gastrins and Precancerous-Conditions

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

Proton pump inhibitors profoundly affect the stomach and have been associated with carcinoid tumors in female rats. There is now sufficient experience with this class of drugs to allow reasonable estimation of their safety in terms of cancer development in humans. Long-term use of proton pump inhibitors is associated with an increase in gastric inflammation and development of atrophy among those with active Helicobacter pylori infections. The actual risk is unknown but is clearly low. However, it can be markedly reduced or eliminated by H. pylori eradication. It is thus recommended that patients being considered for long-term proton pump inhibitor therapy should be tested for H. pylori infection and, if present, this pathogen should be eradicated. Oxyntic cell hyperplasia, glandular dilatations, and fundic gland polyps may develop in patients not infected with H. pylori, but these changes are believed to be reversible and without significant cancer risk.

Topics: Animals; Atrophy; Gastric Acid; Gastric Mucosa; Gastrins; Gastrointestinal Neoplasms; Helicobacter Infections; Helicobacter pylori; Humans; Precancerous Conditions; Proton Pump Inhibitors

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

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

Gastric epithelial dysplasia is the earliest visible stage of neoplasia. Most histopathologists can recognize or at least suspect it, and a set of established clinical responses follow its detection. In contrast, proliferations and dysplastic changes of gastric endocrine cells are difficult to identify and generally neglected. Such changes are known to predispose to the development of carcinoid tumours and usually arise in patients with corpus-predominant atrophic gastritis and elevated gastrin levels. A report in this issue suggests that patients with dysplasia of the enterochromaffin-like cells have a much greater risk of developing carcinoid tumours than previously suspected. These carcinoids (known as type I) tend to have an indolent course, are almost never functional and have a favourable prognosis; nevertheless, they need to be detected and excised endoscopically. Because of the small numbers of patients in this series and the relatively short follow-up time of the study, it would be premature to issue guidelines on the long-term management of patients with atrophic gastritis and hypergastrinaemia. However, it is incumbent on clinical researchers with access to well-defined cohorts, such as the one studied here, to continue the follow-up studies that will lead to a more precise definition of risk and to the development of usable evidence-based clinical strategies.

Topics: Enterochromaffin-like Cells; Epithelium; Gastric Mucosa; Gastrins; Gastritis, Atrophic; Gastrointestinal Neoplasms; Humans; Intestinal Mucosa; Precancerous Conditions; Prognosis; Risk Factors

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

Topics: Acute Kidney Injury; Adenoma, Islet Cell; Adolescent; Adult; Aged; Carcinoid Tumor; Child; Dehydration; Female; Gastric Inhibitory Polypeptide; Gastrins; Gastrointestinal Hormones; Gastrointestinal Neoplasms; Glucagon; Humans; Hyperplasia; Hypokalemia; Insulin; Insulin Secretion; Male; Middle Aged; Pancreatic Neoplasms; Paraneoplastic Endocrine Syndromes; Precancerous Conditions; Serotonin; Somatostatin; Syndrome; Vasoactive Intestinal Peptide; Zollinger-Ellison Syndrome

Topics: 5-Hydroxytryptophan; Adrenocorticotropic Hormone; Chorionic Gonadotropin; Gastrins; Hormones, Ectopic; Humans; Hypercalcemia; Hypoglycemia; Neoplasms; Parathyroid Hormone; Precancerous Conditions; Thyrotropin; Vasopressins

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

Barrett's oesophagus is a common premalignant lesion caused partly by acid reflux. Although the requisite therapy, proton pump inhibitors (PPIs), have been implicated in the progression of Barrett's oesophagus in animal models, harmful effects of prolonged PPI therapy in Barrett's oesophagus is both inconclusive and controversial. We therefore aimed to test the role of PPI-induced hypergastrinaemia in vitro and see whether any biological parameters were useful surrogates of long-term therapy in man.. We undertook detailed serological and tissue assessment of gastrin and CCK(2) receptors in 90 patients randomised to different doses of PPI therapy during a detailed 2-year follow-up. We also undertook a comprehensive study of cell models to study the consequential biological effects of gastrin on the mucosa.. Gastrin and its cognate receptor CCK(2)R were expressed highest in the stomach, then less in Barrett's oesophagus and least in squamous oesophagus (SqE) (n=20 paired t-test, p<0.01). Analysis of the change in Barrett's oesophagus segment length change in 70 patients who were randomised to high or low PPI dose showed no difference over 2 years (n=70 t-test, p=0.8). Prolonged PPI use did, however, increase the serum gastrin, (36 pg/ml+/-57 pg/ml to 103 pg/ml+/-94 pg/ml (paired t test, p<0.05)). In vitro gastrin also induced changes in OE33(E)(cckr) Barrett's oesophagus cells, but not OE21(E)(cckr) squamous cells, transfected with CCK(2)R; migration was induced by 1 ng/ml of gastrin but proliferation only increased with 100 ng/ml (paired t-test, p<0.01) and both were abolished by antagonists.. While the short-term effects of gastrin enhance epithelial restitution in Barrett's oesophagus (but not squamous mucosa) there is no clinical evidence that Barrett's oesophagus length expands over time. This study, which is the largest and longest term randomised controlled trial of gastrin biology in Barrett's oesophagus, is further proof of the clinical safety of PPI therapy.

Topics: Adult; Aged; Barrett Esophagus; Cell Movement; Cell Proliferation; Dose-Response Relationship, Drug; Enzyme-Linked Immunosorbent Assay; Esophageal Neoplasms; Esophagus; Female; Gastric Mucosa; Gastrins; Gene Expression; Humans; Male; Middle Aged; Precancerous Conditions; Proton Pump Inhibitors; Receptor, Cholecystokinin B; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Tumor Cells, Cultured

To assess the possibility of non-invasive screening of atrophic chronic gastritis for preventing further development of gastric cancer.. One hundred and seventy-eight consecutive Helicobacter pylori (H pylori)-positive dyspeptic patients after detection of serum levels of pepsinogen-1 (PG-1) and gastrin-17 (G-17) by enzyme immunoassay were proposed for 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 grade of stomach mucosal antral or corpus atrophy and the proper decreasing of serum G17 or PG1 levels. 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.. Detection of serum G-17 and PG1 levels can be offered as the screening tool for atrophic gastritis. The positive serologic results require further chromoendoscopy with mucosal biopsy, for revealing probable progressing of atrophic process with development of intestinal metaplasia, dysplasia or gastric cancer.

Topics: Atrophy; Biomarkers; Biopsy; Gastric Mucosa; Gastrins; Gastritis; Helicobacter Infections; Helicobacter pylori; Humans; Immunoenzyme Techniques; Mass Screening; Pepsinogen A; Precancerous Conditions; Sensitivity and Specificity

: 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

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

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

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

The clinical spectrum of autoimmune gastritis is silent in the early stages of the disease and no specific symptom is related to this entity. Although gastroscopic findings of this entity are well defined, data regarding colonoscopic findings are limited. The aims of this study were to determine the prevalence of colonoscopic findings and to explore factors that might affect these findings. This is a retrospective chart review of patients with autoimmune gastritis (n=240). Data regarding colonoscopic findings, serum gastrin and chromogranin A (CgA) levels and gastric histopathological results were extracted and compared with 550 patients positive for

Topics: Adult; Aged; Chromogranin A; Colonoscopy; Colorectal Neoplasms; Female; Gastrins; Gastritis; Helicobacter Infections; Helicobacter pylori; Humans; Male; Middle Aged; Precancerous Conditions; Prevalence; Retrospective Studies

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

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

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

Methods for the measure of gastric acid secretion include invasive and non-invasive tests. The gold-standard to measure the acid output is the collection of gastric after in basal condition (Basal Acid Output, B.A.O.) and after an i.m. injection of pentagastrin (Maximal Acid Output, M.A.O.). However, direct measurement of gastric acid production is out of order in clinical practice, but many GI symptoms are claimed to be related with acid disorders and empirically cured. Hypochlorhydria is associated with precancerous conditions such as chronic atrophic gastritis (CAG). Acid measurement with non-invasive methods (pepsinogens) is supported by international guidelines.

Topics: Achlorhydria; Biomarkers; Gastric Acid; Gastric Acidity Determination; Gastrins; Gastritis, Atrophic; Humans; Pentagastrin; Pepsinogens; Peptic Ulcer; Precancerous Conditions

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

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

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

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

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 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

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

Transgenic FVB/N insulin-gastrin (INS-GAS) mice have high circulating gastrin levels, and develop spontaneous atrophic gastritis and gastrointestinal intraepithelial neoplasia (GIN) with 80% prevalence 6 months after Helicobacter pylori infection. GIN is associated with gastric atrophy and achlorhydria, predisposing mice to nonhelicobacter microbiota overgrowth. We determined if germfree INS-GAS mice spontaneously develop GIN and if H pylori accelerates GIN in gnotobiotic INS-GAS mice.. We compared gastric lesions, levels of messenger RNA, serum inflammatory mediators, antibodies, and gastrin among germfree and H pylori-monoinfected INS-GAS mice. Microbiota composition of specific pathogen-free (SPF) INS-GAS mice was quantified by pyrosequencing.. Germfree INS-GAS mice had mild hypergastrinemia but did not develop significant gastric lesions until 9 months old and did not develop GIN through 13 months. H pylori monoassociation caused progressive gastritis, epithelial defects, oxyntic atrophy, marked foveolar hyperplasia, dysplasia, and robust serum and tissue proinflammatory immune responses (particularly males) between 5 and 11 months postinfection (P<0.05, compared with germfree controls). Only 2 of 26 female, whereas 8 of 18 male, H pylori-infected INS-GAS mice developed low to high-grade GIN by 11 months postinfection. Stomachs of H pylori-infected SPF male mice had significant reductions in Bacteroidetes and significant increases in Firmicutes.. Gastric lesions take 13 months longer to develop in germfree INS-GAS mice than male SPF INS-GAS mice. H pylori monoassociation accelerated gastritis and GIN but caused less severe gastric lesions and delayed onset of GIN compared with H pylori-infected INS-GAS mice with complex gastric microbiota. Changes in gastric microbiota composition might promote GIN in achlorhydric stomachs of SPF mice.

Topics: Adenocarcinoma; Animals; Bacteroidetes; Female; Gastrins; Gastritis; Gastrointestinal Neoplasms; Germ-Free Life; Helicobacter Infections; Helicobacter pylori; Inflammation Mediators; Insulin; Male; Mice; Mice, Transgenic; Precancerous Conditions; Sex Factors

Proton pump inhibitors (PPIs) are frequently prescribed to patients with Barrett's esophagus (BE), but in a subset, they can induce significant hypergastrinemia. Elevated levels of gastrin have been associated with tumorigenic effects in a number of gastrointestinal cancers. We decided to investigate the association between serum gastrin levels and dysplasia in BE.. We performed a cross-sectional study and enrolled patients with BE without dysplasia, low-grade dysplasia (LGD), high-grade dysplasia (HGD), or adenocarcinoma (AC), as well as gastroesophageal reflux disease controls, all chronically taking PPIs. Fasting serum gastrin was measured, and data were collected on patient characteristics, medication use, and the highest degree of BE neoplasia.. A total of 95 patients were enrolled. The mean age was 64.7 (+/-10.0) years, and 70.5% were male. The median serum gastrin level was 40 pM. There was no significant difference in gastrin levels with increased degrees of BE neoplasia (overall P=0.68). In multivariable analysis, the highest quartile of gastrin was associated with significantly increased odds of advanced neoplasia (HGD or AC) (odds ratio (OR): 5.46, 95% confidence interval (CI): 1.20-24.8).. In BE patients taking PPIs, an elevated serum gastrin is associated with a history of HGD or AC. Prospective studies are needed to determine whether patients with nondysplastic BE and elevated serum gastrin are at increased risk for neoplastic progression.

Topics: Adenocarcinoma; Aged; Barrett Esophagus; Biomarkers, Tumor; Biopsy, Needle; Cell Transformation, Neoplastic; Confidence Intervals; Cross-Sectional Studies; Esophageal Neoplasms; Esophagoscopy; Female; Gastrins; Gastroesophageal Reflux; Humans; Immunohistochemistry; Incidence; Male; Middle Aged; Multivariate Analysis; Odds Ratio; Precancerous Conditions; Probability; Prognosis; Proton Pump Inhibitors; Regression Analysis; Risk Assessment

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

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

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

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

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

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 authors recently reported that gastrin gene knockout (GAS-KO) mice had an increased risk for colon carcinogenesis in response to azoxymethane (AOM) compared with their wild type (WT) littermates. In the current report, the authors discuss the predisposition of GAS-KO mice to develop obesity and metabolic hormonal changes that may contribute to their increased risk of colon carcinogenesis.. The weight and deposition of fat was monitored in the mice over a 14 month period, using magnetic resonance imaging and nuclear magnetic resonance techniques. Changes in plasma concentrations of ghrelin, leptin, insulin, and glucose were assessed using radioimmunoassay analysis and enzyme-linked immunosorbent assays. Preneoplastic markers of colon carcinogenesis (aberrant crypt foci [ACFs]), in response to AOM, were measured in a subset of obese versus lean GAS-KO mice and were compared with the markers in WT mice.. Increases in visceral adiposity were evident by age 2 months in GAS-KO mice, resulting in macroscopic obesity by age 7 months. Hyperinsulinemia and insulin:glucose ratios were increased significantly in GAS-KO mice as young as 1 month and preceded alterations in nonfasting leptin and ghrelin levels. The number of ACFs per mouse colon were increased significantly in the following order: obese GAS-KO mice > lean GAS-KO mice > WT mice. Fasting plasma insulin levels were 0.88 +/- 0.1 ng/mL, 1.45 +/- 0.3, and 2.76 +/- 0.9 ng/mL in the WT, GAS-KO lean, and GAS-KO obese mice, respectively.. The current results suggest the novel possibility that loss of amidated gastrins may increase adipogenesis, hyperinsulinemia, and colon carcinogenesis in GAS-KO mice. The increase in colon carcinogenesis may be due in part to hyperinsulinemia, increased obesity, and other associated hormone changes that were measured in GAS-KO mice.

Topics: Animals; Azoxymethane; Body Weight; Carcinogens; Colonic Neoplasms; Gastrins; Gene Expression; Ghrelin; Glucose; Hyperinsulinism; Insulin; Insulin Resistance; Leptin; Magnetic Resonance Imaging; Male; Mice; Mice, Knockout; Obesity; Peptide Hormones; Precancerous Conditions; Radioimmunoassay; Thinness

Epidemiological studies suggest that atrophic corpus-dominant gastritis is an increased risk factor for gastric carcinogenesis. The role of the Helicobacter pylori type IV secretion system (T4SS) for pathogenesis in the Mongolian gerbil model was explored.. Mongolian gerbils were infected for 32 weeks either with H. pylori type I strain B128 or with isogenic mutant strain B128delta cytotoxin-associated gene (cagY) or B128delta cagA , defective in T4SS or in the production of its effector protein CagA, respectively. Quantitative H. pylori reisolation was performed from the gastric antrum and corpus separately, cytokines were measured by quantitative reverse-transcription polymerase chain reaction, and gastric pH and hormones were determined.. B128-infected gerbils harbored high numbers of bacteria in the gastric antrum and corpus, whereas B128delta cagY and B128delta cagA colonized the antrum more densely than the corpus. All infected animals showed a strong antral inflammation and epithelial cell proliferation. B128-infected, rather than mutant-infected, gerbils presented a severe transmural inflammation with huge lymph aggregates, increased proliferation, significant atrophy, and mucous gland metaplasia in the corpus. Plasma gastrin levels and gastric pH values were significantly increased only in B128-infected gerbils. In all infected animals, the expression of the proinflammatory cytokines interleukin 1beta, interferon gamma, and growth-regulated protein was considerably increased in the antrum, but only in wild type-infected animals was an increase seen in the corpus mucosa.. The presence of an intact T4SS allows H. pylori to colonize the gastric corpus. This results in atrophic corpus-dominant gastritis, a severe precancerous condition, thus highlighting T4SS and CagA as major risk factors for gastric cancer development.

Topics: Achlorhydria; Animals; Antigens, Bacterial; Atrophy; Bacterial Proteins; Cytokines; Female; Gastric Mucosa; Gastrins; Gastritis; Gerbillinae; H(+)-K(+)-Exchanging ATPase; Helicobacter Infections; Helicobacter pylori; Hypertrophy; Mutation; Precancerous Conditions; Promoter Regions, Genetic; Pyloric Antrum; Reproducibility of Results; Reverse Transcriptase Polymerase Chain Reaction; Virulence

The authors recently reported that transgenic mice (hGAS) expressing pharmacologic levels of progastrin (PG) (> 10 nM to 100 nM) exhibited increased susceptibility to colon carcinogenesis in response to azoxymethane (AOM). It is not known whether PG functions as a cocarcinogen at the concentrations observed in patients with hypergastrinemia (approximately 1.0 nM).. The authors generated transgenic mice that overexpressed either wild-type (wtPG) or mutant (mtPG) human PG in the intestinal mucosa using the murine fatty acid binding protein (Fabp) promoter. Fabp-PG mice and their wild-type littermates were treated with AOM, and their colons were examined for preneoplastic (aberrant crypt foci [ACF]) and neoplastic (adenomas [Ads] and adenocarcinomas [AdCas]) lesions after 2 weeks and 6 months of treatment.. ACF and tumors were significantly more common (by a factor of approximately 2) in colon specimens from both Fabp-wtPG mice and Fabp-mtPG mice relative to wild-type mice. It is noteworthy that the multiplicity of ACF and the total number of small and large Ads and AdCas were significantly greater in colon specimens from Fabp-PG mice compared with colon specimens from wild-type mice, irrespective of gender.. The results of the current study suggest that at concentrations (approximately 1.0 nM) far lower than the ones observed in hGAS mice, PG functions as an equally potent cocarcinogen and significantly increases the risk of colon carcinogenesis in response to AOM. Thus, PG may represent a clinically relevant target molecule in patients with hypergastrinemia or colon carcinoma.

Topics: Animals; Azoxymethane; Carcinogens; Colonic Neoplasms; Female; Gastrins; Humans; Male; Mice; Mice, Transgenic; Polymerase Chain Reaction; Precancerous Conditions; Protein Precursors; Radioimmunoassay

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

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

We recently reported that transgenic mice overexpressing progastrin were at a higher risk for developing colon cancers in response to azoxymethane (AOM), whereas mice overexpressing gastrin-17 were at a reduced risk. To examine further the role of gastrins in colon carcinogenesis, we generated gastrin gene knockout mice (GAS-KO).. The height and proliferative index (PI) of colonic crypts were similar in GAS-KO and wild-type (WT) mice, suggesting that the absence of gastrins in GAS-KO mice did not significantly affect the growth of colonic mucosa. GAS-KO and WT mice were treated with AOM for 3-4 weeks; control mice received saline.. Colonic proliferation in response to AOM was significantly increased in GAS-KO vs. WT mice. Aberrant crypt foci (ACFs) were similarly increased significantly by approximately 2-5-fold in GAS-KO vs. WT mice after 2 weeks of AOM treatment. Female GAS-KO mice developed adenomas (Ads) and adenocarcinomas (AdCAs) at earlier times ( approximately 10 months) than the male GAS-KO mice and the male and female WT mice ( approximately 12 months). The total numbers of Ads and AdCAs were significantly higher in GAS-KO than in WT mice.. These results suggest the novel possibility that loss of gastrin expression (and hence amidated gastrins) significantly increases susceptibility to colon carcinogenesis in response to AOM. Previous studies with FVB/N transgenic mice similarly suggested a protective role of amidated gastrins against colon carcinogenesis, which supports the present findings of an increase in colon carcinogenesis in GAS-KO mice lacking normal physiological levels of amidated gastrins.

Topics: Animals; Azoxymethane; Colonic Neoplasms; Female; Gastrins; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Precancerous Conditions

Previous studies in our laboratory demonstrated that pancreatic carcinomas in rodents express receptors for the peptide hormone gastrin that are not present in normal adult pancreas. In view of an abundant literature suggesting that gastrin may promote growth of various gastrointestinal tissues and tumors, the effect of hypergastrinemia on the process of pancreatic carcinogenesis was evaluated.. Rats received subcutaneous injections of the pancreatic carcinogen azaserine at 19 and 26 days of age. Starting at 12 months of age, animals were randomized to treatment with the proton pump inhibitor lansoprazole or vehicle by gavage for 6 months. At autopsy, pancreatic wet weight normalized to body weight was recorded, as well as the number of benign and malignant pancreatic lesions.. Serum gastrin levels were determined by radioimmunoassay and showed a greater than two-fold increase in lansoprazole-treated animals. Pancreatic wet weight in hypergastrinemic rats was increased compared to controls (p <0.05). Premalignant lesions such as acidophilic atypical acinar cell foci, adenomas, heterogeneous phenotypic populations of nodules within nodules, and carcinoma-in-situ were not increased in the hypergastrinemic group. Likewise, there was no difference in the incidence of invasive carcinoma in hypergastrinemic animals (10%) compared to controls (5.7%).. Hypergastrinemia stimulated an increase in pancreatic weight, but did not stimulate development of premalignant lesions or progression to cancer in the azaserine model of rat pancreatic acinar cell carcinoma.

Topics: 2-Pyridinylmethylsulfinylbenzimidazoles; Adenoma; Animals; Anti-Ulcer Agents; Azaserine; Carcinoma in Situ; Carcinoma, Acinar Cell; Disease Models, Animal; Gastrins; Lansoprazole; Male; Omeprazole; Organ Size; Pancreas; Pancreatic Neoplasms; Precancerous Conditions; Rats; Rats, Inbred Lew

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

Evidence is accumulating that gastrin precursors may act as growth factors for the colonic mucosa in vivo and for colorectal carcinoma cell lines in vitro. The effect of short term administration of synthetic gastrins on the colonic mucosa in vivo, however, has not been reported. The aim of our study was to determine whether continuous systemic infusion of glycine-extended gastrin(17) stimulated proliferation and accelerated carcinogenesis in the colorectal mucosa. A significant increase in colonic mucosal proliferation as assessed by metaphase index was seen in the caecum (23%, p < 0.02) and distal colon (27%, p < 0.001), but not the rectum, after treatment of intact rats with glycine-extended gastrin(17) for 1 week using implanted miniosmotic pumps. Defunctioning of the rectum reduced both the proliferative index and crypt height of the rectal mucosa of untreated rats. Treatment of rectally defunctioned animals with glycine-extended gastrin(17) for either 1 or 4 weeks resulted in a significant increase in both the proliferative index (40% and 93%, respectively) and crypt height (11% and 19%, respectively) of the rectal mucosa. The total number of aberrant crypt foci in intact rats treated with the procarcinogen azoxymethane plus glycine-extended gastrin(17) was increased by 48% compared to the value in controls treated with azoxymethane only (p = 0.01). We conclude that short term administration of glycine-extended gastrin(17) to mature rats not only has a proliferative effect upon colonic mucosa, but also increases the number of aberrant crypt foci formed in the colorectal mucosa after treatment with azoxymethane. Glycine-extended gastrin(17) could thus potentially act as a promoter of carcinogenesis.

Topics: Animals; Azoxymethane; Carcinogens; Cell Division; Colon; Colonic Neoplasms; Gastrins; Glycine; Hormones; Male; Mucous Membrane; Precancerous Conditions; Rats; Rats, Sprague-Dawley; Time Factors

Recent studies show that nonamidated gastrins (Gly-gastrin and progastrin) stimulate colonic proliferation. However, the role of nonamidated vs. amidated gastrins in colon carcinogenesis has not been defined. We measured intermediate markers of carcinogenesis in transgenic mice overexpressing either progastrin (hGAS) or amidated gastrin (INS-GAS) in response to azoxymethane (AOM). The hGAS mice showed significantly higher numbers of aberrant crypt foci (140-200% increase) compared with that in wild-type (WT) and INS-GAS mice (P < 0.05) after AOM treatment. The bromodeoxyuridine-labeling index of colonic crypts also was significantly elevated in hGAS mice vs. that in WT and INS-GAS mice. The results therefore provide evidence for a mitogenic and cocarcinogenic role of nonamidated gastrins (progastrin), which is apparently not shared by the amidated gastrins. Although nonamidated gastrins are now believed to mediate mitogenic effects via novel receptors, amidated gastrins mediate biological effects via different receptor subtypes, which may explain the difference in the cocarcinogenic potential of nonamidated vs. amidated gastrins. In conclusion, our results provide strong support for a cocarcinogenic role for nonamidated gastrins in colon carcinogenesis.

Topics: Animals; Azoxymethane; Bromodeoxyuridine; Carcinogens; Colon; Colonic Neoplasms; Disease Susceptibility; Gastrins; Humans; Mice; Mice, Inbred Strains; Mice, Transgenic; Precancerous Conditions; Protein Precursors

Gastrin and the cholecystokinin type B/gastrin receptor (CCKBR) have been shown to be expressed in colorectal adenocarcinoma. Both exogenous and autocrine gastrin have been demonstrated to stimulate growth of colorectal cancer but it is not known if gastrin affects the growth of colonic polyps. The purpose of this study was to determine if gastrin and CCKBR are expressed in human colonic polyps and to determine at which stage of progression this occurs.. A range of human colonic polyps was assessed for gastrin and CCKBR gene and protein expression.. Normal colonic mucosa did not express gastrin or CCKBR. Gastrin and CCKBR reverse transcription-polymerase chain reaction products were detected and verified by specific hybridisation with an oligo probe on Southern blots. Gastrin and CCKBR were expressed in 78% and 81% of polyps, respectively. Both genes were coexpressed in 97% of cases. Immunohistochemistry identified progastrin in 91%, glycine extended gastrin 17 in 80%, and amidated gastrin 17 in only 47% of polyps. CCKBR was present in 96% of polyps. Expression of gastrin and CCKBR was seen in all histological types and sizes of polyps.. This study is the first to show widespread expression of both gastrin and its receptor in colorectal polyps. Their activation occurs early in the adenoma-carcinoma sequence. Gastrin may promote progression through the adenoma-carcinoma sequence.

Topics: Adenoma; Aged; Carcinoma; Colonic Neoplasms; Colonic Polyps; Disease Progression; Female; Gastrins; Humans; Immunohistochemistry; Male; Middle Aged; Neoplasm Proteins; Precancerous Conditions; Receptor, Cholecystokinin B; Receptors, Cholecystokinin; Reverse Transcriptase Polymerase Chain Reaction

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

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

Topics: Abdominal Pain; Adult; Anemia, Pernicious; Carcinoid Tumor; Diagnosis, Differential; Female; Gastrins; Gastritis, Atrophic; Gastroscopy; Humans; Hyperplasia; Precancerous Conditions; Pyloric Antrum; Stomach Neoplasms

The hormone gastrin is thought to stimulate the growth of certain pancreatic carcinoma cell lines. We have previously detected the presence of the gastrin receptor in rat pancreatic carcinoma cell lines but not in normal rat pancreas. We had not, however, previously demonstrated that gastrin receptor is expressed in pancreatic carcinomas developing in the rat in vivo. Therefore, in the present study, we examined rat pancreatic tissue at various stages in azaserine-induced pancreatic carcinogenesis for gastrin binding and for the presence of gastrin receptor mRNA to determine the temporal expression pattern of the gastrin receptor during the in vivo development of pancreatic cancer. Autoradiography of pancreatic tissue using (125)I-gastrin-17-I from all azaserine-treated and control animals at 2, 4, 8, and 12 months of age demonstrated no specific gastrin binding. At 18 months of age, normal pancreas, azaserine-induced premalignant pancreatic nodules, and internodular pancreas demonstrated no specific gastrin binding. One of three azaserine-treated animals developed an area of pancreatic acinar cell carcinoma at 18 months of age which exhibited significant specific gastrin binding of 141.8 - 32.8 fmole/gm of tissue. Southern blot analysis of pancreatic RNA isolated from animals at 12 months of age revealed no gastrin receptor mRNA; however, by 18 months of age, gastrin receptor mRNA was present in all azaserine-treated animals but absent in control animals. In summary, specific gastrin binding is present in in vivo azaserine-induced pancreatic acinar cell carcinoma but absent in normal pancreas and azaserine-induced premalignant pancreatic nodules. Gastrin receptor mRNA is first expressed in azaserine-treated rat pancreas at some point between 12 and 18 months of age. These results demonstrate that expression of gastrin receptor is altered in azaserine-treated rat pancreas and may play a role in the development of pancreatic cancer.

Topics: Animals; Autoradiography; Azaserine; Base Sequence; Carcinogens; Carcinoma, Acinar Cell; DNA Primers; Gastrins; Gene Expression; Male; Molecular Sequence Data; Pancreas; Pancreatic Neoplasms; Polymerase Chain Reaction; Precancerous Conditions; Rats; Rats, Inbred Lew; Receptors, Cholecystokinin; RNA, Messenger

We surgically prepared a hypergastrinemia model in rats and studied the effects of hypergastrinemia on chemically induced carcinogenesis in the esophagus. Operations were performed on 5-week-old male Donryu rats as follows: (1) truncal vagotomy plus pyloroplasty (group V), (2) segmental gastrectomy plus pyloroplasty (group G), (3) antrectomy (group A), and (4) no operation (group C) as a control. From the age of 6 weeks, the animals were given 0.003% N-methyl- N-amylnitrosamine (MAN) solution as drinking water for 8 weeks. After 20 weeks of MAN administration, the animals were bled and killed. The average serum gastrin levels in groups V and G were significantly higher than those groups C or A. There were significant differences between C and V in the incidence of carcinoma, and between V and A in the incidence of carcinoma including severe dysplasia. The incidence of histologically identified lesions per animal was determined, and significant differences were observed between C and both V and G in the incidence of carcinoma including severe dysplasia. Furthermore, we also detected gastrin receptors in the esophageal lesions produced by the oral administration of MAN to rats. The results of the present study suggest that endogenous hypergastrinemia has a positive influence on chemically induced carcinogenesis in the rat esophagus.

Topics: Animals; Carcinogens; Carcinoma, Squamous Cell; Cell Transformation, Neoplastic; Disease Models, Animal; Esophageal Neoplasms; Gastrins; Male; Nitrosamines; Precancerous Conditions; Rats; Rats, Inbred Strains; Receptors, Cholecystokinin

The effect of somatostatin on hepatocarcinogenesis induced by N-nitrosomorpholine (NNM) was investigated in male Sprague-Dawley rats. Rats were given drinking water containing NNM for 8 weeks and s.c. injections of 200 micrograms/kg body wt of somatostatin every other day from the beginning of the experiment until the end of week 16. Pre-neoplastic and neoplastic lesions staining for gamma-glutamyl transpeptidase (GGT) or placental type glutathione-S-transferase (GST-P) were examined histochemically. Administration of somatostatin for 16 weeks resulted in significant reduction in the percentage volume of GGT-positive and GST-P-positive lesions. The incidence, number and size of hepatocellular carcinomas were significantly less in rats treated with somatostatin than in untreated rats. Administration of somatostatin significantly decreased the labeling indices of pre-neoplastic lesions and adjacent liver. These findings indicate that somatostatin inhibits hepatocarcinogenesis and that this effect may be related to its effect in decreasing cell proliferation in pre-neoplastic lesions.

Topics: Animals; Body Weight; Carcinogens; gamma-Glutamyltransferase; Gastrins; Glutathione Transferase; Liver; Liver Neoplasms, Experimental; Male; Nitrosamines; Organ Size; Precancerous Conditions; Rats; Rats, Sprague-Dawley; Somatostatin

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

We studied the effects of hormonal manipulation by orchiectomy, alone or in combination with the aromatase inhibitor aminoglutethimide (AGT), and by luteinizing hormone-releasing hormone agonist (LH-RH-A) (goserelin) treatment on the development of early putative (pre)neoplastic lesions induced in the pancreas of rats and hamsters by azaserine and N-nitrosobis(2-oxopropyl)amine respectively. Treatment of the animals started 1 week after the last injection with carcinogen and continued for 4 months. Orchiectomy caused a significant inhibition of growth of acidophilic atypical acinar cell nodules in the rat model, whereas surgical castration did not show an effect in the hamster model. In rats, but not in hamsters, orchiectomy resulted in a significant decrease in body weight and in absolute, but not relative pancreatic weight. Treatment of the animals with AGT or goserelin did not cause a significant effect on the development of either putative preneoplastic acinar lesions in rat pancreas or early ductular lesions in hamster pancreas. Hamsters showed clearly higher plasma epidermal growth factor (EGF) and insulin-like growth factor 1 (IGF-1) concentrations than rats, while plasma testosterone levels were significantly lower. Plasma EGF and IGF-1 levels decreased with increasing age in both control and treatment groups. Compared to controls there were no clear unequivocal effects of treatment on EGF, IGF-1 and gastrin levels. Plasma testosterone levels decreased by orchiectomy and LH-RH-A treatment. In rats hormone-induced effects on food intake and altered nutritional status might be important with respect to the development of carcinogen-induced preneoplastic pancreatic lesions.

Topics: Aminoglutethimide; Animals; Azaserine; Body Weight; Buserelin; Carcinogens; Cricetinae; Epidermal Growth Factor; Gastrins; Goserelin; Male; Mesocricetus; Nitrosamines; Orchiectomy; Organ Size; Pancreatic Neoplasms; Precancerous Conditions; Rats; Rats, Inbred Strains; Somatomedins; Testosterone

Clinical and experimental evidence indicates that carcinoid tumours of the stomach fundic mucosa represent another example of hormone-dependent neoplasm, gastrin being the hormone involved in tumour induction. In this context hyperplasia of fundic endocrine cells associated with chronic atrophic gastritis (CAG) and hypergastrinaemia is regarded as the most frequent preneoplastic lesion. However, the cell type involved in this hyperplasia has not been clarified. To elucidate this problem fundic endocrine cells were characterized ultrastructurally in 9 patients from which endoscopic gastric biopsies were obtained. ECL cells were the most frequent cell type in 8 cases, in 4 of which they were more numerous than all other cell types taken together. D1 cells were the most frequent type in one case while they were inconspicuous in the other cases. P cells were found with a frequency in each case intermediate between that of ECL cells and that of D1 cells. These results indicate that fundic endocrine cell hyperplasia occurring in hypergastrinaemic CAG is in most cases cytologically similar to that found in other hypergastrinemic conditions, in which the gastrin-dependent ECL cells were already found to prevail. They also explain why fundic carcinoids arising in CAG are mostly composed of ECL cells. The relation between ECL, D1 and P cells, if any, remains obscure.

Topics: Adolescent; Aged; Biopsy; Carcinoid Tumor; Chronic Disease; Female; Gastric Fundus; Gastric Mucosa; Gastrins; Gastritis; Gastritis, Atrophic; Humans; Hyperplasia; Male; Microscopy, Electron; Middle Aged; Precancerous Conditions

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

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

Topics: Gastric Acidity Determination; Gastrins; Humans; Hyperplasia; Precancerous Conditions; Pyloric Antrum; Stomach; Stomach Neoplasms; Stomach Ulcer