrins; Humans; Hyperplasia; Male; Middle Aged; Pepsinogens; Polyps; Stomach Neoplasms

Eight patients with stomach cancer are described who had also a striking glandular hyperplasia of the fundic mucosa adjacent and remote from the tumor. Five of the eight patients were young women (30 to 37 years of age). The tumors were poorly differentiated carcinomas and six of the eight patients have died of their disease. None of the patients had clinical evidence of endocrine dysfunction including the Zollinger-Ellison syndrome. Immunohistochemistry revealed cells with endocrine differentiation in five of eight tumors, and in two tumors gastrin producing cells were found. Five of seven patients showed increased numbers of antral G-cells. In two patients numerous endocrine (chromogranin-positive) cells were present in the fundic mucosa, specific products of which could not be identified with the antigens tested. No satisfactory explanation exists for this coincidence and its apparent predominance in young female patients. It may be that endocrine substances are responsible for this fundic hyperplasia and that they may also act as promotors of tumor growth.

Topics: Adult; Carcinoma; Female; Gastric Fundus; Gastric Mucosa; Gastrins; Humans; Hyperplasia; Immunohistochemistry; Male; Middle Aged; Sex Factors; Stomach Neoplasms

The effect of oral administration of cysteamine (2-aminoethanethiol hydrochloride) on the incidence and histology of gastric adenocarcinomas induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) was investigated in inbred Wistar rats. Oral administration of 0.4% cysteamine in food after treatment with MNNG for 25 weeks significantly reduced the incidence and number of adenocarcinomas of the glandular stomach in experimental Week 52. Histological examination showed that adenocarcinomas that did develop in rats fed on cysteamine had high mucin-producing activity. Furthermore, oral administration of cysteamine caused a significant increase in serum gastrin level and significant decreases in the antral mucosal pH and the labeling indices of the antral mucosa. These findings indicate that cysteamine inhibits the development of gastric adenocarcinomas when given orally. This effect may be related to its ability to decrease proliferation of antral mucosal cells.

Topics: Adenocarcinoma; Animals; Cysteamine; Gastric Mucosa; Gastrins; Hydrogen-Ion Concentration; Male; Methylnitronitrosoguanidine; Mitosis; Rats; Rats, Inbred Strains; Stomach Neoplasms

The effects of propranolol and cimetidine on inhibition by cysteamine (2-aminoethanethiol hydrochloride) of gastric carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and on gastric acid secretion, serum gastrin level, and labelling index of the gastric mucosa were investigated in inbred Wistar rats. Rats received alternate-day injections of cysteamine (25 mg/kg body weight) with or without propranolol (dl-propranolol hydrochloride) (2 mg/kg bw) or cimetidine (50 mg/kg bw) in depot form after 25 weeks of oral treatment with MNNG. Prolonged administration of cysteamine significantly reduced the incidence of adenocarcinoma of the glandular stomach. A combination of cysteamine and propranolol significantly accelerated the inhibitory effect of cysteamine on gastric carcinogenesis. However, with concomitant administration of cysteamine and cimetidine, the incidence of adenocarcinoma was slightly but not significantly increased as compared to that after treatment with cysteamine alone. Administration of cysteamine caused a significant increase in gastric acid secretion and serum gastrin level, and a significant decrease in the labelling index of the antral mucosa. A combination of cysteamine and propranolol significantly increased gastric acid secretion by cysteamine alone and significantly decreased the labelling index of the antral mucosa. With this treatment, the serum gastrin level was significantly higher than the basal level, but the stimulated serum gastrin level was significantly lower than observed that after administration of cysteamine alone. In contrast, concomitant administration of cysteamine and cimetidine caused a significant decrease in gastric acid secretion and significant increase in the serum gastrin level as compared to the levels seen after treatment with cysteamine alone, but had no influence on the labelling index of the antral mucosa. These findings indicate that hypersecretion of acid, but not hypergastrinemia associated with hyposecretion of acid or achlorhydria, exerts a protective effect against gastric carcinogenesis, and that this effect may be related to its activity in decreasing proliferation of the antral mucosa.

Topics: Adenocarcinoma; Animals; Cimetidine; Cysteamine; Gastric Acid; Gastric Mucosa; Gastrins; Male; Methylnitronitrosoguanidine; Propranolol; Rats; Rats, Inbred Strains; Stomach Neoplasms

The histamine H2-receptor antagonist SK&F 93479 induced gastric neuroendocrine (carcinoid) ECL-cell tumor formation in 6/34 male and 8/37 female rats treated for 22-24 months at 1,000 mg/kg/day po. Focal ECL-cell hyperplasia was present in 21/34 males and 15/37 females, with local infiltration through the muscularis mucosae in half these cases. No focal hyperplasias or carcinoids were present after 200 mg/kg/day po treatment. Investigative studies showed evidence for marked and sustained hypergastrinemia increasing on chronic dosing which was capable of restoring gastric acid secretion and pH to near control values. Using morphometric analysis of immunoperoxidase anti-chromogranin A stained sections, a dose-related and time-dependent neuroendocrine ECL-cell hyperplasia was correlated with the sustained elevated hypergastrinemia. A 21-month mouse oncogenicity study showed no focal neuroendocrine cell hyperplasia or carcinoid tumor induction, but a diffuse neuroendocrine cell hyperplasia and an increase in multifocal glandular hyperplasia of the oxyntic mucosa was observed in mice treated with 1,000 mg/kg SK&F 93479 po. The morphological changes observed in both rat and mouse were considered to be secondary to the hypergastrinemia resulting from the pharmacological suppression of gastric acid secretion by SK&F 93479. These changes were also observed to a more marked degree following omeprazole treatment and were only slight following oxmetidine treatment in the rat.

Topics: Animals; Carcinogens; Carcinoid Tumor; Enterochromaffin Cells; Female; Gastric Acid; Gastric Mucosa; Gastrins; Histamine H2 Antagonists; Hydrogen-Ion Concentration; Hyperplasia; Imidazoles; Male; Mice; Omeprazole; Pyrimidinones; Rats; Stomach Neoplasms

One hundred patients with gastric carcinoma resected surgically were studied by PAP immunoperoxidase and ultrastructural method. It was found that the tumor cells were positive for gastrin, serotonin, somatostatin as well as argyrophil particles in 19 patients. In these 19 patients, the quantity of endocrine tumor cells surpassed half of its total cancer cells in 4, leading to a separate entity of neuroendocrine gastric carcinoma. The authors hope to introduce this new subtype into the classification of gastric carcinoma. Among the 100 cases, 50 patients with undifferentiated carcinomas contained the NE cells in 16 (32%), the remains for high differentiated adenocarcinomas had the NE cells in 3 (6%) only. It was suggested that the appearance of NE tumor cells was closely correlated to differentiation of gastric carcinoma. This study theoretically demonstrated the heterogenicity of gastric carcinoma and supported the theory that different kinds of tumor cells (endocrine and nonendocrine) may have a common origin and are derived from the endoembryogenetic immature precursor cells.

Topics: Adenocarcinoma; Carcinoma; Gastrins; Humans; Immunohistochemistry; Neurosecretion; Serotonin; Somatostatin; Stomach Neoplasms

Multicentric gastric carcinoids develop infrequently in association with atrophic gastritis, achlorhydria, and hypergastrinemia. These unusual tumors, thought to arise from proliferation of enterochromaffin-like (ECL) cells, have not been shown to secrete any measurable biogenic amines and usually grow slowly. Hypergastrinemia, which results from antral G cell stimulation secondary to atrophic gastritis, is believed to be the trophic stimulus, but alternative explanations include production of gastrin-releasing factor (GRF) or gastrin per se by the tumor. We recently encountered two patients with pentagastrin-resistant achlorhydria and multiple gastric carcinoids. Neither had symptoms of carcinoid syndrome. Urinary 5-hydroxyindoleacetic acid and serum human pancreatic polypeptide, vasoactive intestinal peptide, and motilin values were normal. Fasting gastrin values were nearly 1800 pg/ml. Antrectomy and regional lymphadenectomy was performed in each patient. The tumors were locally invasive with penetration through the submucosa. One patient had regional lymph node involvement, and one had an isolated hepatic metastasis. Immunohistochemical stain tests were positive in both patients for neuron-specific enolase and chromogranin, with focal positive staining for gastrin and serotonin. Serum gastrin levels decreased to less than 25 pg/ml after antrectomy. Evaluation with upper gastrointestinal endoscopy and biopsy examination 4 to 6 months after antrectomy showed complete regression of disease in one patient and residual neoplasm in one patient, despite normal serum gastrin levels. Additional studies with careful long-term follow-up will be needed to determine whether antrectomy eliminates the hypergastrinemia associated with enterochromaffin-like hyperplasia and leads to regression of disease.

Topics: Adult; Carcinoid Tumor; Female; Gastrectomy; Gastrins; Gastroscopy; Humans; Male; Middle Aged; Pyloric Antrum; Stomach; Stomach Neoplasms

The hormone gastrin stimulates acid secretion by gastric parietal cells and acts as a growth factor for the gastric mucosa. Gastrin receptors with dissociation constants of approximately 0.5 nM have been detected on isolated gastric parietal cells, and on some cell lines derived from colon carcinomas. We now report that gastrin is also bound by five cell lines derived from human gastric carcinomas, but that the affinities of these lines for gastrin range from 0.2 to 1.3 microM. Cholecystokinin8 binds to the cell line Okajima with an affinity similar to gastrin17, while shorter gastrin analogues bind with reduced affinity. Binding of gastrin is unaffected by acetylcholine, histamine, or a number of other hormones with the exception of insulin which inhibits binding with an IC50 value of 0.5 microM. The ability to bind gastrin with affinities in the microM range appears to be a property widespread among other tumor cell lines.

Topics: Animals; Binding, Competitive; Cell Line; Dogs; Gastrins; Hormones; Humans; Kinetics; Neoplasms; Parietal Cells, Gastric; Receptors, Cholecystokinin; Stomach Neoplasms

Mastomys is a rodent which has been reported to develop spontaneous antral endocrine tumors with acid hypersecretion and duodenal ulceration. This study documents the establishment of a breeding colony and the characterization of the tumors and their possible secretagogues. Parietal cell secretory characteristics were studied using isolated gastric glands (IGG) of both normal (n = 5) and tumor-bearing animals. Tumors (n = 6) and control gastric tissue samples were examined by light transmission microscopy and immunohistochemistry. Gastrin was measured by radioimmunoassay in both plasma and tissue. IGG were prepared by collagenase dispersion and acid sequestration assessed by [14C]AP accumulation. Secretory mechanisms of this species were identified by establishment of a histamine dose-response curve and use of 8-bromo-cAMP. Receptor and proton pump inhibitions were assessed using cimetidine (10(-5)M) and the H/K ATPase inhibitor omeprazole (10(-5]. Both reduced [14C]AP accumulation significantly (P less than 0.05). 8-Bromo-cAMP and histamine significantly stimulated [14C]AP accumulation (P less than 0.05). Although parietal cells were substantially increased in tumor animals as compared to controls, the physiological parameters of acid secretion appeared normal in both and were comparable to other species which have been studied. Tumors were Grimelius positive and contained diffuse electron-dense granules. Immunohistochemistry was negative for gastrin, bombesin, serotonin, neuron-specific enolase, calcitonin, and pancreatic polypeptide. Tumor histamine-like immunoreactivity was, however, positive. Normal stomach contained 1001 +/- 185 compared to less than 0.5 pmole/g gastrin in tumors. Plasma gastrin was normal in both groups (29 +/- 5) as compared to 26 +/- 8 pmole/liter. This study characterizes a spontaneous gastric endocrine tumor which is associated with apparent parietal cell hyperplasia and reports of increased acid secretion and duodenal ulceration. The observations are consistent with the elaboration by the tumor of a nongastrin acid-trophic secretagogue.

Topics: Aminopyrine; Animals; Breeding; Carbon Radioisotopes; Endocrine System Diseases; Female; Gastric Acid; Gastric Mucosa; Gastrins; Immunohistochemistry; Male; Microscopy, Electron; Muridae; Stomach Neoplasms

The effects of combined administration of cimetidine and tetragastrin on gastric acid secretion, the labeling index of the gastric mucosa, and the incidence of gastric adenocarcinomas induced by N-methyl-N'-nitro-N-nitrosoguanidine were investigated in inbred Wistar rats. Prolonged administration of tetragastrin in depot form after treatment with N-methyl-N'-nitro-N-nitrosoguanidine resulted in a significant increase in gastric acid secretion, a significant decrease in the labeling index of the antral mucosa, and a significant decrease in the incidence of adenocarcinomas of the glandular stomach. Administration of cimetidine at 20 mg, but not 10 mg, per kg body weight with tetragastrin significantly reduced the gastric acid secretion induced by tetragastrin alone but did not influence the labeling index of the antral mucosa or the inhibitory effect of tetragastrin on gastric carcinogenesis. These findings indicate that gastric acid secretion has no influence on the development of gastric adenocarcinomas and that the inhibitory effect of tetragastrin on gastric carcinogenesis may be related to its effect in decreasing proliferation of cells in the antral mucosa.

Topics: Adenocarcinoma; Animals; Cimetidine; DNA; Gastric Acid; Gastric Mucosa; Gastrins; Hyperplasia; Male; Methylnitronitrosoguanidine; Rats; Rats, Inbred Strains; Stomach Neoplasms; Tetragastrin

Mucosal atrophy of the gastric antrum (type B atrophic gastritis) is generally accepted as predisposing to the development of the intestinal type of gastric cancer. Since bombesin stimulates gastrin release selectively from the antral mucosa, the response can be used as a marker for antral mucosal atrophy. In this study we have investigated bombesin-stimulated plasma gastrin responses in 21 patients with the intestinal type of gastric cancer and we have compared the results with 12 patients with the diffuse type of gastric cancer, 17 patients with benign gastric ulcer, and 30 dyspeptic patients without endoscopical or histological abnormalities. Gastrin concentrations were also measured in extracts of antral biopsies. Basal plasma gastrin concentrations were not significantly different. In contrast, patients with the intestinal type of gastric cancer had a significantly lower plasma gastrin response to bombesin than did the normal subjects (P less than 0.01) and patients with the diffuse type of gastric cancer (P less than 0.05), but the result was not significantly different from that of the gastric ulcer patients. The antral gastrin content of the patients with the intestinal type of gastric cancer was significantly lower than in controls (P less than 0.005), the patients with the diffuse type of gastric cancer (P less than 0.05), and those with gastric ulcer (P less than 0.05). It is concluded that patients with the intestinal type of gastric cancer have, in contrast to those with the diffuse type of gastric cancer, an abnormally low plasma gastrin response to bombesin. This low response is due to a reduced gastrin content of the antral mucosa.

Topics: Aged; Aged, 80 and over; Bombesin; Female; Gastric Mucosa; Gastrins; Humans; Male; Metaplasia; Middle Aged; Pyloric Antrum; Stomach Neoplasms

The effect of ad libitum feeding of a defined diet in liquid form on the incidence of gastric adenocarcinomas induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) was investigated in Wistar rats. Fresh defined diet was supplied once every 24 h from 2 weeks before oral administration of MNNG to the end of the experiment in week 52. Oral administration of the defined diet resulted in significant decrease in the incidence of gastric cancers in experimental week 52. It also caused a significant increase in the incidence of atypical glandular hyperplasia, which is a precursor of gastric cancer. Furthermore, administration of the defined diet for 30 and 52 weeks also resulted in significant decrease in the serum gastrin level and the marked gastric mucosal hypoplasia. These findings indicate that the defined diet in liquid form inhibited the development of gastric cancers and that this effect may have been related to its effect in decreasing proliferation of cells in the antral mucosa.

Topics: Animals; Food, Formulated; Gastric Mucosa; Gastrins; Male; Methylnitronitrosoguanidine; Rats; Rats, Inbred Strains; Stomach Neoplasms

Among 196 patients examined in 1972-1985 because of pernicious anemia (PA), 105 patients under the age of 76 years were invited for gastroscopic screening, and 71 patients (68%) participated. Gastroscopy revealed carcinoid tumor(s) in 5 patients (7%) but no case of carcinoma. In addition, one patient with gastric carcinoid, 5 patients with adenocarcinomas and one with a concomitant carcinoid and carcinoma had already been diagnosed earlier in the overall PA group on the basis of clinical symptoms. Thus, within a follow-up of 0-20 years (mean 7 years) the total frequency of gastric carcinoid tumors was 4% and that of carcinoma 3%. Patients with carcinoid tumors had a long duration of PA and young age of onset; these cases were not necessarily those with the highest serum gastrin levels. Even though most gastric carcinoids are small subclinical tumors of uncertain clinical significance, their unexpectedly high frequency, combined within the risk of carcinoma in PA, might indicate the need for gastroscopic follow-up, at least in cases of juvenile onset PA.

Topics: Adult; Aged; Anemia, Pernicious; Carcinoid Tumor; Female; Gastrins; Gastroscopy; Humans; Male; Middle Aged; Stomach Neoplasms

Topics: Adult; Aged; Female; Gastrins; Humans; Male; Middle Aged; Pyloric Antrum; Stomach Neoplasms

After administration of N-methyl-N'-nitro-N-nitrosoguanidine for 15 weeks, the effects of bilateral, anterior and posterior vagotomy on the incidence, number and location of gastric adenocarcinomas, gastric acid secretion and cell proliferation of the gastric mucosa were investigated in inbred Wistar rats. Bilateral or anterior vagotomy, but not posterior vagotomy, significantly increased the incidence and number of adenocarcinomas at experimental week 52. In sham-operated control rats and rats subjected to bilateral vagotomy, there was no significant difference between the incidence or number of gastric tumors in the anterior and posterior walls. After anterior and posterior vagal denervation, however, there were significantly more gastric cancers on the denervated side than on the other. Bilateral and unilateral vagotomy resulted in significantly reduced gastric acid secretion by experimental weeks 25 and 52. Bilateral vagotomy significantly increased the labelling indices of both the fundic and antral mucosa at both times, but did not cause any significant difference between those of the anterior and posterior wall. Anterior or posterior vagotomy resulted in a significant increase in the labelling indices of both the fundic and antral mucosa on the denervated side. These findings indicate that the vagal nerve exerts a trophic action on the gastric mucosa, and that the promoting effect of vagotomy on gastric carcinogenesis may be related to its effect in increasing proliferation of cells in the antral mucosa.

Topics: Animals; Gastric Acid; Gastric Mucosa; Gastrins; Hyperplasia; Male; Methylnitronitrosoguanidine; Rats; Rats, Inbred Strains; Stomach Neoplasms; Vagotomy

Topics: Achlorhydria; Antacids; Carcinoid Tumor; Enterochromaffin Cells; Gastrins; Gastritis, Atrophic; Histamine H2 Antagonists; Humans; Hyperplasia; Peptic Ulcer; Risk; Somatostatin; Stomach Neoplasms; Vagotomy, Proximal Gastric

The heterogeneity of gastrin-containing G cells present in human gastric mucosa has been examined immunohistochemically. Calcitonin gene-related peptide (CGRP), calcitonin and human chorionic gonadotropin (hCG)-immunoreactivity were detected in about 500, 20 and 10 cells pro 1,000 G cells, respectively, these findings supporting the "one cell, multi-hormone theory". Gastrin, calcitonin immunoreactive tumor cells were demonstrated in 13%, 3% of the antral adenocarcinomas and 17% and 10% of antral endocrine tumors, but they were not found in fundic adenocarcinomas and endocrine tumors. Cell hybridization between the tumor cell and the G-cell might be a possible mechanism for the occurrence of gastric and calcitonin in the gastric tumors. HCG-immunoreactive tumor cells were detected in 27% of antral adenocarcinomas, and in 24% of the fundic adenocarcinomas, and the production of hCG by gastric tumor cells might be based on the gene expression during carcinogenesis, regardless of the tumor localization.

Topics: Adenocarcinoma; Calcitonin; Calcitonin Gene-Related Peptide; Carcinoma; Chorionic Gonadotropin; Duodenal Ulcer; Gastric Mucosa; Gastrins; Humans; Immunochemistry; Neuropeptides; Pyloric Antrum; Stomach Neoplasms

The prevalence of gastric carcinoid in fundic atrophic gastritis is probably greater than previously recognized. To help elucidate the clinicopathology of this syndrome, we report a series of 11 patients with solitary or multicentric carcinoid tumors. In these patients, basal gastrin levels and density of fundic mucosal endocrine cells were greater than that for patients with uncomplicated fundic atrophic gastritis (p = 0.02 and p = 0.002, respectively). The polypoid tumors, of which the largest measured 30 mm, frequently showed characteristic endoscopic features. They were all situated in the fundic mucosa, which showed micronodular endocrine cell hyperplasia. Small, endoscopically evident tumorlets, or "early carcinoids," limited to the lamina propria were observed in some patients. These lesions may represent intermediate stages between micronodules and invasive carcinoids, all of which infiltrated at least into the muscularis mucosae of the gastric wall. Although some consistent characteristics features were noted, there were structural variations. The cells were argyrophil but nonargentaffin and did not stain with conventional mucus stains. They did not stain significantly for carcinoembryonic antigen (CEA). The secretory product of these tumors remains to be identified. Ultrastructurally, some tumors were mainly composed of enterochromaffinlike (ECL) cells, but in other tumors most of the cells could not be classified.

Topics: Carcinoid Tumor; Endoscopy; Gastrins; Gastritis; Gastritis, Atrophic; Humans; Microscopy, Electron; Prospective Studies; Stomach Neoplasms; Syndrome

Low gastric acid output leads to hypergastrinaemia, which results in the stimulation of dormant enterochromaffin-like cells in the gastric mucosa; these can progress to carcinoid tumours. A patient is described with this syndrome. Reduction in gastrin levels by antrectomy resulted in regression of the carcinoids.

Topics: Anemia, Pernicious; Carcinoid Tumor; Female; Gastrins; Humans; Middle Aged; Postoperative Period; Pyloric Antrum; Stomach Neoplasms

Topics: Achlorhydria; Animals; Carcinoid Tumor; Cell Division; Enterochromaffin Cells; Gastric Mucosa; Gastrins; Humans; Stomach Neoplasms

The effects of combined administration of propranolol and tetragastrin on gastric acid secretion and the incidence and histological types of gastric adenocarcinomas induced by N-methyl-N'-nitro-N-nitrosoguanidine were investigated in inbred Wistar rats. Prolonged administration of tetragastrin, 1 but not 0.2 mg/kg body weight in depot form after treatment with N-methyl-N'-nitro-N-nitrosoguanidine significantly reduced the incidence of adenocarcinoma of the glandular stomach. The adenocarcinomas that did develop in rats treated with the higher dose of tetragastrin had high mucin-producing activity and showed little or no typical glandular structure. A combination of propranolol (2 mg/kg) and tetragastrin (1 mg/kg) did not influence the inhibitory effect of gastrin on gastric carcinogenesis. However, concomitant administration of propranolol (2 mg/kg) and tetragastrin (0.2 mg/kg) caused a significant increase in gastric acid secretion and a reduction in the incidence of gastric carcinomas. With this treatment, the incidence of adenocarcinoma was similar to that of treatment with tetragastrin (1 mg/kg). Histological examinations showed that like the cancers in control rats, the adenocarcinomas induced in these rats were all highly differentiated.

Topics: Adenocarcinoma; Animals; Drug Synergism; Gastric Acid; Gastric Mucosa; Gastrins; Hyperplasia; Male; Methylnitronitrosoguanidine; Propranolol; Rats; Rats, Inbred Strains; Stomach Neoplasms; Tetragastrin

Gastric mucosal pepsinogen A phenotype, serum pepsinogen A level, serum pepsinogen C level, serum pepsinogen A/pepsinogen C ratio, and serum gastrin level were evaluated as potential markers for gastric cancer or its precursors in 19 healthy volunteers and 341 patients from the gastroscopy program. Gastric cancer, atrophic gastritis, and intestinal metaplasia of the stomach were associated with pepsinogen A phenotypes, characterized by an intense fraction 5, and with a low serum pepsinogen A level (less than 25 micrograms/l), a low serum pepsinogen A/pepsinogen C ratio (less than 1.5), and a high serum gastrin level (greater than 79 ng/l). The specificity of pepsinogen A phenotypes with an intense fraction 5 for gastric cancer or its precursors was 95.1% with a sensitivity of 20.4%. The sensitivity and specificity of the noninvasive tests were evaluated with the receiver operating characteristic. For clinical purposes, a serum pepsinogen A/pepsinogen C ratio less than 1.8 is the most suitable test, with a sensitivity of 74% and a specificity of 76% for gastric cancer or its precursors, with a reference population of patients with benign gastric disorders. However, the sensitivity and specificity of the single or combined tests are too low for population screening purposes.

Topics: Adult; Aged; Gastrins; Gastritis, Atrophic; Humans; Intestines; Isoenzymes; Metaplasia; Middle Aged; Pepsinogens; Phenotype; Stomach Neoplasms

Twenty-one specimens of heterotopic pancreas were investigated using the indirect immunoperoxidase method for insulin, somatostatin, glucagon, pancreatic polypeptide (PP) and gastrin. Ten specimens showed ducts, acini and islets, seven showed ducts and acini, and four showed a ductal component alone. Pyloric gland-like mucous glands were occasionally identified in association with the ductal component. In eight of ten lesions containing islets, the islets were round and had a clearly defined outline with many glucagon cells and either none or a modest number of PP cells (dorsal type). In the remaining two lesions, the islets showed varying sizes and irregular outline with many PP cells and a few or no glucagon cells (ventral type). In either type of islets, insulin and somatostatin were detected, but gastrin cells were absent. Some isolated endocrine cells were also present among the acinar and ductal components. Their occurrence in ducts was more frequent in lesions or areas mainly composed of the ductal component than in those with less prominent ductal tissue. In eight lesions a few gastrin cells were found in the ductal component which showed goblet cell metaplasia and pyloric gland metaplasia. An intimate relationship between goblet cell metaplasia and appearance of G cells is noteworthy.

Topics: Adolescent; Adult; Aged; Choristoma; Duodenal Neoplasms; Endocrine Glands; Female; Gastrins; Glucagon; Histocytochemistry; Humans; Ileal Neoplasms; Immunoenzyme Techniques; Infant, Newborn; Insulin; Jejunal Neoplasms; Male; Middle Aged; Pancreas; Pancreatic Polypeptide; Somatostatin; Staining and Labeling; Stomach Neoplasms

This study evaluated the dose-related trophic effects of glutamine, gastrin, and somatostatin on the in vitro growth of human gastric cancer cells and normal human gastric mucosal cells. Quadruplicate cell cultures were seeded into growth medium with or without glutamine, gastrin, or somatostatin. After 72 hours' incubation, cells were counted and their numbers compared with those of controls. Glutamine and gastrin stimulated the growth of both normal and malignant gastric mucosal cells. Compared with normal cells, the malignant cells responded to these growth factors at lower concentrations. Somatostatin enhanced growth of gastric cancer cells at all concentrations and inhibited growth of normal cells at high concentrations. Further studies on the responsiveness of gastric adenocarcinoma to gastrointestinal tract hormones may elucidate mechanisms of oncogenesis and suggest new therapeutic avenues for patients with gastric cancer.

Topics: Adenocarcinoma; Cells, Cultured; Dose-Response Relationship, Drug; Drug Evaluation; Gastric Mucosa; Gastrins; Glutamine; Humans; In Vitro Techniques; Somatostatin; Stomach Neoplasms

Gut endocrine cells in a total of 18 gastric adenocarcinomas in inbred Wistar rats induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and gastrin or serotonin, were examined histologically, ultrastructurally, and immunohistochemically for gastrin, somatostatin, calcitonin, glicentin, and serotonin. A large number of argyrophil cells were observed in 17 tumors (94.4%) and 14 tumors (77.8%) had argentaffin cells. Immunohistochemically, C-terminal fragment of gastrin (G17) immunoreactivity was observed in 15 (82.2%) out of the 18 tumors, but 3 G17-positive tumors had no G 34 immunoreactive cells in rats treated with MNNG plus gastrin. Serotonin immunoreactivity was detected in 14 tumors (77.8%). Somatostatin immunoreactivity was detected in 7 of the 11 tumors (63.6%) in rats treated with MNNG plus gastrin whereas no tumor in rats treated with MNNG plus serotonin had somatostatin, the difference of the incidence being significant (P less than 0.05). One endocrine cell carcinoma which consisted mainly of serotonin-producing cells was observed in a rat treated with MNNG plus serotonin. Calcitonin and glicentin immunoreactivity was not demonstrated in any tumors. Ultrastructurally, three types of endocrine granule were found in the tumor cells. These data suggest that hormonal environment in stomach carcinogenesis may influence the expression of endocrine cells within the tumors.

Topics: Adenocarcinoma; Animals; Calcitonin; Chromaffin System; Enterochromaffin Cells; Female; Gastrins; Glucagon; Histocytochemistry; Male; Methylnitronitrosoguanidine; Microscopy, Electron; Proglucagon; Protein Precursors; Rats; Serotonin; Somatostatin; Stomach Neoplasms; Time Factors

Topics: Achlorhydria; Gastrins; Humans; Somatostatin; Stomach Neoplasms

The localization of immunoreactive calcitonin (IR-CT) in the human gastric mucosa and tumor tissues was studied using an immunohistochemical peroxidase-antiperoxidase method. A small number of IR-CT-containing cells were observed in both infant and adult gastric antral mucosa and the ratio of IR-CT-containing cells to G cells was about 1:50-100. Moreover, tissue content of IR-CT in normal antral mucosa was 2.37 +/- 0.35 ng/g wet weight. IR-CT-containing cells and G cells decreased with the progress of chronic atrophic gastritis and were totally absent in intestinal metaplastic glands. IR-CT was detected in G cells, suggesting a paracrine relation between gastrin and CT. IR-CT was not found in tumor cells of 35 gastric adenomas and 40 well differentiated adenocarcinomas. On the other hand, it was demonstrated in a very small number of tumor cells in 4 of 46 poorly differentiated adenocarcinomas, and in a good number in 3 of 7 scirrhous argyrophil cell carcinomas. IR-CT in plasma could serve, therefore, as a tumor marker of scirrhous endocrine cell carcinoma, and its production in cancer cells was considered to be eutopic rather than ectopic.

Topics: Adenocarcinoma, Scirrhous; Adenoma; Adult; Aged; Calcitonin; Female; Gastric Mucosa; Gastrins; Humans; Immunoenzyme Techniques; Infant; Male; Microscopy, Electron; Middle Aged; Peptic Ulcer; Pregnancy; Stomach Neoplasms; Tissue Distribution

Blood enzymatic activities in gastric carcinoma depend on the release from carcinomatous tissues, surrounding non-neoplastic tissues, increased permeability and necrosis of carcinomatous tissues. However, those enzymatic activities did not parallel the extent and macroscopic appearance of the tumor. Various enzyme proteins and gastrointestinal hormones concerning gastric carcinoma and intestinal metaplasia including pepsin, LDH, AFP, beta-glucuronidase, rGTP, lysozyme, ferritin, sialic acid, polyamine, CEA, Ca 19-9, collage, gastrin, immunoglobulin are discussed in this paper. The variation of enzymes and proteins occurring in gastric carcinoma and intestinal metaplasia are well documented. Some of them would be a useful indicator of diagnosis and treatment as a tumor marker.

Topics: Alkaline Phosphatase; Antigens, Neoplasm; Antigens, Tumor-Associated, Carbohydrate; Carcinoembryonic Antigen; Collagen; Gastric Mucosa; Gastrins; Glucuronidase; Humans; Immunoglobulins; L-Lactate Dehydrogenase; Metaplasia; Pepsin A; Stomach Neoplasms

Tumours of the glandular stomach and upper small intestine were induced in rats by oral administration of MNNG. In most cases the lesions were identified histologically as adenocarcinomas and their prestages, such as polypeous and downward growing adenomatous hyperplasias. Out of 48 adenomatous hyperplasias and adenocarcinomas of the stomach and 24 well differentiated adenocarcinomas of the small intestine, we observed argyrophilic cells in nearly the half of the cases. Endocrine cells were also identified by electron microscopy. The frequency of endocrine cells was reduced with decreasing degree of tissue differentiation. In poorly differentiated carcinomas, including signet ring cell carcinomas, no argyrophilic cells were found. Out of 10 adenomatous hyperplasias and tumours of the stomach investigated immunohistochemically, 5 cases showed gastrin producing cells. Most of these animals were radioimmunologically characterized by strongly elevated serum gastrin levels. Derivation and potential relevance of the endocrine cells in tumours are discussed.

Topics: Adenocarcinoma; Administration, Oral; Animals; Duodenal Neoplasms; Endocrine Glands; Fluorescent Antibody Technique; Gastrins; Histocytochemistry; Male; Methylnitronitrosoguanidine; Microscopy, Electron; Precancerous Conditions; Rats; Rats, Inbred Strains; Stomach; Stomach Neoplasms

The effects of tetragastrin and histamine on the incidence and histology of tumors induced in the small intestine by N-methyl-N'-nitro-N-nitrosoguanidine [(MNNG) CAS: 70-25-7] were investigated in male W rats. Animals were given MNNG at 150 micrograms/ml in their drinking water for 25 weeks and then 300 micrograms tetragastrin or 4 mg histamine dihydrochloride sc per day in depot form. Administration of tetragastrin or histamine after MNNG treatment resulted in a significant increase in gastric acid secretion and a significant reduction in the incidence of tumors in the duodenum; however, only histamine decreased the incidence of tumors in the jejunum. Histologically, the tumors induced in the small intestine were mostly adenocarcinomas, and their histologic type was not affected by either tetragastrin or histamine.

Topics: Adenocarcinoma; Animals; Drug Antagonism; Duodenum; Gastric Acidity Determination; Gastrins; Histamine; Intestinal Neoplasms; Jejunum; Male; Methylnitronitrosoguanidine; Rats; Stomach Neoplasms; Tetragastrin

Omeprazole is a long acting inhibitor of gastric acid secretion in different species including rat and dog. Due to the long duration of action, steady state inhibition at repeated once daily administration is reaches within 4-5 days in dogs and in about 3 days in rats. Daily dosing at high dose levels results in virtually complete 24-hour inhibition of acid secretion in experimental animals. The elimination of the inhibitory feedback effect of acid on gastrin secretion leads to hypergastrinaemia. Because gastrin has a trophic effect on the oxyntic mucosa, the hypergastrinaemia results in a reversible hypertrophy of the oxyntic mucosa and an increased capacity to produce acid following maximal stimulation with exogenous secretagogues after discontinuing treatment. Despite the increased capacity to produce acid, basal acid secretion seems to be unchanged. The pronounced hypergastrinaemia which occurs during long-term treatment with high doses rapidly normalizes after discontinuing treatment. The hyperplasia of the oxyntic endocrine ECL cells, and the eventual development of gastric ECL cell carcinoids after lifelong treatment of rats with high doses, can also be attributed to the hypergastrinaemia developing after almost complete elimination of gastric acid secretion in these animals.

Topics: Animals; Anti-Ulcer Agents; Benzimidazoles; Carcinoid Tumor; Dogs; Female; Gastric Acid; Gastric Mucosa; Gastrins; Hypertrophy; Male; Omeprazole; Rats; Stomach Neoplasms; Time Factors

Gastrin is a trophic stimulant of the acid producing gastric mucosa. Experiments have been carried out in rats, in which chronic states of either low or high serum gastrin levels were induced by surgical manipulation or drug treatment. A relationship between circulating gastrin and a trophic effect could be demonstrated in the oxyntic mucosa, but not in the pancreas and small intestine. Endocrine cells in the oxyntic mucosa (the ECL cells and A-like cells) are among the target cells for the trophic action of gastrin. The functional significance of these two cell populations is unknown. There is much experimental evidence indicating that they are under functional as well as tropic control of gastrin. The vagus nerve also exerts trophic control on the oxyntic mucosa, including the endocrine cells within it. This could be demonstrated by one-sided truncal vagotomy which caused atrophy of the mucosa and hypoplasia of endocrine cells (notably the ECL cells) on the denervated side of the stomach. Conversely, portacaval shunt greatly increased the number of ECL cells. There was no hypergastrinaemia after portacaval shunt, and no trophic effect on other cell types in the oxyntic mucosa. The factors responsible for the ECL cell proliferation after portacaval shunting remain unknown. Tumours may arise spontaneously from the ECL cells. Such neoplasias have been described in Mastomys (Praomys natalensis) and in man. ECL cell hyperplasia and neoplasia in man, but not in Mastomys, are usually associated with hypergastrinaemia either as a result of a gastrin producing tumour or as a result of achylia (sometimes associated with pernicious anaemia). It is unlikely that gastrin alone is responsible for the neoplasia, though it is quite likely that long-standing hypergastrinaemia triggers or facilitates a sequence of events that ultimately leads to tumour formation, via diffuse ECL cell hyperplasia.

Topics: Animals; Atrophy; Carcinoid Tumor; Gastric Mucosa; Gastrins; Humans; Hyperplasia; Parietal Cells, Gastric; Portacaval Shunt, Surgical; Stomach Neoplasms; Vagus Nerve

In an attempt to elucidate histogenesis of stomach cancer, quantitative analysis and measurement of DNA contents of various atypical lesions were sequentially made in the process of gastric carcinogenesis of Wistar strain of rats. Along with this, the effect of vagotomy on the development of atypical or neoplastic lesions were studied. A variety of focal lesions in the glandular stomach were seen in the middle or 4 and 12 weeks after the oral administration of N-methyl-N'-nitrosoguanidine (MNNG, 83 mg/l in drinking water) for 25 weeks. Both upward and downward growth was found in the intramucosal atypical lesions as well as frank carcinoma; the former lesions were histologically classified into 3 (Type I--Type III). On the basis of DNA distribution pattern, Type III lesions were considered to be intramucosal carcinoma and Type II to include precancerous state in some instances. In a group of rats vagotomized 1 week prior to the start of MNNG administration, there were significantly more lesions than in a group of MNNG alone. In contrast to the latter group which developed lesions in an uniform distribution pattern along the lesser curvature in the pyloric region, lesions in the former were characterized by random distribution pattern.

Topics: Adenocarcinoma; Animals; Body Weight; DNA, Neoplasm; Gastric Mucosa; Gastrins; Male; Methylnitronitrosoguanidine; Rats; Rats, Inbred Strains; Stomach Neoplasms; Vagotomy

Nonantral gastric carcinoid tumours in association with pronounced hypergastrinaemia are reported in 6 patients. It is suggested that the hypergastrinaemia, as a result of lack of a negative acid feedback inhibition in an achlorhydric stomach, promoted the tumour development, possibly initiated by action of carcinogenic nitrosamines, in the gastric juice.

Topics: Adult; Aged; Carcinoid Tumor; Female; Gastric Mucosa; Gastrins; Humans; Middle Aged; Stomach Neoplasms

Topics: Gastrins; Humans; Neoplasm Recurrence, Local; Polyps; Prognosis; Stomach Neoplasms

The purpose of this experiment was to determine whether chronic gastric ulcers in the rat are predisposed to tumor formation when exposed to a usually noncarcinogenic dose of the carcinogen, N-Methyl-N'-nitro-N-nitrosoguanidine (MNNG). Two groups of rats were prepared; one subjected to a standard ulcer-producing operation, the other as control. Both groups were given oral MNNG (100 mg/liter as drinking water) for 12 weeks, the carcinogen was then stopped and replaced with tap water, and the experiment terminated at 52 weeks. Results showed that a low dose of carcinogen (200 mg) did not induce tumor formation in any of the normal rats. In the presence of a chronic gastric ulcer, only intestinal metaplasia and hyperplastic glandular nodules were observed, but there were no gastric tumors. It is concluded that the presence of a chronic gastric ulcer did not increase the likelihood of gastric tumor formation in rats treated with a noncarcinogenic dose of the carcinogen MNNG.

Topics: Animals; Carcinogens; Female; Gastric Acid; Gastrins; Liver; Methylnitronitrosoguanidine; Rats; Rats, Inbred Strains; Stomach; Stomach Neoplasms; Stomach Ulcer

Small intramucosal tumours in the oxyntic area of the rat stomach were observed in an oncogenicity study with omeprazole. The tumours could be defined as carcinoids of enterochromaffin-like (ECL) cell origin. ECL cells occur exclusively in oxyntic mucosa and respond to the trophic hormone gastrin with a proliferation that becomes exaggerated in old rats. Inhibition of gastric acid secretion is known to induce hypergastrinaemia in rats. According to the common concept of endocrine cells, a sustained hormonal stimulation with gastrin may induce a continuous gradient between hyperplasia and neoplasia of the ECL cells. The tumours found are thus to be regarded as hormone-induced endocrine tumours of the ECL cells in the stomach. The ECL-cell tumours of the rats in the oncogenicity study appeared to belong to the low-malignancy type of carcinoids and did not make their appearance until the end-life period of the study. The sex and species differences observed may be explained by inherent differences in gastrin response, spontaneous ECL cell density or in responsiveness to gastrin-stimulated ECL cell proliferation between sexes and species.

Topics: Animals; Carcinoid Tumor; Chromaffin System; Enterochromaffin Cells; Female; Gastric Mucosa; Gastrins; Male; Mice; Microscopy, Electron; Omeprazole; Rats; Rats, Inbred Strains; Sex Characteristics; Species Specificity; Stomach Neoplasms

Topics: Gastric Mucosa; Gastrins; Humans; Polyps; Stomach Neoplasms

Topics: Gastric Acid; Gastric Mucosa; Gastrins; Humans; Muscle, Smooth; Peptic Ulcer; Receptors, Cell Surface; Receptors, Cholecystokinin; Stomach Neoplasms

Multiple polypoidal carcinoid tumours of the stomach were found in 5 patients with achlorhydria (4 of whom had pernicious anaemia) as a result of autoimmune atrophic gastritis. The tumours were small (nearly all less than 1 cm diameter) and appeared to grow very slowly, if at all; no significant enlargement or complications were seen during periods of observation of up to 6 years. No extragastric hormonal syndromes were identified. They differed from the carcinoid tumours usually found in the intestinal tract by being composed of argyrophil (not argentaffin) cells of the enterochromaffin-like (ECL) type. Fasting plasma levels of gastrin, which is believed to be trophic to ECL cells, were very high in all patients. Thus, chronic hyperplasia of gastric ECL cells (as a result of hypergastrinaemia) may have been responsible for development of the tumours. Long-term, uninterrupted achlorhydria produced by potent inhibitors of gastric acid secretion might therefore predispose to carcinoid tumours of the stomach.

Topics: Achlorhydria; Aged; Anemia, Pernicious; Carcinoid Tumor; Female; Gastrins; Humans; Male; Middle Aged; Neoplasms, Multiple Primary; Stomach Neoplasms

The effect of hydrochlorhydria caused by vagotomy on carcinogenesis in the glandular stomach of male rats was studied. Group A (35 rats): After N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) 80 mg/l solution was orally administered during the first 15 weeks of life, vagotomy was performed. Group B (35 rats): After the oral administration of MNNG 80 mg/l solution during the first 15 weeks of life, laparotomy was done. Group C (10 rats): As the control, vagotomy was undertaken at the 15th week of life. Group D (10 rats): As the control, laparotomy was done at the same time. At the 52nd week, all surviving rats were autopsied, and gastrin cell counts and body weight were ascertained. The incidence of adenocarcinoma was 62% in Group A, 32% in Group B (p less than 0.05) and nil in Group C and D. These results strongly support the view that the hypochlorhydria plays the role of a promoting factor in producing gastric carcinoma.

Topics: Adenocarcinoma; Animals; Gastric Acidity Determination; Gastrins; Histamine H2 Antagonists; Male; Methylnitronitrosoguanidine; Rats; Rats, Inbred Strains; Stomach Neoplasms; Vagotomy

Synthetic human gastrin 17-I (MG) and an analogue, [Leu15]gastrin-17-I (LG), were radiolabeled with Na125I by Iodo-Gen, EnzymoBead, and chloramine-T methods, and the characteristics of the radiolabeled peptides were determined. When 125I-MG was iodinated by chloramine-T, its biological activity and its binding activity were almost abolished, whereas the biological activity of 125I-LG, iodinated by either of the methods, and of 125I-MG, iodinated by Iodo-Gen and EnzymoBeads, was not significantly affected. The kinetics, affinity, and specificity of binding of 125I-MG, iodinated by Iodo-Gen, to crude and purified membranes from rat fundic mucosa were examined and found to be similar to that for 125I-LG. Age-associated changes in the number and affinity of gastrin receptors (GR) on the crude membranes of gastrointestinal mucosa of rats was also examined. Significantly fewer GR were observed on the crude membranes of fundic mucosa of aged (24 mo old) compared with young (3- and 6-mo-old) rats. In addition, specific gastrin-binding sites (4.7 +/- 0.9 fmol/mg prot) with low affinity (Kd = 3.7 +/- 1.2 nM) were observed in the antrum of aged rats, the significance of which is not understood. There were, however, no differences in the number and characteristics of GR in other regions of the intestine of old and young rats. The presence of GR was additionally assessed in cell lines of gastrointestinal cancers from humans, mice, and hamsters.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Age Factors; Animals; Cell Line; Cell Membrane; Colonic Neoplasms; Cricetinae; Dogs; Dose-Response Relationship, Drug; Gastric Fundus; Gastric Mucosa; Gastrins; Gastrointestinal Neoplasms; Humans; Intestinal Mucosa; Kinetics; Male; Mice; Rats; Rats, Inbred Strains; Receptors, Cell Surface; Receptors, Cholecystokinin; Stomach Neoplasms

A human gastric carcinoma cell line TMK-1 was established in vitro by the soft agar method from SC-6-JCK, a poorly differentiated adenocarcinoma xenotransplanted in nude mice. TMK-1 cells had a doubling time of approximately 35 hr and showed carcinoembryonic antigen (CEA), alpha 1-antitrypsin and secretory component immunoreactivity. Ultrastructurally, the tumor cells were characterized by numerous mitochondria, tubulovesicles and intracytoplasmic canaliculi filled with abundant microvilli. The growth of TMK-1 cells was promoted by 10nM human gastrin (G-17), 2 microM tetragastrin or 2 microM pentagastrin, among which human gastrin showed the most effective growth promotion. Moreover, incorporation of [3H]thymidine into TMK-1 cells was stimulated by gastrin in a dose-dependent manner. The content of cyclic adenosine 3',5'-monophosphate (cAMP) in TMK-1 cells was increased by gastrin treatment but decreased to the control level within 10 min. cAMP-dependent protein kinase was also activated by gastrin administration.

Topics: Carcinoma; Cell Cycle; Cell Line; Cyclic AMP; DNA, Neoplasm; Dose-Response Relationship, Drug; Gastrins; Humans; Microscopy, Electron; Protein Kinases; Stomach Neoplasms; Time Factors

Topics: Gastrins; Gastritis, Atrophic; Gastrointestinal Diseases; Humans; Peptic Ulcer; Radioimmunoassay; Stomach Neoplasms

Attempts were made to examine strain differences in the susceptibility of rats to intestinal metaplasia induced by X-irradiation. The gastric regions of 4 inbred male rats (SHR, F344, WKY, and LEW strains) in 5-week-old and 2 random bred male rats (SD, and WIS strains) were irradiated with a total dose of 20 Gy X-ray given in two equal fractions separated by three days. Upon sacrifice at 6 months after the last irradiation, the number of intestinal metaplastic crypts with positive reaction to alkaline phosphatase (ALP) appeared highest in the SHR and lowest in the WIS rats. Morphologically, the number of crypts with intestinal metaplasia in whole glandular stomachs of SHR, WIS, F344, and SD rats were higher than those in WKY and LEW rats. In the pyloric gland, it was highest in WIS rats, while in the fundic gland it was highest in SHR rats. The results show that the appearance and location of intestinal metaplasia by X-irradiation are greatly influenced by the strain of the rat.

Topics: Alkaline Phosphatase; Animals; Gastric Mucosa; Gastrins; Hydrogen-Ion Concentration; Neoplasms, Radiation-Induced; Rats; Rats, Inbred F344; Rats, Inbred Lew; Rats, Inbred SHR; Rats, Inbred Strains; Rats, Inbred WKY; Species Specificity; Stomach; Stomach Neoplasms

The present immunoelectron microscopic study was carried out in order to evaluate the influence of several technical parameters of the immunogold staining procedure on the labelling intensity of gastrin-storing cells in normal and pathological states. Ultra-thin sections of double-fixed Epon embedded human pyloric mucosa were immunolabelled using a C-terminal directed antigastrin serum, followed by colloidal gold linked immunoglobulins. When the labelling density occurring over the endocrine secretory granules was quantitatively evaluated, the following conclusions could be drawn: the density increased dramatically when particles of decreasing diameter (40 nm, 20 nm, 10 nm) were comparatively used, the dilution of the primary antiserum had to be adjusted in order to obtain an intense specific labelling together with a negligible background (non specific) labelling. However, a long incubation time of the primary antiserum, as well as the use of etching procedures, resulted in an increase of the labelling density when a highly diluted antiserum was applied. Subsequent attempts to immunolabel ultrathin sections of gastrin-secreting malignant tumours showed that the goal could be achieved on tissues routinely processed for electron microscopy, provide the previous parameters were carefully selected according to the control G cell model.

Topics: Cytoplasmic Granules; Gastric Mucosa; Gastrins; Gold; Histocytochemistry; Humans; Immunologic Techniques; Pyloric Antrum; Stomach Neoplasms

The effects of truncal vagotomy after administration of N-methyl-N'-nitro-N-nitrosoguanidine on the incidence and number of gastric carcinomas and gastric acid secretion, gastrin secretion, antral pH, and duodenal reflux were investigated in inbred Wistar rats. Rats were subjected to truncal vagotomy after N-methyl-N'-nitro-N-nitrosoguanidine treatment. Vagotomy significantly increased the incidence and number of adenocarcinomas of the glandular stomach. It also resulted in significantly more atypical glandular hyperplasias, which are precursors of gastric cancer. Furthermore, it caused a decrease in gastric secretion and an increase in mucosal pH in the antrum but did not increase duodenal reflux. These findings indicate that vagotomy has a promoting effect on the development of gastric cancers. The reduced gastric acid secretion, but not duodenal reflux, may be related to this increased incidence of gastric cancer.

Topics: Animals; Body Weight; Duodenogastric Reflux; Gastric Acid; Gastric Juice; Gastrins; Male; Methylnitronitrosoguanidine; Rats; Rats, Inbred Strains; Stomach Neoplasms; Time Factors; Vagotomy

Topics: Antigens; Biopsy; Carcinoembryonic Antigen; Cytodiagnosis; Endoscopy; Gastric Acidity Determination; Gastrins; Glycoproteins; Humans; Pepsinogens; Prostaglandins E; Stomach Neoplasms; Stomach Ulcer; Tomography, X-Ray Computed

Clinical, histological, histochemical and ultrastructural characteristics of eight cases of carcinoid tumors of the non-antral portion of the stomach are presented. Four cases with multiple polypoid lesions are accompanied by an increased level of gastrin. A normal level of gastrin was present in the other four cases with isolated tumor and a normal component of endocrine cells in the uninvolved mucosa. In the first group with multiple lesions, the histological and histochemical analysis of the endocrine cells revealed a wide range of appearances: a) "simple hyperplasia", b) "nodular hyperplasia", and c) carcinoid tumor. These aspects suggested a different pathogenesis for the carcinoid tumors of the non-antral portion of the stomach with possible therapeutical implications.

Topics: Achlorhydria; Adult; Aged; Carcinogens; Carcinoid Tumor; Chromaffin System; Enterochromaffin Cells; Female; Gastrins; Humans; Hyperplasia; Male; Middle Aged; Precancerous Conditions; Stomach; Stomach Neoplasms

This was a study of the effects of gastrin on gastric mucosal cyclic-adenosine 3':5'-monophosphate (cAMP)-dependent protein kinase activity and DNA synthesis in rat stomach carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) in order to clarify the mechanism of the enhanced effect of gastrin on the early stage of stomach carcinogenesis. Inbred Basel-Wistar rats received MNNG in drinking water (50 micrograms/ml for 32 weeks) and were treated with s.c. injections of pentagastrin (300 micrograms/kg twice daily for 4 weeks) beginning with the fourth and eighth weeks after the initiation of MNNG treatment. The incidence of gastric adenocarcinoma in fourth-week gastrin-treated rats and of gastric carcinoid in eighth-week gastrin-treated rats was higher than that in rats treated with MNNG alone. The former tumors developed in the antrum and most of the latter tumors in the fundus. In the early stage of carcinogenesis the labeling index [( 3H]thymidine-labeled nuclei/one gland) in both the antrum and fundus was the same in MNNG-plus-gastrin-treated groups and in the MNNG-only-treated group. With regard to the distribution of cAMP-dependent protein kinase isoenzyme in fourth-week gastrin-treated rats, the proportion of type I cAMP-dependent protein kinase significantly increased in the antrum during the eighth week after the initiation of MNNG treatment (P less than 0.01). The increased type I activity in the antrum of the gastrin-treated rats agreed with the high incidence of gastric adenocarcinoma in the antrum. Type I isoenzyme clearly increased in gastric adenocarcinoma. These results suggest that type I cAMP-dependent protein kinase can play an important role in the enhanced effect of gastrin on rat stomach carcinogenesis induced by MNNG.

Topics: Adenocarcinoma; Animals; DNA; Drug Synergism; Gastric Mucosa; Gastrins; Isoenzymes; Methylnitronitrosoguanidine; Protein Kinases; Rats; Rats, Inbred Strains; Stomach Neoplasms

Topics: Adenocarcinoma; Aged; Animals; Colonic Neoplasms; Female; Gastrins; Humans; Leucine; Male; Mice; Mice, Nude; Middle Aged; Neoplasm Proteins; Secretin; Stomach Neoplasms

From 1978 to 1984, six patients (four men and two women) with functioning extrapancreatic gastrinomas were treated at the University of Michigan Medical Center. In all but one patient, who was known to have a liver metastasis, selective portal and peripheral venous sampling was performed to localize the site(s) of increased gastrin levels. Serum levels of carboxy (C) and amino (N) terminal gastrin moieties were measured before surgery with region-specific antisera and N/C ratios were calculated. All patients underwent operative exploration and successful resection of all gastrinomas present including a single large liver metastasis in one case. The C-terminal gastrin level was elevated in all cases and the N/C ratios were well below 1.0 (greater than 1 is consistent with malignancy and metastases) in all but the one patient with a liver metastasis. All patients have remained clinically free of tumor and have had normal basal and secretin-stimulated gastrin levels for as long as 5 years after operation. Three of the patients had undergone previous total gastrectomies and had done well apart from persistent hypergastrinemia before resection of the tumor. Two patients have not undergone any type of gastric operation. Appropriately selected patients with Zollinger-Ellison syndrome, particularly those with extrapancreatic primary lesions, may be candidates for a curative resection.

Topics: Adult; Angiography; Female; Gastrins; Humans; Jejunal Neoplasms; Liver Neoplasms; Lymph Nodes; Male; Middle Aged; Peptide Fragments; Pyloric Antrum; Secretin; Stomach Neoplasms; Tomography, X-Ray Computed; Zollinger-Ellison Syndrome

Serum levels of gastrin and secretin were measured in experimental animals and in man following gastric surgery. Serum gastrin was higher in the fasting, and increased further after test meal in proximally gastrectomized subjects as compared in those receiving total gastrectomy and in normal controls. Serum secretin level, however, was unchanged before and after test meal irrespective to two surgical procedures. Dogs undergoing proximal gastrectomy showed increased output of bicarbonate and amylase as an exocrine pancreatic secretion after instillation of 0.1N HCl into the duodenum. Increased DNA synthesis was observed in the small intestine and pancreas in the proximally gastrectomized dogs. Therefore, higher level of serum gastrin may possess trophic activity in animals undergoing proximal gastrectomy. The findings obtained in this study suggest that we should select, if possible, the proximal gastrectomy leaving the antral region from the view point of trophic action of gastrointestinal hormones.

Topics: Animals; Dogs; Gastrectomy; Gastrins; Humans; Secretin; Stomach Neoplasms

A consecutive series of 357 endoscopic gastric biopsies was investigated after staining of histological sections with the Grimelius silver method. Argyrophil cells were classified according to the type of mucosa (fundic, antropyloric or intestinalized) in which they were located. Cases of argyrophil cell hyperplasia detectable on a qualitative basis were selected and their associations with various gastroduodenal disorders of the patients as well as with functional and pathological findings of the gastric mucosa were investigated. Hyperplasia of fundic argyrophil cells was more frequent in patients with atrophic gastritis of the fundic mucosa and a relatively well preserved antral mucosa as well as in patients with hyperplastic polyps. In contrast, it was infrequent in patients with duodenal ulcer and gastric stump. Hyperplasia of antropyloric argyrophil (non-G) cells was most frequent in patients with gastric peptic ulcer or with hyperplastic polyps as well as in those with atrophic gastritis of the fundic mucosa irrespective of the concomitant condition of antral mucosa. Hyperplasia of metaplastic argyrophil cells was more frequent in intestinal metaplasia of the antral mucosa than in that of fundic mucosa. Moreover, it was more frequent in patients with gastric cancer.

Topics: Adolescent; Adult; Aged; Biopsy; Female; Gastric Acidity Determination; Gastric Mucosa; Gastrins; Gastritis; Gastrointestinal Diseases; Gastroscopy; Humans; Hyperplasia; Intestinal Mucosa; Male; Metaplasia; Middle Aged; Peptic Ulcer; Polyps; Silver; Staining and Labeling; Stomach Neoplasms

This study deals with the growth effect of gastrin on two xenotransplantable human gastric carcinomas (SC-6-JCK, poorly differentiated adenocarcinoma; and St-15, mucinous adenocarcinoma) and on one colonic carcinoma (Co-3, well-differentiated adenocarcinoma). In SC-6-JCK, the treatment with s.c. injection of pentagastrin at a dose of 10 micrograms/mouse once daily for 25 days promoted the growth of the tumor transplanted in nude mice, but gastrin had no effect at all on St-15 and Co-3. In SC-6-JCK, the weight, size, and labeling index of [3H]thymidine of the tumor were significantly increased in comparison with those of the control (p less than 0.05). In SC-6-JCK, cyclic adenosine 3':5'-monophosphate (cAMP) in the tumor was increased by a single i.p. injection of pentagastrin at a dose of 20 micrograms/mouse in nude mice, but such an increase was not observed in St-15 and Co-3. Cyclic guanosine 3':5'-monophosphate in SC-6-JCK was slightly increased by gastrin treatment but was not affected in the other tumors. In SC-6-JCK, at 30 min after gastrin treatment when cAMP showed a maximum increase, the activity ratio of cAMP-dependent protein kinase in the tumor was also elevated. In vitro also, gastrin stimulated cAMP production and cAMP-dependent protein kinase activation. The data suggest that some human gastric carcinomas may have receptor for gastrin.

Topics: Adenocarcinoma; Adult; Animals; Cell Division; Cell Line; Colonic Neoplasms; Cyclic AMP; Cyclic GMP; Female; Gastrins; Humans; Kinetics; Male; Mice; Mice, Nude; Middle Aged; Neoplasm Transplantation; Protein Kinases; Stomach Neoplasms; Transplantation, Heterologous

37 patients suffering from apudomas of the pancreas are reported (18 insulinomas, 6 isletcell-hyperplasias, 9 Zollinger-Ellison syndroms, 1 glucagonoma, 3 without hormone production). In preoperative localization computerized tomography and angiography were the best with 65% positive findings. Insulinomas were enucleated, all free of recidives. 50% of operated isletcell hyperplasias had a postoperative resisting hyperinsulinism. Either gastrectomy or tumour enucleation was performed in the Zollinger-Ellison syndrome. The five-years survival rate was 43%.

Topics: Adenoma, Islet Cell; Adolescent; Adult; Aged; Child; Female; Follow-Up Studies; Gastrectomy; Gastrins; Glucagon; Humans; Hyperplasia; Insulin; Insulinoma; Islets of Langerhans; Male; Middle Aged; Pancreatectomy; Pancreatic Neoplasms; Postoperative Complications; Stomach Neoplasms; Zollinger-Ellison Syndrome

A total of 87 surgical cases of gastric carcinoma including 3 carcinoid tumors were investigated with the methods of silver reaction and immunoperoxidase stain for 8 different brain-gut hormones. Argyrophil (AP) cells were demonstrated in 38 cases (44%), argentaffin (AF) cells in 18 (21%) and endocrine cells in 13 (14%). The occurrence of endocrine cells had no relation with histological types. Glicentin cells were demonstrated in 10 cases, somatostatin in 7, motilin in 3, beta-endorphin in 2 and gastrin in one. Endocrine cells appeared generally in small numbers except one carcinoid tumor which had numerous somatostatin cells. No single cell positive for more than two kinds of hormones could be demonstrated. Two undifferentiated carcinomas looking like carcinoid tumors had argyrophil cells and endocrine cells of either somatostatin or beta-endorphin. These results suggest that carcinoid-like carcinoma or endocrine cell carcinoma may lie on the intermediate state between carcinoma and carcinoid tumor.

Topics: Adenocarcinoma; Adenocarcinoma, Mucinous; Adult; Carcinoid Tumor; Endorphins; Female; Gastrins; Gastrointestinal Hormones; Glucagon; Histocytochemistry; Humans; Male; Microscopy, Electron; Middle Aged; Motilin; Proglucagon; Protein Precursors; Somatostatin; Stomach Neoplasms; Vasoactive Intestinal Peptide; Vasopressins

Glicentin-containing cells (Glic. cells) in intestinal metaplasia, adenoma and carcinoma of the stomach were examined using immuno-histochemical techniques. Glic. cells first occurred in the gastric mucosa of the transitional area between metaplastic and intact gastric glands. They frequently showed hyperplasia or micronoduli in the budding area of the deeper metaplastic glands, but in completely intestinalized mucosa these endocrine cells decreased remarkably. Gastric adenomas with mild dysplasia had a good number of glicentin-immunoreactive cells which were located in the deeper adenoma glands. Gastrin- and somatostatin-positive cells were also detected in the adenomas. The incidence of glicentin-positive tumor cells was significantly higher in well differentiated adenocarcinoma than in poorly differentiated adenocarcinoma. Among the seven cases of scirrhous argyrophil cell carcinoma, three showed glicentin- and glucagon-immunoreactivity in the same area of the tumor. These findings suggest that the selective increase of Glic. cells in intestinal metaplasia may be closely related to the development of gastric adenoma. Glicentin positive tumor cells in gastric carcinomas can be regarded to be an expression of intestinal or fetal markers.

Topics: Adenoma; Carcinoma; Gastrins; Glucagon; Growth Hormone-Releasing Hormone; Hormones, Ectopic; Humans; Intestinal Mucosa; Intestines; Metaplasia; Proglucagon; Protein Precursors; Stomach Neoplasms

Significance of proximal partial gastrectomy for carcinoma of the upper portion of the stomach is reported. The 5-year postoperative survival rate was 58% in patients receiving proximal partial gastrectomy while it was 61% in those undergoing total gastrectomy. With respect to stage III cancer cases, there was no difference in the 5-year postoperative survival between the 2 groups. Therefore, we suppose that proximal partial gastrectomy is a treatment of choice for patients with carcinoma of the upper portion of the stomach. Late postoperative laboratory examination showed less incidence of hyperchromic anemia in patients receiving proximal partial gastrectomy, and lowered serum vitamin B12 level was noted in patients undergoing total gastrectomy. Hypergastrinemia was found in patients receiving proximal partial gastrectomy, although its physiologic significance remains to be elucidated.

Topics: Cardia; Gastrectomy; Gastrins; Humans; Lymphatic Metastasis; Secretin; Stomach Neoplasms

Topics: Adenocarcinoma; Adult; Aged; Female; Gastric Mucosa; Gastrins; Gastrointestinal Diseases; Humans; Male; Middle Aged; Peptic Ulcer; Peptide Fragments; Protein Precursors; Pyloric Antrum; Stomach Neoplasms

Topics: Administration, Oral; Female; Gastrectomy; Gastric Acidity Determination; Gastrins; Glycine; Humans; Male; Middle Aged; Peptic Ulcer; Stomach Neoplasms

A radioimmunoassay of the carcinoembryonic antigen, gastrin and immunoglobulin E was performed in the blood serum of more than 300 esophageal and gastric cancer patients. It has been noted that the CEA study makes it possible to determine the severity of disease and may serve as a yard-stick of radical therapy. Hypogastrinemia develops in 82-84% of patients with tumors of these sites. The gastrin level after therapy depends on the nature and type of antitumor therapy. An increase in the IgE level is a risk factor which makes it possible to identify patients with an "unfavorable" or complicated course of disease and to determine, to some extent, prognosis, to control therapeutic measures in combined treatment. The use of the radioimmunoassay for CEA, gastrin and IgE in the combined study of esophageal and gastric cancer patients allows one to evaluate the patients's status before treatment and to determine their response to tumor therapy.

Topics: Carcinoembryonic Antigen; Combined Modality Therapy; Esophageal Neoplasms; Gastrins; Humans; Immunoglobulin E; Prognosis; Radioimmunoassay; Stomach Neoplasms; Time Factors

The present study includes a histopathological and immunohistochemical study of 4 cases of diffuse hyperplasia of gastric argyrophil cells. The mode of proliferation of these cells and the production of hormone by these cells have been documented. The distribution of microacinar nests composed of argyrophil cells was thought to be related to chronic gastritis in which there are atrophy of mucosa and intestinal metaplasia. In the case in which these nests were found only in the corpus ventriculi, there was intestinal metaplasia throughout the stomach. On the other hand, in the case in which these nests appeared only in the pyloric area, atrophy of the mucosa with mild intestinal metaplasia was observed only in the pyloric area. The microacinar nests composed of argyrophil cells were distributed in the deep mucosa at the basal portion of the glands in the area with intestinal metaplasia. Serial sections revealed a sprout composed of argyrophil cells budding from the gland with intestinal metaplastic changes. The sprout buds out from the growth zone of glands with intestinal metaplasia and then becomes isolated and gives rise to reactive hyperplasia. The peptide hormone contained in these cells differs according to the mucosal environments. Cells containing gastrin were observed in the pyloric area, but not in the corpus ventriculi where there was marked intestinal metaplasia. The cells in this area were assumed to contain other hormones.

Topics: Adenocarcinoma; Adult; Chromaffin System; Enterochromaffin Cells; Female; Gastrectomy; Gastric Mucosa; Gastrins; Humans; Hyperplasia; Immunoenzyme Techniques; Male; Middle Aged; Somatostatin; Stomach Neoplasms

This report presents a case of multicentric gastric carcinoid (gastrin containing) tumors of the fundus associated with achlorhydria and pernicious anemia. It is suggested that stimulation of the antral G cells and possibly fundic argyrophilic cells by achlorhydria associated with atrophic gastritis may lead to hyperplasia, and eventually to neoplasia in the latter, in the form of gastric carcinoid with gastrin production.

Topics: Achlorhydria; Anemia, Pernicious; Carcinoid Tumor; Gastric Fundus; Gastric Mucosa; Gastrins; Histocytochemistry; Humans; Immunoenzyme Techniques; Male; Middle Aged; Pyloric Antrum; Staining and Labeling; Stomach Neoplasms

It is believed that the immature precursor cells of gastric mucosa have multidirectional potency of differentiation and these cells can differentiate into both endocrine and nonendocrine tumor cells. Fifteen cases of surgically resected stomach with gastric nonendocrine carcinoma were studied by the three-layer immunoperoxidase method. Serotonin was found in five cases, gastrin in one case, and both serotonin and gastrin in three cases. Serotonin also was detected in the noncancerous mucosa in thirteen cases: ten showing positive cells in the antrum and seven in the body. Gastrin was found in the noncancerous mucosa in 13 cases: eight in the antrum, five in the body. In four cases, a few serotonin positive cells were found in glands showing intestinal metaplasia. No correlation was found between the endocrine tumor cells and the types of carcinoma. Because endocrine cells can be detected in general types of gastric carcinoma, these findings suggest that the different kinds of cancer cells (endocrine and nonendocrine) may have a common origin.

Topics: Animals; Cell Differentiation; Cell Transformation, Neoplastic; Gastric Mucosa; Gastrins; Histocytochemistry; Humans; Immunoenzyme Techniques; Intestinal Mucosa; Rabbits; Serotonin; Stomach Neoplasms

Many gastrointestinal hormones have a stimulating action on the proliferation and growth of stomach and intestinal mucosa and on pancreas. This so-called trophic action was investigated most intensive on gastrin. We reproduced this effect autoradiographically by 3H-thymidine incorporation on the stomach corpus mucosa of rats. The animals had increased serum gastrin levels by partial stomach corpus resection that increased the endogenous serum gastrin level. The proliferation stimulating action of gastrin is also detectable at chronic oral application of N-Methyl-N'-nitroso-N-nitroguanidine for induction of stomach and intestinal tumors simultaneously to pentagastrin administration or partial stomach resection in the intact, tumor free oxyntic mucosa of stomach.

Topics: Animals; Cell Division; Gastrectomy; Gastric Fundus; Gastric Mucosa; Gastrins; Male; Methylnitronitrosoguanidine; Pentagastrin; Radioimmunoassay; Rats; Rats, Inbred Strains; Stomach Neoplasms

Topics: Animals; Atrophy; Gastric Mucosa; Gastrins; Gastritis; Gastritis, Atrophic; Male; Neoplasms, Experimental; Pilot Projects; Rats; Rats, Inbred Strains; Stomach Neoplasms

Topics: Chronic Disease; Gastrins; Gastritis; Gastritis, Atrophic; Humans; Stomach Neoplasms

A rare case with gastrin-producing carcinoid, adenocarcinoma and xanthoma of the stomach is presented. A 69-year-old male underwent total gastrectomy with splenectomy and distal pancreatectomy. The histological type of the carcinoid was poorly differentiated (type D), and argyrophil cell carcinoma. Immunoperoxidase staining of the carcinoid was positive for gastrin and negative for glucagon, somatostatin or insulin. The histological findings of the carcinoma were tub 2, medullary, INF alpha, se, ly 2, v 1, ow(-), aw(-), n 1. Histologically, the xanthoma consisted of foamy macrophages accumulated in the lamina propria.

Topics: Adenocarcinoma; Aged; Carcinoid Tumor; Gastrins; Humans; Male; Neoplasms, Multiple Primary; Stomach Diseases; Stomach Neoplasms; Xanthomatosis

The effects of gastrointestinal hormones on gastric carcinomas were examined in vitro and in vivo. In five of seventeen cases of human gastric carcinomas, the uptake of 14C-leucine into the tumor tissue in organ culture was enhanced by 10 micrograms/ml of gastrin. Also, in four of thirteen cases of human gastric carcinomas, the production of 14C-labelled proteins in medium was increased by gastrin. All the cases in which protein synthesis was enhanced by gastrin were histologically poorly differentiated adenocarcinomas. The effects of gastrin and secretin on the growth of gastric carcinoma, which was serially transplanted in athymic mice, were examined. The doubling time of the tumor was 7.1 days. The doubling time was shortened to 4.1 days by daily administration of 250 micrograms/kg of gastrin. This topic effect of gastrin on gastric carcinoma was inhibited by 100 U/kg of secretin. These results showed that the growth and protein synthesis of gastrointestinal tumor may be regulated by gastrointestinal hormones.

Topics: Adenocarcinoma; Animals; Carcinoma; Cell Division; Gastrins; Humans; Leucine; Mice; Mice, Nude; Neoplasm Proteins; Neoplasm Transplantation; Secretin; Stomach Neoplasms

Topics: Acromegaly; Adenocarcinoma; Adolescent; Adult; Chromaffin System; Enterochromaffin Cells; Gastrins; Humans; Hyperplasia; Male; Middle Aged; Pyloric Antrum; Stomach Neoplasms; Stomach Ulcer

Sixteen argyrophil cell carcinomas in 59 gastric scirrhous carcinomas were examined histologically, ultrastructurally, and immunohistochemically for polypeptide hormones, CEA, lysozyme, and HCG. In nine of these 16 tumors, polypeptides such as gastrin, somatostatin, and glucagon were demonstrated. Six of these nine tumors contained all three hormones, and three of these six tumors also had argentaffin cells. In all of these 16 tumors CEA were observed. Eight of them had CEA, lysozyme, and acid mucin synchronously. Of the above six tumors containing three peptides, three produced focal HCG. Ultrastructurally, several types of secretory granules were noted. Histologically, these 16 tumors showed poorly differentiated adenocarcinomas or signet ring cell carcinomas. Macroscopically, generalized type was 11 and localized type five. No hormonal syndrome was detected in any of the patients. It was suggested that these scirrhous argyrophil cell carcinomas of the stomach with the multifunction originate from totipotent immature cells of endodermal origin.

Topics: Adenocarcinoma, Scirrhous; Adult; Aged; Carcinoembryonic Antigen; Chorionic Gonadotropin; Female; Gastrins; Glucagon; Histocytochemistry; Hormones, Ectopic; Humans; Male; Middle Aged; Muramidase; Somatostatin; Staining and Labeling; Stomach Neoplasms

Eighteen argyrophil cell carcinomas in 101 early gastric carcinomas were explained histologically, ultrastructurally, and immunohistochemically for polypeptides, carcinoembryonic antigen (CEA), lysozyme, and human chorionic gonadotrophin (hCG). Seven of these 18 tumors had gastrin, and two of seven tumors also contained somatostatin. In all of these 18 tumors CEA were demonstrated. Seven had lysozyme and five of seven tumors also contained gastrin; hCG were present in four of the 18 tumors and two of four tumors had gastrin, CA, mucin, and lysozyme simultaneously. Argentaffin cells were found in seven of 18 tumors. Of the above seven tumors containing gastrin, three had argentaffin cells. Ultrastructurally, several types of secretory granules were noted and tumor cells resembling D1- or P cells were present in nine of the 18 tumors. Macroscopically, many of the tumors showed IIc or IIc + III type. Histologically, the 18 tumors consisted of six well differentiated adenocarcinomas and 12 poorly differentiated adenocarcinomas including signet-ring cell carcinoma. These 12 tumors frequently developed in the stomach of young females. In view of our previous investigations, it was suggested that the IIc-type argyrophil cell carcinoma histologically showing poorly differentiated adenocarcinoma may be related to scirrhous carcinoma of the stomach.

Topics: Adenocarcinoma; Adenocarcinoma, Scirrhous; Adult; Aged; Carcinoembryonic Antigen; Chorionic Gonadotropin; Female; Gastrins; Histocytochemistry; Humans; Male; Microscopy, Electron; Middle Aged; Silver; Staining and Labeling; Stomach Neoplasms

Topics: Gastrins; Gastritis, Atrophic; Humans; Male; Middle Aged; Radionuclide Imaging; Sodium Pertechnetate Tc 99m; Stomach Neoplasms; Technetium; Tetragastrin

The effects of gastrin on the histopathology of the glandular stomach and on the incidence of gastric carcinoma induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) were investigated in inbred Wistar (W) rats. Prolonged administration of gastrin after treatment with MNNG significantly reduced the incidence of adenocarcinomas of the glandular stomach. In addition, atypical glandular proliferations were significantly less frequent and were smaller, and the incidence of marked mucosal atrophy was significantly reduced in both the antral and oxyntic gland mucosae. Both atypical glandular hyperplasia and mucosal atrophy are precursors of gastric cancers; prolonged administration of gastrin to rats after treatment with MNNG suppressed development of precursors of gastric cancer and so prevented development of gastric cancers.

Topics: Adenocarcinoma; Animals; Atrophy; Delayed-Action Preparations; Drug Interactions; Gastric Mucosa; Gastrins; Male; Methylnitronitrosoguanidine; Rats; Rats, Inbred Strains; Stomach; Stomach Neoplasms

Topics: Adult; Aged; Enterochromaffin Cells; Female; Gastrins; Humans; Male; Middle Aged; Stomach Neoplasms

Gastric acid secretion and plasma gastrin response to test meals were examined in 110 patients with gastric cancer and a comparative study was made in accordance with depth of invasion, macroscopic shape, histological type, location and size of the lesion. Cases were classified into two large groups by the depth of invasion: early cancer (invasion was limited to the mucosa and submucosa) and advanced cancer (invasion reached the muscularis propria or deeper). Patients showed hypoacidity on the whole. Cases of early cancer showed significantly higher acid secretion than cases of advanced cancer, although no significant differences were observed in gastrin release. Among the cases of early cancer, cases of the elevated shape showed significantly lower acid secretion and higher gastrin release than cases of the depressed shape, and cases of the histologically differentiated type showed significantly higher acid secretion than cases of the undifferentiated type although no significant differences were observed in gastrin release. Among the cases of advanced cancer, cases with large carcinomas in the corpus tended to show low acid secretion and cases with large carcinomas in the antrum tended to show low gastrin release. High gastrin release was observed in cases of the Borrmann IV type with giant folds.

Topics: Aged; Eating; Endoscopy; Female; Gastric Juice; Gastrins; Humans; Male; Middle Aged; Neoplasm Staging; Stomach Neoplasms; Stomach Ulcer

Topics: Adult; Female; Gastric Acid; Gastrins; Gastrointestinal Diseases; Humans; Male; Middle Aged; Peptic Ulcer; Pyloric Antrum; Stomach Neoplasms

Topics: Adult; Aged; Female; Gastric Fundus; Gastric Mucosa; Gastrins; Gastritis; Humans; Male; Middle Aged; Pyloric Antrum; Stomach Neoplasms

A histological and immunohistological investigation was performed on biopsy specimens from ten patients 3 to 35 years after antrectomy, to study the type of epithelium and the possible occurrence of gastrin-producing cells (G cells) in the distal stump of the stomach remnant. The study showed that parietal cells were present in all patients, whereas G cells could not be demonstrated, although areas of pyloric-type epithelium (pseudopyloric metaplasia, were seen in eight. We conclude that the pyloric-type metaplasia, which occurs in the fundic mucosa after antrectomy, does not involve the G cells. It is suggested that the normal levels of fasting serum gastrin in these patients originate from outside the gastric mucosa, presumably from the duodenal bulb.

Topics: Adenocarcinoma; Biopsy; Epithelium; Fibrosis; Follow-Up Studies; Gastrectomy; Gastric Acid; Gastrin-Secreting Cells; Gastrins; Gastritis, Atrophic; Gastroscopy; Humans; Postoperative Period; Pyloric Antrum; Radioimmunoassay; Stomach Neoplasms; Stomach Ulcer; Time Factors

Adrenocorticotropin (ACTH)-like and alpha-melanotropin (alpha-MSH)-like peptides have been localized to a subpopulation of cytoplasmic (secretory) granules of human antropyloric gastric cells and of fetal and neoplastic gastrin cells. These granules also store gastrin and belong to the electron-dense variety of gastrin cell granules. Gastrin cells also contain granules of low to medium electron density; these store only gastrin and do not react with ACTH or alpha-MSH antisera. The alpha-MSH immunoreactive peptide was shown also to display alpha-MSH bioactivity by a combined immunosorbent-bioassay technique. This peptide cochromatographs with synthetic alpha-MSH in several systems and is not detected in oxyntic mucosa or in gastric muscle wall. As in the pituitary intermediate lobe, the alpha-MSH-like peptide may be formed by cleavage of ACTH-like peptides also in gastrin cells. These data provide additional evidence for local formation of ACTH/alpha-MSH-related peptides in gastrin cells and suggest a heterogenous peptide make-up of endocrine cell granules.

Topics: Adrenocorticotropic Hormone; Biological Assay; Cytoplasmic Granules; Fluorescent Antibody Technique; Gastric Mucosa; Gastrins; Humans; Immunoenzyme Techniques; Melanocyte-Stimulating Hormones; Microscopy, Electron; Peptides; Stomach; Stomach Neoplasms

Topics: Carcinoid Tumor; Female; Gastric Mucosa; Gastrins; Gastroscopy; Humans; Middle Aged; Stomach Neoplasms

Topics: Carcinoid Tumor; Gastrins; Humans; Stomach Neoplasms

The relation of gastric polyps to acid-secreting mucosa was examined in 120 patients with gastric polyps. Studies were made by the endoscopic Congo red test developed in this clinic. In 23 patients (19.1%) gastric polyps were located in acid-secreting mucosa and may have arisen from normal oxyntic mucosa. These polyps were of two histological types: oxyntic gland polyps containing many parietal cells, and nonoxyntic gland polyps without parietal cells. Only the former type appeared to secrete acid, judging endoscopically from the change of Congo red from red to blue-black on the surface of the polyps after administration of gastrin.

Topics: Adult; Aged; Congo Red; Female; Fiber Optic Technology; Gastric Juice; Gastric Mucosa; Gastrins; Gastroscopy; Humans; Male; Middle Aged; Polyps; Stomach Neoplasms

A 51 year old man was found to have a malignant gastrinoma. A phaeochromocytoma had been diagnosed and removed previously. The occurrence of these two rare tumours in a single patient suggests the possibility of a crossover between MEA I and MEA II. Reported cases of the "crossover syndrome" are reviewed and the status of this phenomenon as a syndrome is discussed.

Topics: Adrenal Gland Neoplasms; Gastrins; Humans; Male; Middle Aged; Multiple Endocrine Neoplasia; Neoplasms, Multiple Primary; Pheochromocytoma; Stomach Neoplasms; Syndrome

Topics: Biopsy; Diagnosis, Differential; Gastrins; Gastroscopy; Humans; Male; Middle Aged; Neuroma; Stomach Neoplasms

Topics: Adenocarcinoma; Gastrins; Gastritis; Humans; Peptic Ulcer; Radioimmunoassay; Stomach Neoplasms

Topics: Adenocarcinoma; Adult; Aged; Animals; Dogs; Fasting; Female; Gastrectomy; Gastrins; Humans; Male; Middle Aged; Postoperative Period; Stomach Neoplasms

Topics: Adenocarcinoma; Animals; Gastrectomy; Gastric Juice; Gastrins; Intestinal Polyps; Male; Methylnitronitrosoguanidine; Neoplasms, Experimental; Rats; Stomach Neoplasms; Stomach Ulcer

We determined the relative concentrations of gastrin molecular species in serum samples from 21 patients with Zollinger-Ellison syndrome with localized gastrinoma (n = 11) or gastrinoma with hepatic metastases (n = 10). Gastrin molecular species were separated by gel-filtration chromatography and quantitated by radioimmunoassay with a gastrin antiserum produced in our laboratory. The percentage gastrin-17 of the total gastrin in the two groups differed significantly (nonparametric Wilcoxon rank test; p less than 0.01). Patients with the Zollinger-Ellison syndrome with apparently localized gastrinoma had a lower percentage of G- 17 (7.6%, SEM 1.6%) than did patients with gastrinoma with hepatic metastases (31.1%, SEM 6.1%). This procedure may be useful in the early classification of tumors in patients with Zollinger-Ellison syndrome.

Topics: Gastrins; Humans; Liver Neoplasms; Neoplasm Metastasis; Stomach Neoplasms; Zollinger-Ellison Syndrome

Topics: Adenocarcinoma; Animals; Gastrins; Histamine; Male; Methylnitronitrosoguanidine; Rats; Stomach Neoplasms

A study of 177 patients undergoing distal subtotal gastrectomy indicates that a preoperative serum pepsinogen I (PGI) level below 20 ng/ml predicts the presence of gastic carcinoma and the degree of intestinal metaplasia of the gastric antrum. The serum gastrin level was not predictive of carcinoma or of the degree of intestinal metaplasia. Of the 15 patients with a low serum PG level, 13 had carcinoma and 2 had atypical polyps. The PG I level in a stored serum sample from 4 of 30 patients fell from normal to abnormal over a period of 8-9 years. Each of these converters had invasive carcinoma of the stomach. This suggests that persons showing a fall in serum PG I to abnormal levels during serial analyses should be evaluated for the possibility of gastric carcinoma.

Topics: Adult; Aged; Female; Gastrectomy; Gastrins; Humans; Intestines; Male; Metaplasia; Middle Aged; Pepsinogens; Pyloric Antrum; Stomach Neoplasms; Time Factors

Topics: Dumping Syndrome; Gastric Acid; Gastric Mucosa; Gastrins; Humans; Peptic Ulcer; Postgastrectomy Syndromes; Pyloric Stenosis; Stomach Neoplasms

Topics: Adult; Female; Gastrins; Humans; Stomach Neoplasms; Streptozocin

The morphology and histochemistry of gastroduodenal endocrine tumors from 16 patients were studied. All patients underwent operation, in most cases with a preoperative diagnosis of nonendocrine tumor, ulcer, o polyp(s). The argentaffin reaction was positive in three tumors, and the Hellerström--Hellman argyrophil reaction was positive in four tumors. All tumors reacted positively to the Grimelius argyrophil stain, and 13 were positive with the Sevier--Munger argyrophil stain. Gastrin immunoreactivity was found in eight tumors, and substance-P immunoreactivity in seven tumors. No enteroglucagon, adrenal cortex hormone, or pancreatic polypeptide was observed in any of the tumors. Three patients with Sevier--Munger-positive gastric tumors had concurrent pernicious anemia, and 2 patients with gastrin-immunoreactive tumors had acute or chronic gastroduodenal ulceration. The results indicate that the gastroduodenal endocrine tumor as a rule gives no endocrine symptoms and that the tumor type is an unexpected finding at operation. The tumors may contain gastrin, substance P, somatostatin, and serotonin and tend to be multihormonal.

Topics: Adrenocorticotropic Hormone; Adult; Aged; Duodenal Neoplasms; Endocrine System Diseases; Female; Gastrins; Glucagon-Like Peptides; Hormones; Humans; Male; Middle Aged; Pancreatic Polypeptide; Stomach Neoplasms; Substance P

Gastro-entero-pancreatic (GEP) and bronchial endocrine tumours have been studied by immunohistochemistry using specific antisera against a variety of hormonal and neuronal peptides. In gastrinomas numerous tumour cells were found to contain GH-like immunoreactivity. These cells were identical with those storing gastrin. Gastrinomas as a rule were extremely heterogeneous containing a variety of minority cell populations, including CCK immunoreactive cells and neurotensin immunoreactive cells. Glucagonoma cells were found to store GIP-like material in addition to glucagon. In some insulinomas calcitonin-like material was encountered in the insulin producing tumour cells. In both glucagonomas and insulinomas other pancreatic endocrine cell types constituted minority cell populations. One intestinal somatostatinoma contained gastrin cells as a minority cell population. Bronchial endocrine tumours contained scattered cells displaying ACTH-like or enkephalin-like immunoreactivity. Two such tumours in addition contained cells displaying neurophysin immunoreactivity.

Topics: Adenoma, Islet Cell; Adrenocorticotropic Hormone; Bronchial Neoplasms; Cholecystokinin; Enkephalins; Fluorescent Antibody Technique; Gastrins; Glucagon; Growth Hormone; Humans; Insulin; Insulin Secretion; Neurophysins; Pancreatic Neoplasms; Serotonin; Somatostatin; Stomach Neoplasms; Zollinger-Ellison Syndrome

Eight beagle dogs of four-month-old received both oral administration of N-Ethyl-N'-Nitro-N-Nitrosoguanidine (ENNG) and subcutaneous injection of gastrin, and one of them was found to have an annularly infiltrating advanced carcinoma with marked fibrous thickening of the antral wall resulting in stenosis of the antrum (carcinoma scirrhosum) which resembled "Linitis plastica" (Borrmann's type IV carcinoma) in human stomach.

Topics: Adenocarcinoma, Scirrhous; Animals; Carcinogens; Dogs; Gastric Acidity Determination; Gastrins; Methylnitronitrosoguanidine; Neoplasms, Experimental; Stomach Neoplasms

In a consecutive material consisting of 24 stomachs resected due to adenocarcinoma, intestinal metaplasia occurred in 21. Gastrin-producing cells (G-cells) were found to be distributed in a sporadic manner in antra with intestinal metaplasia. Not a single G-cell could be demonstrated in areas with metaplasia, while in the nonmetaplastic areas the distribution of the G-cells corresponded to that of the middle part of the mucosa. This means, that an error can occur when determining the quantity of G-cells, and can explain the previous controversial results regarding the density of G-cells. Enteroglucagon containing cells (GLI-cells) on the contrary were demonstrated in areas with intestinal metaplasia in antra of 19 of the stomachs showing intestinal metaplasia but never in the nonmetaplastic mucosa. This indicated that metaplasia also includes the endocrine cells. The identification of the G-cells and the GLI-cells was carried out by means of indirect immunoperoxidase technique combined with alcian blue pH 2,6-PAS staining.

Topics: Adenocarcinoma; Cell Count; Gastrins; Glucagon-Like Peptides; Humans; Metaplasia; Pyloric Antrum; Stomach Neoplasms

Growth hormone (GH)-immunoreactive material was found to occur in the antral gastrin cells and in scattered cells of the pancreatic islets in several mammalian species, including man. Examination of gastrinomas revealed the majority of tumour cells to display GH-like immunoreactivity.

Topics: Animals; Fluorescent Antibody Technique; Gastrins; Growth Hormone; Humans; Intestines; Islets of Langerhans; Pancreatic Neoplasms; Pyloric Antrum; Species Specificity; Stomach Neoplasms

Topics: Duodenitis; Esophagitis, Peptic; Female; Gastrins; Gastritis; Humans; Male; Peptic Ulcer; Postgastrectomy Syndromes; Stomach Diseases; Stomach Neoplasms

Topics: Adult; Aged; Cell Count; Duodenal Ulcer; Female; Fluorescent Antibody Technique; Gastrectomy; Gastric Juice; Gastric Mucosa; Gastrins; Histocytochemistry; Humans; Male; Middle Aged; Peptic Ulcer; Pyloric Antrum; Staining and Labeling; Stomach; Stomach Neoplasms; Stomach Ulcer; Uremia

The mucosal distribution of G cells was quantitatively mapped in resected stomachs from 42 patients (12 with gastric ulcer, 11 with duodenal ulcer, 14 with duodenal ulcer and uremia, and 5 with gastric cancer). Along the histological border of the proximal part of the pyloric antrum there was in all patient categories a transitional zone of varying extent, with a low G-cell density before the cells disappeared in the body of the stomach. The proximal end of the duodenum contained considerably fewer G cells than in the antrum, and the number was virtually equal in all groups. Within the antrum there was in the material as a whole a gradual increase in G-cell density from the proximal to the distal part, but this difference was not apparent for the gastric ulcer patients. When corresponding antral segments were compared between the various patient groups, the G-cell density was found to be significantly decreased in the distal antrum of the gastric ulcer patients. In all patient categories, except the duodenal ulcer group with uremia, the circumferential distribution of G cells showed reduced density along the curvatura minor. For the material as a whole there were great individual variations in the overall antral G-cell density, in the antral area corresponding to the distribution of G cells and in the total G-cell mass; these three variables were not significantly related to diagnosis, age or sex.

Topics: Adult; Aged; Cell Count; Duodenal Ulcer; Female; Fluorescent Antibody Technique; Gastrectomy; Gastric Mucosa; Gastrins; Humans; Male; Middle Aged; Pyloric Antrum; Stomach Neoplasms; Stomach Ulcer; Uremia

In a patient with a duodenal ulcer, with acid hypersecretion and moderately disturbed gastrin secretion tests, immunocytochemical examination of the vagotomy-antrectomy specimen revealed a pyloric microgastrinoma (clinically silent and apparently benign) and focal antropyloric gastrinosis. These localised lesions represent a new variant of abnormalities affecting the gastrin cells in the context of hypersecretory duodenal ulcers.

Topics: Adenoma; Carcinoid Tumor; Duodenal Ulcer; Gastric Juice; Gastrins; Humans; Hyperplasia; Male; Middle Aged; Pyloric Antrum; Pylorus; Stomach Neoplasms

Topics: Fasting; Female; Gastrins; Glucagon; Humans; Male; Middle Aged; Stomach Neoplasms

A patient with atrophic gastritis and excessively raised serum gastrin concentrations (4000 to 5000 pg/ml) was found to have multiple polypous tumors of the gastric corpus mucosa. Following gastrectomy, serum gastrin concentrations decreased to undetectable levels. The tumors consisted of a mixed population of endocrine cells. The majority of tumor cells were of the ECL type, but, in addition, enterochromaffin cells of various subtypes as well as agranular cells were found. The tumors were locally invasive and invaded the walls of submucosal blood vessels. The surrounding mucosa showed a severe atrophic gastritis with intestinalization and contained numerous goblet cells, enterochromaffin cells, and cholecystokinin cells. Cholecystokinin cells do not occur in the normal oxyntic mucosa. Hence, the observation of this cell type in intestinalized gastric epithelium suggests that "intestinalization also is associated with changes in endocrine cell populations. Gastrin has been shown to affect the function of the ECL cells. Indications for a trophic action of gastrin on these cells have been obtained. It is discussed whether greatly raised serum gastrin levels in patients with atrophic gastritis may be associated with increased risks for the development of certain types of gastric tumors.

Topics: Diabetes Complications; Enterochromaffin Cells; Female; Gastric Mucosa; Gastrins; Gastritis; Humans; Middle Aged; Stomach; Stomach Diseases; Stomach Neoplasms

Topics: Aged; Antibodies; Female; Gastric Mucosa; Gastrins; Hawaii; Humans; Japan; Male; Metaplasia; Middle Aged; Pepsinogens; Risk; Stomach; Stomach Neoplasms

Topics: Electrolytes; Enzymes; Gastric Acidity Determination; Gastric Juice; Gastric Mucosa; Gastrins; Gastrointestinal Hormones; Histamine; Humans; Intrinsic Factor; Pentagastrin; Pepsinogens; Peptic Ulcer; Secretory Rate; Stomach Neoplasms; Vagus Nerve; Zollinger-Ellison Syndrome

Topics: Adolescent; Adult; Aged; Duodenal Ulcer; Fasting; Female; Gastrins; Humans; Male; Middle Aged; Radioimmunoassay; Stomach Neoplasms; Stomach Ulcer

Topics: Animals; Carcinoid Tumor; Cholecystokinin; Dogs; Enterochromaffin Cells; Gastric Inhibitory Polypeptide; Gastric Mucosa; Gastrins; Gastrointestinal Hormones; Glucagon; Glucagon-Like Peptides; Humans; Intestinal Mucosa; Intestinal Neoplasms; Pancreatic Polypeptide; Rats; Secretin; Somatostatin; Stomach Neoplasms; Vasoactive Intestinal Peptide

The distribution of parietal cells in the body mucosa, and of G cells in the antral mucosa, was quantitatively mapped in resected stomachs from 42 patients (12 with gastric ulcer, 11 with duodenal ucler, 14 with duodenal ulcer and uremia, and 5 with gastric cancer) who preoperatively had had their gastric acid secretion measured. In the material as a whole there was a significant positive correlation between the parietal-cell density and maximal acid output (MAO), and a significant negative correlation between the parietal-cell density and patient age. A significant positive correlation was found between the antral G-cell mass and basal acid output (BAO). When the individual patient categories were analyzed, the correlation between parietal-cell density and MAO were significant in the group with duodenal ulcer and uremia, and in the group with gastric cancer. Correlation between parietal-cell density and age was found only in the group with duodenal ulcer and uremia. There was no correlation between the parietal-cell density and various parameters of the antral G-cell population in the material as a whole or in any of the individual groups.

Topics: Adult; Aged; Cell Count; Duodenal Ulcer; Female; Gastric Juice; Gastrins; Humans; Male; Middle Aged; Peptic Ulcer; Stomach; Stomach Neoplasms; Stomach Ulcer; Uremia

The pathogenesis of peptic ulceration cannot be explained by an abnormal capacity to secrete acid, for ulcers develop in patients who secrete acid normally. Duodenal and gastric ulcers have a common cause. The location of an ulcer in each individual is primarily determined by his capacity to secrete acid at that time. There is a difference between the mechanisms which heal an ulcer and cure a patient of his disease. Procedures that reduce an individual's capacity to secrete acid, heal an ulcer by moving the focus of the ulcerogenic forces to a more proximal site. It is necessary to remove an antral factor if in addition the patient is to be cured of his disease. It is postulated that this antral factor is the gastrin (G17) which is released in abnormal amounts into gastric juice in patients with ulcers and with gastrinomas. The abnormal amount of G17 in gastric juice may be responsible for releasing abnormal amounts of G34 into the circulation from the duodenum and from gastrinomas. The abnormal release of gastrin develops as a result of an impaired response to duodenal acidification manifest in part by an impaired release of secretin. It is postulated that the abnormal stimulation of antral gastrin release may on occasions give rise to antral G-cell hyperplasia, and that the abnormal secretion of gastrin into gastric juice may on occasions give rise to gastrinomas. These abnormalities may cause ulcers by producing an uncontrolled secretion of acid and an abnormal exposure to bile.

Topics: Duodenum; Gastric Juice; Gastrins; Hormones, Ectopic; Humans; Hyperplasia; Paraneoplastic Endocrine Syndromes; Peptic Ulcer; Pyloric Antrum; Stomach Neoplasms; Vagotomy

Topics: Adolescent; Adult; Aged; Anemia, Pernicious; Betazole; Cyclic AMP; Cyclic GMP; Female; Gastric Juice; Gastric Mucosa; Gastrins; Histamine; Humans; Male; Middle Aged; Pentagastrin; Peptic Ulcer; Stomach Neoplasms; Zollinger-Ellison Syndrome

The authors report three anatomoclinical studies concerning apparently moderately aggressive endocrine tumors developped in the sub-mucosa of the duodenal bulb (2 cases) and of the pyloro-bulbar region (1 case), not connected with the pancreas, and occuring in the absence of a parietal ectopic pancreas. Two of these tumors were ulcerous but the associated syndromes (pains and hemorrhage) did not evoke, clinically, a Zollinger-Ellison syndrome. However, examination with immunofluorescence showed the presence of immunoreactive gastrine in a large number of cells. Having found some similar cases in the literature, the authors precise the features of these silent pyloro-duodenal gastrinomas: it is a variety of carcinoids or of "carcinoid-islet cell tumors". The cells contain argyrophile granules (Grimelius stain) which correspond in electron microscopy to neuro-secretory granules that may be quite different from G. granules. In the absence of significant clinical signs and of a radio-immunologic blood test, the presence of immunoreactive gastrin in the cells is the main feature for the diagnostic of these tumors. These tumors seem to arise from the gastrin cells of the mucosa or from their precursors as is suggested by the transitional forms with the fundus of the glands. Whatever the reason of the peculiar functional behavior, these neoplasms can be easily isolated from the anonymous group of duodenal carcinoids.

Topics: Aged; Carcinoid Tumor; Duodenal Neoplasms; Female; Fluorescent Antibody Technique; Gastrins; Humans; Middle Aged; Pylorus; Stomach Neoplasms

Topics: Adenoma; Adult; Aged; Carcinoma; Cell Differentiation; Female; Fluorescent Antibody Technique; Gastric Mucosa; Gastrins; Humans; Male; Middle Aged; Stomach Neoplasms

Topics: Adult; Duodenal Ulcer; Eating; Gastrectomy; Gastrins; Humans; Middle Aged; Stomach Neoplasms; Stomach Ulcer; Vagotomy

The effects of gastrin on gastric acid secretion and on the incidence of gastric carcinoma induced by N-methyl-N'-nitro-N-nitrosoquanidine were investigated in rats. At Week 50 after the start of the experiment, it was found that prolonged administration of gastrin after treatment with N-methyl-N'-nitro-N-nitrosoquanidine resulted in a significant increase in gastric acid secretion and a significant reduction in the incidence of adenocarcinomas of the glandular stomach. The administration of gastrin did not influence the histological appearance of the few gastric adenocarcinomas that did develop.

Topics: Adenocarcinoma; Animals; Drug Administration Schedule; Gastric Juice; Gastrins; Male; Methylnitronitrosoguanidine; Neoplasms, Experimental; Rats; Stomach Neoplasms

Topics: Fasting; Female; Gastrectomy; Gastrins; Humans; Male; Peptic Ulcer; Radioimmunoassay; Stomach Diseases; Stomach Neoplasms

In patients with gastric cancer who were to undergo gastrectomy, the fasting serum gastrin concentration in the peripheral vein was estimated by radioimmunoassay. The blood samples were also collected from the gastric veins and artery during the time of operations. These gastrin values were compared with morphological findings in the resected stomach. No significant differences in serum gastrin concentration was found between the patients of gastric cancer and normal subjects. In the patients with mucosal atrophy in the oxyntic gland area but with no atrophy in the pyloric gland area, however, significant increase in serum gastrin concentration was observed. In cases where fundal atrophy was accompanied by atrophy in the pyloric gland area, the increase was not observed. The amount of gastrin content in cancer tissue was negligible. These results indicate that the increase in serum gastrin concentration in some patients with gastric cancer might be due to the accompanied atrophy of oxyntic glands in the stomach.

Topics: Adult; Aged; Atrophy; Female; Gastrectomy; Gastric Acidity Determination; Gastric Juice; Gastric Mucosa; Gastrins; Gastritis; Gastroscopy; Humans; Male; Middle Aged; Radioimmunoassay; Stomach Neoplasms; Stomach Ulcer

Topics: Gastric Acidity Determination; Gastric Juice; Gastric Mucosa; Gastrins; Gastrointestinal Diseases; Humans; Stomach Neoplasms

Sessile polyps in the antrum were found in 12 of 51 patients with pernicious anaemia. During gastroscopy, mucosal biopsies for gastrin determination were taken from the antrum and fundus and from the polyps. Patients with high gastrin concentration in the antral mucosa showed high serum gastrin concentrations, while most patients with low antral gastrin concentrations also had low serum gastrin values. On an average, the gastrin concentrations in the antrum were approximately 10 times, and those in the fundus approximately 100 times, higher than the corresponding values obtained in a reference group. The gastrin content in the polyps was not different from that in the surrounding antral mucosa. This study suggests that the polyps are not due to a functional hypertrophy of the antral mucosa caused by locally increased production of gastrin.

Topics: Adult; Aged; Anemia, Pernicious; Female; Gastric Mucosa; Gastrins; Humans; Male; Middle Aged; Polyps; Stomach Neoplasms

MSH-producing gastric tumour. A case report. A patient with melanosis due to MSH-production by a gastric tumour is described. It is also possible that the tumour was producing gastrin, whereas there was no sign of increased ACTH-production. This is the first patient described with a MSH-producing tumour without concomitant ACTH-production.

Topics: Adenocarcinoma, Papillary; Aged; Gastrins; Humans; Male; Melanocyte-Stimulating Hormones; Melanosis; Stomach Neoplasms

Topics: Animals; Chronic Disease; Dogs; Duodenal Ulcer; Gastrins; Histamine Release; Humans; Hydrogen-Ion Concentration; Polyps; Stomach Neoplasms

Topics: Diagnosis, Differential; Diarrhea; Gastrectomy; Gastrins; Humans; Neoplasm Metastasis; Neoplasm Recurrence, Local; Pancreatectomy; Pancreatic Neoplasms; Postoperative Complications; Radiography; Stomach Neoplasms; Zollinger-Ellison Syndrome

As streptozocin has a toxic effect on gastrin producing cells in some patients with gastrinomas, the action of the drug upon normal gastrin release was evaluated in patients with carcinoid tumours (n=6) and malignant insulinomas (n=2). No acute effects were recorded in 22 instances where gastrin levels were followed during the first 24 hours after infusion of streptozocin. When gastrin levels were compared throughout a course of repeated infusions during months a significant increase was noted. Concentrations were doubled after 6 g streptozocin given during a four months period, and tripled after 10 g in nine months period. One patients developed bleeding duodenal ulcer after a total dose of 6 g. It is concluded that streptozocin does not damage normal G cells, but by some action seems to stimulate gastrin relase. Peptic ulceration may be an important side effect during a long term treatment.

Topics: Adenoma, Islet Cell; Carcinoid Tumor; Female; Gastrins; Humans; Male; Neoplasm Metastasis; Pancreatic Neoplasms; Stomach Neoplasms; Streptozocin

Over a period of 21 years 39 patients with gastrinoma were surgically treated. Thirty-three patients had total gastrectomy with two postoperative deaths, and 6 patients had a lesser procedure. The postoperative fasting gastrin levels remained elevated and did not always indicate the extent of tumor involvement. Further mobilization of tumor gastrin by provocative infusion of calcium gluceptate, 15 mg/kg of body weight, should be carried out routinely. A hepatic angiogram should be considered when the gastrin levels exceed 1,000 picograms per ml. Chemotherapy consisting of Tubercidin, Streptozotocin and 5-Fluorouracil was given to 5 patients with extensive gastrinoma. All patients felt better and gained from three to 35 pounds in weight. Since 60% of the patients died or have definite evidence of tumor activity it is assumed that the tumor growth was not inhibited and that it is malignant. Approximately 40% of the patients seem to do well despite modest elevations in gastrin levels suggesting that the retained tumor could be considered benign.

Topics: Adenoma, Islet Cell; Fasting; Fluorouracil; Gastrins; Humans; Liver Neoplasms; Neoplasm Metastasis; Neoplasm Recurrence, Local; Postgastrectomy Syndromes; Prognosis; Stomach Neoplasms; Streptozocin; Tubercidin

The mean concentration of gastrin in serum was determined in healthy fasting persons (n = 27), it amounted to 56.8 pg/ml (SD = 19.8 PG/ML). The values of gastrin in serum of patients, who were grouped by endoscopicbioptic criteria of antral mucosa and who exceptionally showed diffuse inflammation of gastric mucosa, amounted to 73.2 pg/ml in patients with mild superficial gastritis (n = 24), to 73.4 pg/ml in those with severe superficial gastritis (n = 55), to 82.3 pg/ml in patients with chronic atrophic gastritis (n = 11) and to 70.7 pg/ml in those with chronic atrophic gastritis and intestinal metaplasia (n = 17). The concentration of serum gastrin in patients with additional pathological processes of gastric or duodenal mucosa was also determined. Patients with gastric resection according to Billroth II (n = 15) revealed gastrin values of 47.8 pg/ml, those with duodenal ulcer (n = 5) of 58.5 pg/ml, with gastric ulcer (n = 50) of 61.3 pg/ml, with polyps in stomach (n = 10) of 109.6 pg/ml and with neoplasms of the stomach (n = 27) of 77.7 pg/ml. Gastrin values were not correlated to age or sex. The difference between the mean gastrin concentrations of the mentioned groups of patients however is not marked enough and the range of values is too wide to characterize those groups by specific gastrin levels. The determination of gastrin in serum of fasting patients is not helpful for diagnosis of gastritis without antibodies to intrinsic factor or for diagnosis of certain localized pathological conditions in stomach or duodenum obviously.

Topics: Adolescent; Adult; Aged; Duodenal Ulcer; Female; Gastrectomy; Gastric Mucosa; Gastrins; Gastritis; Humans; Male; Metaplasia; Middle Aged; Polyps; Stomach Diseases; Stomach Neoplasms; Stomach Ulcer

Topics: Achlorhydria; Anemia, Pernicious; Diet; Esophagogastric Junction; Gastrectomy; Gastrins; Gastritis; Humans; Lymphatic Metastasis; Methods; Stomach Neoplasms

Topics: Animals; Dogs; Duodenum; Gastrectomy; Gastrins; Humans; Jejunum; Stomach Neoplasms

Topics: Adult; Aged; Anemia, Pernicious; Female; Gastrins; Humans; Male; Middle Aged; Polyps; Pyloric Antrum; Stomach Neoplasms

Fasting and after meals serum gastrin levels were determined in healthy subjects and patients with different gastroenterological diseases (duodenal and gastric ulcer, hiatal hernia with gastroesophageal reflux, Billroth II gastric resection, atrophic gastritis, Zollinger-Ellison, Ménétrier, chronic calcifying pancreatitis, gastric carcinoma and lymphoma). The results pointed to the usefulness of evaluating both fasting levels and "gastrin curve" after meals as an expression of the rapidity of response of hormone-secreting gastric cells. Calculation of the I.G.O. (Integrated Gastrin Output) must also be carried out to provide a parameter from which the overall ability of G cells to secrete in response to feeding can be assessed.

Topics: Duodenal Ulcer; Gastrins; Gastritis; Gastroesophageal Reflux; Gastrointestinal Diseases; Hernia, Hiatal; Humans; Pancreatitis; Stomach Neoplasms; Zollinger-Ellison Syndrome

A total of 1 035 routine serum gastrin investigations was undertaken with a commercially available kit. Levels in 49 normal subjects were similar to those found in 200 patients with duodenal ulcertaion, in 42 patients with gastric ulcers, in 9 patients with carcinoma of the stomach, in 55 patients with chronic alcohol-induced pancreatitis, and in 27 with iron deficiency anaemia. Significantly raised levels of serum gastrin were found in 32 patients with megaloblastic anaemias, where the rise in serum gastrin concentration correlated with a fall in maximal acid output, and in 14 patients with complete vagotomies. It is suggested that a level of less than 2 mEq/h of acid after insulin and a raised serum gastrin level are useful criteria of completeness of vagotomy.

Topics: Adult; Anemia, Hypochromic; Anemia, Megaloblastic; Duodenal Ulcer; Female; Gastric Juice; Gastrins; Gastrointestinal Diseases; Humans; Male; Pancreatitis; Stomach Neoplasms; Stomach Ulcer; Vagotomy

The distributions of acid alpha1-glycoprotein, alpha1-fetoprotein, beta-galactosidase and gastrin in gastric carcinoma and gastric ulcer as well as in the neighbourhood of these lesions were studied by means of immunohistochemical methods on imprint preparation. We could not find significant differences between gastric carcinoma and the nonneoplastic lesions, except for the acid alpha1-glycoprotein. The results of this first study indicate that the immunochemical and immunohistological assay of acid alpha1-glycoprotein might be of practical value in diagnosing malignant changes of gastric mucosa.

Topics: ABO Blood-Group System; alpha-Fetoproteins; Animals; Colonic Neoplasms; Duodenal Ulcer; Fluorescent Antibody Technique; Galactosidases; Gastric Mucosa; Gastrins; Goats; Guinea Pigs; Histocytochemistry; Humans; Peptic Ulcer; Rabbits; Stomach Neoplasms

One of five gastro-entero-pancreatic hormones, gastrin, serotonin, histamine, glucagon, and insulin, was intraperitoneally administered for a long period to the rats that received N-methy-N'-nitro-N-nitrosoguanidine. A frequent development of scirrhous carcinoma was demonstrated in the group treated with gastrin.

Topics: Adenocarcinoma, Mucinous; Adenocarcinoma, Scirrhous; Animals; Gastrins; Glucagon; Histamine; Insulin; Male; Methylnitronitrosoguanidine; Neoplasms, Experimental; Nitrosoguanidines; Pancreatic Hormones; Rats; Serotonin; Stomach; Stomach Neoplasms

Foregut endocrine polypeptide-secreting APUD cells (Amine-Precursor-Uptake and Decarboxylation), in their embryologic migration from neural crest to foregut may become "arrested" in the mesoderm or in other ectopic locations. They may become hyperplastic, adenomatous or malignant. Eight illustrative patients are reported. One patient had "pancreatic hyperparathyroidism" with hypercalcemic crises, pancreatic apudocarcinoma, normal parathyroids, biologically active parathormone, but inert immunochemically to the usual parathyroid antisera. Two had gastrin-secreting malignancies in the mesoderm. Remission after excision, but eventual recurrence of the syndrome due to islet cell hyperplasia required total gastrectomy. One patient had a gastric corpus apudocarcinoma found prospectively with hypergastrinemia which required excision of the tumor. One patient had acromegaly with hypergastrinemia and antral gastrinosis treated by pituitary irradiation, One patient had the antral or intermediary type of the Zollinger-Ellison syndrome with moderate hypergastrinemia, duodenal ulcer and antral gastrinosis, treated by vagotomy and antrectomy. One patient had hyperparathyroidism with antral gastrinosis, treated by parathyroidectomy. One patient had malignant Zollinger-Ellison syndrome and developed associated thyroid parafollicular cell hyperplasia and parathyroid chief cell hyperplasia, treated by total gastrectomy and multiple endocrine excisions. These investigative observations demonstrate ectopic loci and associated hyperplasias which support the concept of migration and bizarre potentiality of polypeptide-secreting cells of the foregut.

Topics: Adenoma; Adult; Aged; Amines; Child; Decarboxylation; Endocrine System Diseases; Endoderm; Female; Gastrins; Humans; Hyperplasia; Male; Middle Aged; Multiple Endocrine Neoplasia; Neoplasms; Pancreatic Neoplasms; Parathyroid Diseases; Parathyroid Hormone; Peptides; Stomach Neoplasms; Zollinger-Ellison Syndrome

Material from eight peptide hormone-secreting tumours, extirpated from the pancreas or from the antrum-duodenum region, was examined. Four of the patients had the clinical manifestations of the Zollinger-Ellison syndrome, two showed the features of an insulin-secreting tumour and one had a glucagonoma. Gastrin-producing cells, identified by immunohistochemistry, were found in five of the tumours. These cells displayed a varying degree of formaldehyde-ozone-induced fluorescence. This agrees with previous observations on the gastrin cell of human antral and duodenal mucosa. From model experiments, formaldehyde-ozone-induced fluorescence is thought to reflect the presence of peptides having tryptophan in the NH2-terminal position. The nature of this peptide in gastrin-producing cells is unknown.

Topics: Adult; Aged; Duodenal Neoplasms; Female; Fluorescence; Formaldehyde; Gastrins; Gastrointestinal Neoplasms; Glucagon; Humans; Insulin; Insulin Secretion; Male; Middle Aged; Ozone; Pancreatic Neoplasms; Stomach Neoplasms; Tryptophan; Zollinger-Ellison Syndrome

In addition to the previously described molecular forms of gastrin, a new component has been found in high concentrations in the serum of 6 patients with Zollinger-Ellison syndrome. Serum was fractionated by gel filtration, and ion exchange chromatography, and the new component was identified in eluates by radioimmunoassay using an antibody with specificity for the N-terminal portion of heptadecapeptide gastrin. The precise chemical nature of the new component is not known, but its chromatographic behavior and its reactivity to various antibodies is indistinguishable from that of the natural or synthetic N-terminal 1 to 13 fragment of G-17. The new component is present in gastrinoma tumor tissue. Its concentration in serum of gastrinoma patients increases markedly when secretin is injected.

Topics: Antibodies, Neoplasm; Chemical Fractionation; Chromatography, Gel; Chromatography, Ion Exchange; Gastrins; Humans; Iodine Radioisotopes; Radioimmunoassay; Secretin; Stomach Neoplasms; Zollinger-Ellison Syndrome

50 cases of interposition of jejunal loop (32 for gastric cancer and 18 for ulcerous pathology) carried out over the last 3 years are reported. From a technical point of view and as an alternative to degastroenteroanastomosis, interposition of the loop is preferred in partial oral end-to-end on the stomach. In neoplastic lesions, Mouchet-Camey type reconstruction was adopted as a routine measure. After describing the complications of the operation and analyzing the causes, the long-term results are evaluated using absorption curves with 131-I labelled oleic acid. The excellent weight increase in the inflammatory forms, and the lack of reflow and dumping in patients subjected to total gastrectomy for cancer, confirm the value of the technique.

Topics: Adult; Aged; Dumping Syndrome; Duodenal Ulcer; Gastrectomy; Gastrins; Humans; Iodine Radioisotopes; Jejunum; Middle Aged; Neoplasm Metastasis; Oleic Acids; Peptic Ulcer; Postoperative Complications; Radioimmunoassay; Stomach Neoplasms; Stomach Ulcer; Zollinger-Ellison Syndrome

Topics: Anemia, Pernicious; Bicarbonates; Duodenal Ulcer; Endocrine System Diseases; Esophagitis, Peptic; Esophagus; Gastric Juice; Gastrins; Humans; Hyperplasia; Intestines; Kidney Failure, Chronic; Pancreas; Pheochromocytoma; Pyloric Antrum; Stomach; Stomach Neoplasms; Stomach Ulcer; Vagotomy; Zollinger-Ellison Syndrome

A method for measurement of gastrin in gastric mucosa has been developed, and distribution of gastrin in the stomach of pig, dog, cat, rabbit, and man was examined. Measurable amounts of gastrin were found in corpus of all species, but the content in the antrum was considerably higher. The highest concentration of gastrin was seen in man. The borderline between corpus and antrum was abrupt, and in both parts of the stomach gastrin was evenly distributed. In 44 patients with duodenal ulcer the antral gastrin concentration was 21.3 mug eqv. per g mucosa, in 15 patients with prepyloric ulcer 23.0, in 10 patients with gastric ulcer 5.9, and in 16 patients with gastric carcinoma 7.9. The control group consisted of 10 healthy volunteers and 12 patients with minor abdominal complaints. Mean antral gastrin concentrations were 28.1 and 20.7 respectively. No significant relationship was observed between PAO and gastrin content of antral mucosa in any group.

Topics: Adult; Animals; Cats; Dogs; Duodenal Ulcer; Female; Gastric Mucosa; Gastrins; Humans; Male; Middle Aged; Rabbits; Radioimmunoassay; Species Specificity; Stomach Neoplasms; Stomach Ulcer; Swine

Serum gastrin radioimmunoassay (RIA) is a sensitive and specific method suitable for measurement of circulating concentrations of this peptide hormone, which is a major regulator of gastric acid secretion. When performed under optimal conditions this RIA permits measurement of low and normal serum gastrin levels and changes that occur after physiologic stimulation. Hypergastrinemia may be secondary to atrophy of the acid-secreting gastric mucosa. This form of pypergastrinemia is appropriate and leads to no seriousequences. Hypergastrinemia associated with gastric acid hypersecretion is inappropriate. The major cause is a gastrinsecreting tumor (gastrinoma) that produces the clinical picture of the Aollinger-Ellison syndrome. The differential diagnosis of inappropraite hypergastrinemia includes antral G-cell hyperplasia and ISOLATED RETAINED ANTRUM. Accurate diagnosis of these conditions may be aided by ancillary studies including feeding, secretin, and calcium stimulation tests. Distinction among these conditions is important in planning appropriate surgical tratment.

Topics: Antibody Specificity; Arthritis, Rheumatoid; Catecholamines; Duodenal Ulcer; Gastrectomy; Gastrins; Humans; Kidney Failure, Chronic; Pentagastrin; Pheochromocytoma; Pyloric Antrum; Radioimmunoassay; Stimulation, Chemical; Stomach Neoplasms; Vagotomy; Zollinger-Ellison Syndrome

Endocrine cells in the normal glandular stomach and gastric carcinoids of mastomys were observed by electron microscopy and at least five types of endocrine cells, EC, G, D-like, R (round-granule) and ECL cells were identified. Of these, four types excepting G cells were recognized in the fundic mucosa. Characteristic in mastomys was a scarcity of endocrine cells in the fundic mucosa, where ECL and R cells were predominant types. Silver impregnation methods including SEVIER-MUNGER's argyrophil reaction of our own modifications were applied to tissue sections and the endocrine cells were examined by electron microscopy. Only EC cells revealed argentaffin granules under the light and electron microscope. R, ECL and some of the G cells were non-argentaffin and argyrophil in reaction and D-like cells and the rest of the G cells failed to show even an argyrophil reaction. Granules of mastomys carcinoid cells, as noted in the previous reports, were non-argentaffin but faintly argyrophil. Mastomys gastric carcinoids were studied by the same method, with special reference to the parent cells of this particular neoplasia. Noteworthily, mastomys gastric carcinoids arise mostly from the fundus, the area where R and ECL cells mainly occur in normal animals. The neoplasms are composed of cells containing granules resembling partly those of R cells and partly those of ECL cells. ECL cells and neoplastic cells in the present investigation have a similar reactivity to SEVIER-MUNGER's method. Considering the generally accepted fact that neoplastic cells may not fully duplicate their parent cells in cytological features, it seems reasonable to presume that R and/or ECL cells might be the parent cells of the mastomys gastric carcinoids. In connection with this assumption histamine has been demonstrated to be produced both in mastomys carcinoid cells and normal ECL cells.

Topics: Animals; Carcinoid Tumor; Enterochromaffin Cells; Gastric Mucosa; Gastrins; Golgi Apparatus; Mice; Rodent Diseases; Stomach Neoplasms

Topics: Gastrins; Humans; Meat; Peptic Ulcer; Recurrence; Stomach Neoplasms

Topics: Gastric Acidity Determination; Gastrins; Humans; Hyperplasia; Precancerous Conditions; Pyloric Antrum; Stomach; Stomach Neoplasms; Stomach Ulcer

Topics: Afferent Loop Syndrome; Anemia, Macrocytic; Diarrhea; Dumping Syndrome; Folic Acid Deficiency; Gastrectomy; Gastric Juice; Gastrins; Humans; Intestinal Absorption; Intrinsic Factor; Mucus; Osteoporosis; Postgastrectomy Syndromes; Stomach Neoplasms; Vitamin B 12 Deficiency; Vomiting

Topics: Child; Duodenal Neoplasms; Duodenum; Gastric Mucosa; Gastrins; Histocytochemistry; Humans; Hyperplasia; Male; Microscopy, Electron; Pancreas; Pylorus; Serotonin; Stomach Neoplasms; Zollinger-Ellison Syndrome

Topics: Adult; Cardia; Contrast Media; Dumping Syndrome; Duodenal Ulcer; Esophagoscopy; Esophagus; Female; Follow-Up Studies; Gastrins; Gastroesophageal Reflux; Hernia, Hiatal; Humans; Male; Manometry; Middle Aged; Peptic Ulcer; Peristalsis; Postgastrectomy Syndromes; Posture; Radiography; Radioimmunoassay; Stomach Neoplasms

Topics: Duodenal Ulcer; Gastrectomy; Gastrins; Humans; Postoperative Care; Radioimmunoassay; Stomach Neoplasms; Zollinger-Ellison Syndrome

Topics: Adrenalectomy; Adult; Age Factors; Aged; Diabetes Mellitus; Female; Gastrectomy; Gastrins; Gastrointestinal Diseases; Humans; Hypophysectomy; Liver Diseases; Male; Middle Aged; Obesity; Pituitary Diseases; Radioimmunoassay; Sex Factors; Stomach Neoplasms; Thyroid Diseases

Topics: Adenoma; Adult; Aged; Carcinoid Tumor; Diagnosis, Differential; Duodenal Neoplasms; Endocrine Glands; Female; Gastrins; Glucagon; Humans; Hyperparathyroidism; Male; Middle Aged; Pancreas; Pancreatic Neoplasms; Parathyroid Neoplasms; Radiography; Stomach Neoplasms; Syndrome; Zollinger-Ellison Syndrome

Topics: Cholecystokinin; Cholelithiasis; Duodenal Ulcer; Esophageal Achalasia; Gastrins; Gastritis; Gastrointestinal Hormones; Humans; Pancreatic Diseases; Peptic Ulcer; Secretin; Stomach Neoplasms; Stomach Ulcer

Topics: Aged; Antibodies; Atrophy; Biopsy; Female; Follow-Up Studies; Gastric Mucosa; Gastrins; Gastritis; Humans; Intestinal Polyps; Intrinsic Factor; Male; Metaplasia; Middle Aged; Pyloric Antrum; Stomach; Stomach Diseases; Stomach Neoplasms

Although histochemical, immunohistochemical, and electron microscopic methods have led to the identification of a large variety of endocrine cells in the upper gastrointestinal mucosa, no conventional light microscopic technique capable of the simultaneous identification of these cells has been reported. Such a staining method would be of considerable value to the pathologist as the malfunction of the endocrine cells of the gut, which produce numerous digestive hormones and biogenic amines, is closely related to a number of clinical conditions afflicting man. In this work, after testing three different polychrome staining methods, it has been concluded that a slightly modified Herlant's tetrachrome in tissues fixed in Zenker-formol is the procedure of choice. This method allows the distinction of several different cell types in the upper gastrointestinal mucosa of man and dog and permits the easy identification of the gastrin-producing cells on a routine basis. This identification has been confirmed in the case of two patients with gastrin cell hyperplasia, seen by both light and electron microscopy. Herlant's tetrachrome has proven valuable in the screening of human as well as experimental gastrointestinal tissues and it has been found to be very suitable for recognizing gastrin-producing cell hyperplasias. The usefulness of this method is expected to increase with the establishment of further correlations between the light and electron microscopy of the endocrine cells of the gut.

Topics: Adenocarcinoma; Animals; Chromates; Dogs; Duodenal Ulcer; Duodenum; Gastric Mucosa; Gastrins; Humans; Hyperplasia; Intestinal Mucosa; Methods; Microscopy, Electron; Peptic Ulcer; Staining and Labeling; Stomach Neoplasms

Topics: Adenoma; Aged; Duodenal Ulcer; Fluorescent Antibody Technique; Gastrins; Humans; Islets of Langerhans; Male; Pancreas; Pancreatic Ducts; Stomach Neoplasms

Topics: Anemia, Pernicious; Chronic Disease; Duodenal Ulcer; Epithelial Cells; Fluorescence; Gastric Mucosa; Gastrins; Gastritis; Humans; Immune Sera; Metaplasia; Methods; Stomach Neoplasms; Stomach Ulcer

Topics: Carcinoma; Female; Gastric Juice; Gastric Mucosa; Gastrins; Humans; Iodine Isotopes; Male; Middle Aged; Radioimmunoassay; Secretory Rate; Stomach Neoplasms

Topics: Adult; Aged; Anemia, Pernicious; Duodenal Ulcer; Ethylamines; Female; Gastric Acidity Determination; Gastric Juice; Gastric Mucosa; Gastrins; Gastritis; Humans; Insulin; Male; Middle Aged; Postoperative Complications; Pyrazoles; Recurrence; Stomach Neoplasms; Stomach Ulcer; Vagotomy; Zollinger-Ellison Syndrome

Topics: Acromegaly; Dietary Proteins; Gastrectomy; Gastrins; Gastrointestinal Diseases; Humans; Kidney Diseases; Liver Cirrhosis; Peptic Ulcer; Radioimmunoassay; Stomach Neoplasms

Topics: Achlorhydria; Depression, Chemical; Fluoroscopy; Gastric Acidity Determination; Gastrins; Humans; Hydrogen-Ion Concentration; Injections, Intravenous; Radioimmunoassay; Secretin; Stomach Neoplasms; Time Factors

In this survey the antral, pancreatic and, where present, the neoplastic gastrin cells, were studied in eight cases of the Zollinger-Ellison syndrome. The antral G cells alone were studied in one case of Z-E syndrome, seven cases of simple duodenal ulcer, and five cases of pernicious anaemia. The Z-E cases were divided into two numerically equal groups. The first group had ;short' histories, high serum gastrin levels, and profound antral G cell hyperplasia. The second group had ;long' histories, relatively lower serum gastrin levels, normal antral G cells, and either pancreatic D cell hyperplasia or gastrinoma. Antral G cell hyperplasia, with maximal gastrin storage and normal serum gastrin levels, was found in the duodenal ulcer cases. Antral G cell hyperplasia with minimal storage and high serum gastrin levels was observed in the cases of pernicious anaemia. On the basis of our findings we propose that there exist at least two distinct types (or perhaps stages) of the Z-E syndrome. Suggestions for their pathogenesis are offered.

Topics: Anemia, Pernicious; Duodenal Ulcer; Fluorescent Antibody Technique; Gastric Mucosa; Gastrins; Histocytochemistry; Humans; Iodine Isotopes; Microscopy, Electron; Pancreas; Pyloric Antrum; Radioimmunoassay; Stomach Neoplasms; Zollinger-Ellison Syndrome

This is the first case report of the Zollinger-Ellison syndrome due to an infiltrating tumour of the stomach. Plasma gastrin levels were high and gastrin was demonstrated in argyrophil tumour cells by an immunofluorescent technique. Evidence is presented that the tumour arose from the G cells.

Topics: Aged; Fluorescent Antibody Technique; Gastric Mucosa; Gastrins; Humans; Male; Stomach; Stomach Neoplasms; Zollinger-Ellison Syndrome

Topics: Adult; Aged; Caffeine; Female; Gastric Acidity Determination; Gastrins; Gastritis; Humans; Male; Middle Aged; Stomach Neoplasms; Stomach Ulcer

Topics: Duodenal Ulcer; Duodenum; Electrophoresis; Gastric Mucosa; Gastrins; Gels; Humans; Immunochemistry; Intestinal Mucosa; Iodine Isotopes; Jejunum; Methods; Radioimmunoassay; Starch; Stomach Neoplasms; Tissue Extracts; Zollinger-Ellison Syndrome

Topics: Atrophy; Biopsy; Chromium Isotopes; Gastric Juice; Gastric Mucosa; Gastrins; Gastritis; Gastrointestinal Motility; Humans; Peptides; Stomach; Stomach Neoplasms

Thirty specimens of stomach, duodenum, and jejunum, removed at operation, were examined by optical microscopical, cytochemical, and electron microscopical techniques. The overall distribution of four types of endocrine polypeptide cell in the stomach, and three in the intestine, was determined. The seven cell types are described by names and letters belonging to a scheme for nomenclature agreed upon at the 1969 Wiesbaden conference on gastrointestinal hormones. The gastrin-secreting G cell was the only cell for which firm identification with a known hormone was possible. Although there was wide variation in the distribution of the various cells, from one case to another, striking differences were nevertheless observable, with respect to the G cell, between antra from carcinoma and from ulcer cases.

Topics: Bile Duct Neoplasms; Carcinoma; Duodenal Ulcer; Duodenum; Fluorescent Antibody Technique; Gastric Mucosa; Gastrins; Gastrointestinal Hormones; Humans; Jejunum; Microscopy; Microscopy, Electron; Peptides; Placenta; Stomach; Stomach Neoplasms

Topics: Adult; Carcinoma; Computers; Female; Gastric Acidity Determination; Gastric Juice; Gastrins; Gastritis; Humans; Male; Middle Aged; Peptides; Pyrazoles; Statistics as Topic; Stimulation, Chemical; Stomach Neoplasms; Stomach Ulcer

Topics: Biopsy; Celiac Artery; Congo Red; Cytodiagnosis; Gastric Mucosa; Gastrins; Gastritis; Gastroscopy; Histamine; Humans; Peptides; Phosphorus Isotopes; Pyrazoles; Radiography; Stomach Neoplasms; Technetium; Zollinger-Ellison Syndrome

Topics: Achlorhydria; Anemia, Pernicious; Gastric Acidity Determination; Gastric Mucosa; Gastrins; Histamine; Humans; Peptic Ulcer; Pyrazoles; Stomach Neoplasms; Vagotomy

Topics: Adult; Diagnosis, Differential; Gastrectomy; Gastric Acidity Determination; Gastric Juice; Gastrins; Humans; Hyperplasia; Male; Stomach Neoplasms; Zollinger-Ellison Syndrome

Topics: Adult; Aged; Female; Gastric Acidity Determination; Gastric Juice; Gastrins; Gastritis; Heart Diseases; Histamine; Humans; Injections, Subcutaneous; Male; Melena; Middle Aged; Neurotic Disorders; Nitrogen; Oral Hemorrhage; Peptic Ulcer; Proteins; Sclerosis; Secretory Rate; Stomach Neoplasms

Topics: Diagnosis, Differential; Gastric Juice; Gastrins; Histamine; Humans; Nitrogen; Pyrazoles; Stimulation, Chemical; Stomach Neoplasms; Stomach Ulcer

Topics: Adenocarcinoma, Scirrhous; Carcinoma; Cats; Duodenal Ulcer; Duodenum; Gastric Mucosa; Gastrins; Histamine; Physiology; Stomach Neoplasms; Stomach Ulcer

These three papers present studies on gastrin. The first paper describes a method of biological assay using the rat. The second paper demonstrates that the highest concentration of gastrin-like activity occurs in the antral mucosa, with a clear gradient of concentration of activity down the gut. However, it is to be noted that the total amount of extractable activity is greatest in the duodenum, although the concentration there is less than in the antrum. No activity was detected in the pancreas. The third paper studies the contents of gastrin-like activity in patients with duodenal ulcer and demonstrates higher figures when stenosis is present. Patients with benign gastric ulcer and carcinomata showed results equal to or greater than in those with the average uncomplicated duodenal ulcer. It was noted that two patients with dilated antra both had very low total gastrin-like activity. There was no correlation between total activity and maximal histamine-stimulated output of acid. There was, however, a positive correlation between the insulin-stimulated acid secretion and the total gastrin-like activity in the cases of uncomplicated duodenal ulcers. The clinical studies are still tentative in view of the several variables present, but it seems likely that they will in due course clarify the role of gastrin in the ulcer problem.

Topics: Biological Assay; Biomedical Research; Colon; Duodenal Ulcer; Duodenum; Freeze Drying; Gastrectomy; Gastric Mucosa; Gastrins; Histology; Humans; Ileum; Insulin; Jejunum; Pancreas; Rats; Research; Statistics as Topic; Stomach Neoplasms; Stomach Ulcer; Zollinger-Ellison Syndrome