gastrins and Adenocarcinoma

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

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

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

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

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

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

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

Gastrin is the main hormone responsible for the stimulation of gastric acid secretion; in addition, gastrin and its derivatives exert proliferative and antiapoptotic effects on several cell types. Gastrin synthesis and secretion are increased in certain situations, for example, when proton pump inhibitors are used. The impact of sustained hypergastrinemia is currently being investigated. In vitro experiments and animal models have shown that prolonged hypergastrinemia may be related with higher cancer rates; although, this relationship is less clear in human beings. Higher gastrin levels have been shown to cause hyperplasia of several cell types; yet, the risk for developing cancer seems to be the same in normo- and hypergastrinemic patients. Some tumors also produce their own gastrin, which can act in an autocrine manner promoting tumor growth. Certain cancers are extremely dependent on gastrin to proliferate. Initial research focused only on the effects of amidated gastrins, but there has been an interest in intermediates of gastrin in the last few decades. These intermediates aren't biologically inactive; in fact, they may exert greater effects on proliferation and apoptosis than the completely processed forms. In certain gastrin overproduction states, they are the most abundant gastrin peptides secreted. The purpose of this review is to examine the gastrin biosynthesis process and to summarize the results from different studies evaluating the production, levels, and effects of the main forms of gastrin in different overexpression states and their possible relationship with Barrett's and colorectal carcinogenesis.

Topics: Adenocarcinoma; Animals; Apoptosis; Barrett Esophagus; Biopsy; Cell Proliferation; Colorectal Neoplasms; Esophageal Neoplasms; Gastrins; Gene Expression Regulation, Neoplastic; Humans; Mice

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

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

Oesophageal adenocarcinoma (OA) remains one of the more deadly forms of gastro-intestinal cancer with a mortality rate exceeding 90%. The incidence of OA remains unabated and has a reported fivefold increase since 1970 [Pera M, Cameron AJ, Trastek VF, Carpenter HA & Zinsmeister AR. Increasing incidence of adenocarcinoma of the esophagus and esophagogastric junction. Gastroenterology 1993; 104(2): 510-513]. Gastro-oesophageal reflux disease and its sequelae, Barrett's oesophagus, is one of the principle risk factors in the development of OA, with a 30-fold increased risk in Barrett's patients compared with the general population [Tytgat GNJ. Does endoscopic surveillance in esophageal columnar metaplasia (Barrett's-Esophagus) have any real value. Endoscopy 1995; 27(1): 19-26]. OA is thought to be a microcosm of evolution, developing sequentially along the metaplasia-dysplasia-adenocarcinoma sequence. Progression is attributed to a series of genetic and epigenetic events that ultimately allow for clonal selection of Barrett's cells via subversion of intrinsic control mechanisms regulating cellular proliferation and/or apoptosis. This review will describe the current suppositions of the mechanisms behind the selection and subsequent expansion of Barrett's clones, and focus on some of the principle hallmarks associated with this transition.

Topics: Adenocarcinoma; Animals; Barrett Esophagus; Bile Acids and Salts; Cell Transformation, Neoplastic; Disease Progression; Esophageal Neoplasms; Esophagogastric Junction; Gastrins; Gastroesophageal Reflux; Humans; Inflammation Mediators; Metaplasia; Prevalence

Colorectal cancer is one of the leading causes of cancer-associated death in the United States and United Kingdom. In England and Wales, it is the second most common cancer in women and the third most common in men. Currently, treatment options for this debilitating disease are limited and surgical resection is the only curative treatment available. Despite rapid advances in surgery, as well as in adjuvant therapies such as radiotherapy and chemotherapy, there has been only a relatively modest improvement in mortality. The majority of colorectal cancers are epithelial-derived adenocarcinomas and arise from benign adenomas through the gain of mutations in key genes. Gastrin, an important polypeptide hormone, responsible for gastric acid secretion has been found to be involved in tumourigenesis in the gastrointestinal tract. When aberrantly expressed, the gastrin and gastrin/CCK-2 receptor genes can mediate powerful down stream events; the gastrin gene can impart anti-apoptotic properties while the gastrin/CCK-2 receptor can activate the transcription of a number of factors including ligands of the epidermal growth factor (EGF) receptor, the REG protein and matrix metalloproteinases (MMPs). In colonic tumourigenesis, gene expression of both gastrin and the gastrin/CCK-2 receptor is activated within epithelial cells at an early stage of the adenoma-carcinoma sequence. This review details the role played by gastrin in the adenoma-carcinoma sequence of colorectal carcinogenesis.

Topics: Adenocarcinoma; Cholecystokinin; Colorectal Neoplasms; Gastrins; Gene Expression Regulation, Neoplastic; Humans

Several case reports have emphasized that esophageal carcinoid tumors are associated with a poor prognosis. To expand our knowledge about the pathology and biologic behavior of these rare tumors, we reviewed the clinicopathologic and immunohistochemical findings of four cases of primary esophageal carcinoid. The age of the patients ranged from 48 to 82 years (mean 63 years; median 61 years). The lower segment of the esophagus was involved in two cases and the mid segment was involved in one case. The sizes of the tumors ranged from 0.3 cm to 3.5 cm. Two tumors were confined to the lamina propria and two invaded into the muscular wall. Two tumors appeared polypoid, whereas the remaining two were incidental findings and associated with adenocarcinoma arising in a background of Barrett esophagus. The adenocarcinoma was superficially invasive in one case, whereas it penetrated the muscular wall in the other. All four carcinoid tumors were immunoreactive with chromogranin and synaptophysin. There was focal expression of serotonin in two cases, glucagon in one case, and pancreatic polypeptide in one case. Endocrine cell hyperplasia was noted in both the Barrett esophagus and the invasive adenocarcinoma. One patient died secondary to postoperative pneumonia. Three patients are alive and disease free at 1, 6, and 23 years status post therapy. None of the patients had metastatic disease. These findings show that esophageal carcinoids are associated with a favorable prognosis. They arise in two settings: (1) a single large polypoid tumor or (2) an incidental finding and in association with adenocarcinoma arising in the background of Barrett esophagus. The presence of endocrine cell hyperplasia in the Barrett mucosa and the adenocarcinoma supports the hypothesis that these lesions arise from a common stem cell.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Barrett Esophagus; Carcinoid Tumor; Chromogranins; Esophageal Neoplasms; Female; Gastrins; Glucagon; Humans; Immunohistochemistry; Keratins; Male; Middle Aged; Pancreatic Polypeptide; Polyps; Prognosis; Synaptophysin

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

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

Increased basal serum gastrin level has been described in patients presenting with colorectal cancer. The aim of this work was to study the evolution of serum gastrin levels after cancer treatment. We measured basal serum gastrin levels before and 1 to 2 months after treatment in 15 patients (7 men, 8 women; mean age: 61.6 years). There were 3 malignant polyps, 4 Dukes A, 3 Dukes B, 4 Dukes C and 1 Dukes D colonic cancers. Treatment included 3 endoscopic polypectomies, 2 laser photodestructions, and 10 surgical resections, Mean basal gastrin level after treatment (49.07 +/- 12.65 mIU/l) was significantly lower (P less than 0.002) than before treatment (104.47 +/- 26.98 mIU/l). In the 2 patients treated by laser therapy, recurrences were associated with reincreasing serum gastrin levels. These results suggest an "autocrine" secretion of gastrin.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Colonic Neoplasms; Endoscopy, Gastrointestinal; Female; Gastrins; Humans; Laser Therapy; Male; Middle Aged; Neoplasm Recurrence, Local; Postoperative Care; Preoperative Care; Rectal Neoplasms; Time Factors

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

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

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

There is a significant inverse relationship between intragastric acidity and plasma gastrin concentration. All generally available gastric acid antisecretory drugs induce a release of gastrin into the circulation. The more potent the gastric antisecretory dosage regimen or drug, the greater the rise of plasma gastrin concentration. The drug-induced rise of plasma gastrin concentration is of no direct clinical concern, although it may be partly responsible for the phenomenon of tolerance to H2-blockade. Drug-induced hypergastrinemia could stimulate the proliferation of certain cell lines associated with the gastrointestinal tract, for example, the gastric epithelium, ECL cells, or colonic neoplasms.

Topics: Adenocarcinoma; Animals; Campylobacter Infections; Gastric Acid; Gastrins; Gastritis; Gastrointestinal Neoplasms; Humans

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

The aim of this study was to determine the ability of G17DT to generate anti-gastrin antibodies in jaundiced patients with biliary obstruction due to advanced pancreatic cancer.. G17DT was administered to 41 patients with advanced pancreatic adenocarcinoma by intramuscular (i.m.) injection at a dose of 250mcg at weeks 0, 1 and 3 of the study.. Thirty-five of 41 patients participating in the study were categorized as responders in terms of their gastrin-17 antibody response. There was no correlation between the maximum G17 antibody response and the bilirubin level at either week 0 or week 12. The median survival of patients from the time of the first injection of G17DT was 204 days with 25% of patients surviving for or=305 days.. This study shows that G17DT administered to jaundiced patients with advanced pancreatic cancer is immunogenic and well tolerated.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antibody Formation; Bilirubin; Cancer Vaccines; Cholestasis; Disease Progression; Female; Gastrins; Humans; Immunization; Injections, Intramuscular; Jaundice; Male; Middle Aged; Pancreatic Neoplasms; Survival Analysis; Time Factors; Treatment Outcome; United Kingdom

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

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

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

Twelve patients with rectal carcinoma were treated for 2 weeks with the somatostatin analogue SMS 201.995. Effects of this therapy were assessed using serum marker concentration, Ki67 and gastrin-immunoreactivity of the primary tumour. In four out of 12 patients, a significant decrease in Ki67 immunoreactivity was seen during SMS 201.995 treatment while in the remaining eight patients there was no significant change in Ki67 expression. Four patients had elevated pretreatment serum carcinoembryonic antigen (CEA) levels. In two of these four patients, serum CEA levels fell modestly during SMS 201.995 therapy. This is the first clinical evidence that a somatostatin analogue can inhibit the growth of some colorectal cancers.

Topics: Adenocarcinoma; Antigens, Tumor-Associated, Carbohydrate; Antineoplastic Agents; Biomarkers, Tumor; Carcinoembryonic Antigen; Cell Division; Gastrins; Humans; Infusions, Parenteral; Ki-67 Antigen; Kinetics; Nuclear Proteins; Octreotide; Rectal Neoplasms

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

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

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

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

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

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

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

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

Staging of colorectal cancer often fails to discriminate outcomes of patients with morphologically similar tumours that exhibit different clinical behaviours. Data from several studies suggest that the gastrin family of growth factors potentiates colorectal cancer tumourigenesis. The aim of this study was to investigate whether progastrin expression may predict clinical outcome in colorectal cancer.. Patients with colorectal adenocarcinoma of identical depth of invasion who had not received neoadjuvant therapy were included. The patients either had stage IIa disease with greater than 3-year disease-free survival without adjuvant therapy or stage IV disease with liver metastases on staging CT. Progastrin expression in tumour sections was scored with reference to the intensity and area of immunohistochemical staining.. Progastrin expression by stage IV tumours was significantly greater than stage IIa tumours with mean progastrin immunopositivity scores of 2.1 ± 0.2 versus 0.5 ± 0.2, respectively (P < 0.001).. This is the first study to show that progastrin expression may be predictive of aggressive tumour behaviour in patients with colorectal cancer and supports its clinical relevance and potential use as a biomarker.

Topics: Adenocarcinoma; Aged; Biomarkers, Tumor; Colorectal Neoplasms; Female; Gastrins; Humans; Liver Neoplasms; Male; Middle Aged; Neoplasm Staging; Protein Precursors

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Understanding gene transcription regulatory networks is critical to deciphering the molecular mechanisms of different cellular states. Most studies focus on static transcriptional networks. In the current study, we used the gastrin-regulated system as a model to understand the dynamics of transcriptional networks composed of transcription factors (TFs) and target genes (TGs). The hormone gastrin activates and stimulates signaling pathways leading to various cellular states through transcriptional programs. Dysregulation of gastrin can result in cancerous tumors, for example. However, the regulatory networks involving gastrin are highly complex, and the roles of most of the components of these networks are unknown. We used time series microarray data of AR42J adenocarcinoma cells treated with gastrin combined with static TF-TG relationships integrated from different sources, and we reconstructed the dynamic activities of TFs using network component analysis (NCA). Based on the peak expression of TGs and activity of TFs, we created active sub-networks at four time ranges after gastrin treatment, namely immediate-early (IE), mid-early (ME), mid-late (ML) and very late (VL). Network analysis revealed that the active sub-networks were topologically different at the early and late time ranges. Gene ontology analysis unveiled that each active sub-network was highly enriched in a particular biological process. Interestingly, network motif patterns were also distinct between the sub-networks. This analysis can be applied to other time series microarray datasets, focusing on smaller sub-networks that are activated in a cascade, allowing better overview of the mechanisms involved at each time range.

Topics: Adenocarcinoma; Cell Line, Tumor; Gastrins; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Gene Regulatory Networks; Humans; Molecular Sequence Annotation; Nucleotide Motifs; Transcription Factors

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Atrophic gastritis of the corporal mucosa is a frequent cause of hypergastrinemia. Hypergastrinemia is implicated in colorectal cancer development.. To assess whether hypergastrinemic atrophic gastritis is associated with a higher risk of neoplastic colorectal lesions.. Among 441 hypergastrinemic atrophic gastritis patients, 160 who were aged >40 and underwent colonoscopy for anaemia, diarrhoea or colorectal cancer-screening were retrospectively selected. Each patient was age- and gender-matched with a normogastrinemic control with healthy stomach. Controls had colonoscopy, gastroscopy with biopsies and gastrin assessment.. 160 hypergastrinemic atrophic gastritis patients and 160 controls were included. 28 atrophic gastritis patients and 36 controls had neoplastic colorectal lesions (p=0.33). Patients and controls did not differ for frequency of colorectal adenomas (10.6% vs. 13.1%, p=0.60) or cancer (6.9% vs. 9.4%, p=0.54). Hypergastrinemic atrophic gastritis was not associated with a higher probability of developing colorectal cancer (OR 1.03, 95% CI 0.34-3.16). Age >50 years (OR 3.86) but not hypergastrinemia (OR 0.61) was associated with colorectal cancer.. Hypergastrinemic atrophic gastritis is not associated with higher risk for colorectal cancer. Atrophic gastritis-related hypergastrinemia is not associated with an increased risk of neoplastic colorectal lesions. Closer surveillance of colonic neoplasia in atrophic gastritis patients seems not appropriate.

Topics: Adenocarcinoma; Adenoma; Adult; Age Factors; Aged; Aged, 80 and over; Case-Control Studies; Colorectal Neoplasms; Confidence Intervals; Female; Gastrins; Gastritis, Atrophic; Humans; Male; Middle Aged; Odds Ratio; Retrospective Studies; Risk Factors; Statistics, Nonparametric

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

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

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

Cholecystokinin (CCK) and gastrin stimulate growth of pancreatic cancer. Although down-regulation of gastrin inhibits growth of pancreatic cancer, the contribution of endogenous CCK to tumor growth is unknown. The purpose of this study was to evaluate the role of endogenous CCK on autocrine growth of pancreatic cancer. Pancreatic cancer cell lines were analyzed for CCK mRNA and peptide expression by real-time RT-PCR and radioimmunoassay, respectively. The effect of endogenous CCK on growth was evaluated by treating cancer cells with CCK neutralizing antibodies and by down-regulating CCK mRNA by RNAi. Wild-type pancreatic cancer cells expressed significantly lower CCK mRNA and peptide levels than gastrin. Neither treatment of pancreatic cancer cells with CCK antibodies nor the down-regulation of CCK mRNA and peptide by shRNAs altered growth in vitro or in vivo. Conversely, when gastrin mRNA expression was down-regulated, the same cells failed to produce tumors in spite of having sustained levels of endogenous CCK. Pancreatic cancer cells produce CCK and gastrin; however, the autocrine production of gastrin is more important for stimulating tumor growth.

Topics: Adenocarcinoma; Animals; Antibodies, Neutralizing; Autocrine Communication; Cell Line, Tumor; Cell Proliferation; Cholecystokinin; Gastrins; Gene Expression Regulation, Neoplastic; Humans; Male; Mice; Mice, Nude; Pancreatic Neoplasms; RNA, Messenger; RNA, Small Interfering; Tissue Distribution; Xenograft Model Antitumor Assays

Barrett's esophageal cancer is usually included in gastroesophageal (GE) junction adenocarcinoma in Japanese people. No study on the pathogenesis of Barrett's esophageal cancer in comparison with GE junction adenocarcinoma other than Barrett's esophageal cancer has been reported in Japan. The aim of this study was to evaluate the clinical and pathological characteristics and gastric acid secretion of Barrett's esophageal cancer and GE junction adenocarcinoma other than Barrett's esophageal cancer in Japanese subjects.. Twenty-three patients with Barrett's esophageal cancer and 23 patients with GE junction adenocarcinoma other than Barrett's esophageal cancer were enrolled in this study. We evaluated and compared them by assessing the Helicobactor pylori (HP) infection status and gastric acid secretion using the endoscopic gastrin test (EGT).. In the patients with Barrett's esophageal cancer, no significant difference was found in the mean EGT value between HP-positive and -negative patients, but in the patients with GE junction adenocarcinoma other than Barrett's esophageal cancer, the mean EGT value in HP-positive patients was significantly lower than that in HP-negative patients.. Two distinct types of cancer of different origin may be mixed in GE junction adenocarcinomas. One is Barrett's esophageal cancer associated with high gastric acid secretion and reflux of gastric acid into the esophagus, the other is cancer resembling distal gastric cancer associated with gastric atrophy and low gastric acid secretion.

Topics: Adenocarcinoma; Aged; Barrett Esophagus; Case-Control Studies; Endoscopy, Digestive System; Esophageal Neoplasms; Esophagogastric Junction; Female; Gastric Acid; Gastrins; Gastritis; Helicobacter Infections; Helicobacter pylori; Humans; Japan; Male; Middle Aged; Prevalence; Severity of Illness Index

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

Barrett's oesophagus (BO) and oesophageal adenocarcinoma (OAC) are regarded as complications of gastro-oesophageal reflux disease, although all the factors that contribute to the development of these lesions are unknown. Acid suppressive drugs are widely used for symptomatic therapy of reflux disease but may induce hypersecretion of gastrin peptides. Amidated gastrin (G-17) has been shown to be a growth factor for OAC cells. We have examined the effects of glycine-extended gastrin (G-Gly), an alternative product of progastrin processing on apoptosis in the QhERT Barrett's oesophageal cell line and OE33 and BIC-1 OAC cells. G-Gly inhibited serum-starvation and camptothecin-induced apoptosis in all three cell lines, G-17 was only effective in OE33 cells. By contrast to the effects of G-17, the anti-apoptotic effect of G-Gly was independent of both the CCK(2) receptor and cyclo-oxygenase-2 activity. G-Gly stimulated JAK2 phosphorylation and kinase activity and JAK2-dependent STAT3 phosphorylation and transcriptional activity. G-Gly also increased mRNA and protein levels of the anti-apoptotic proteins survivin and BCL2L1 but did not affect the levels of BAD, BAX or BCL-2. Novel small molecule inhibitors of JAK2 and STAT3 as well as STAT3 siRNA blocked the anti-apoptotic effects of G-Gly and inhibited the induction of survivin and BCL2L1 in OE33 cells. We conclude that G-Gly inhibits apoptosis in BO and OAC via mechanisms distinct from those activated by G-17 and involving JAK2 and STAT3 activation. Release of gastrin peptides in response to acid suppressive therapy may adversely influence the dynamics of the epithelium in BO.

Topics: Adenocarcinoma; Apoptosis; Barrett Esophagus; Cell Line, Tumor; Cyclooxygenase Inhibitors; Enzyme Activation; Esophageal Neoplasms; Gastrins; Humans; Janus Kinase 2; Receptors, Cholecystokinin; RNA Interference; RNA, Small Interfering; Signal Transduction; STAT3 Transcription Factor

Glycine-extended gastrin (G-Gly) is a mitogen for several gastrointestinal tissues although the mechanisms responsible are ill-defined and it is unknown if G-Gly can influence signalling in Barrett's oesophagus. G-Gly stimulated proliferation in OE19 and OE33 cells in a dose-dependant manner. This was unaffected by a CCK2 receptor antagonist but abolished by COX-2 inhibitors. G-Gly induced proliferation, COX-2 mRNA abundance, and PGE2 secretion, were all abolished by inhibition of JAK2, PI3-kinase, Akt or NF-kappaB. G-Gly stimulated phosphorylation of JAK2 and increased PI3-kinase activity in JAK2 immunoprecipitates. G-Gly increased Akt phosphorylation and kinase activity and NF-kappaB reporter activity in a JAK2-, PI3-kinase- and Akt-sensitive manner. G-Gly increased COX-2 promoter transcription in an Akt and NF-kappaB-dependent manner and also reduced COX-2 mRNA degradation in an Akt-insensitive manner. We conclude that G-Gly induced signalling involves a JAK2/PI3-kinase/Akt/NF-kappaB sequence leading to COX-2 transcription. G-Gly also seems to stabilise COX-2 mRNA via a separate pathway.

Topics: Adenocarcinoma; Barrett Esophagus; Cell Line, Tumor; Cell Proliferation; Cyclooxygenase 2; Dinoprostone; Esophageal Neoplasms; Gastrins; Humans; Janus Kinase 2; NF-kappa B; Oncogene Protein v-akt; Phosphatidylinositol 3-Kinases; Receptor, Cholecystokinin B; RNA Stability; Signal Transduction

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

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

Gastrin is known to enhance the growth of pancreatic carcinoma via the cholecystokinin (CCK)-2/gastrin receptor. We investigated the anti-tumor effect of Z-360 (calcium bis [(R)-(-)-3-[3-{5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl}ureido]benzoate]), a novel orally active CCK-2 receptor antagonist alone or combined with the chemotherapeutic agent, gemcitabine in human pancreatic adenocarcinoma cell lines.. Z-360 potently inhibited specific binding of [3H]CCK-8 to the human CCK-2 receptor, with a Ki value of 0.47 nmol/l, and showed antagonistic activity for this receptor. The anti-tumor effect of Z-360 alone or combined with gemcitabine was assessed using subcutaneous xenografts of MiaPaCa2 and PANC-1 and an orthotopic xenograft model (PANC-1). Oral administration of Z-360 significantly inhibited the growth of MiaPaCa2 (41.7% inhibition at 100 mg/kg, P<0.01). Combined administration of Z-360 and gemcitabine significantly inhibited subcutaneous PANC-1 tumor growth compared with either agent alone (27.1% inhibition compared to effect with gemcitabine, P<0.05), and significantly prolonged survival compared with the vehicle control (median survival of 49 days in vehicle compared to 57 days in the combination group, P<0.05). In vitro studies showed that Z-360 significantly inhibited gastrin-induced proliferation of human CCK-2 receptor-expressing cells, and also significantly reduced gastrin-induced PKB/Akt phosphorylation to the level of untreated controls.. In the present study, we have shown that Z-360 combined with gemcitabine can inhibit pancreatic tumor growth and prolong survival in a pancreatic carcinoma xenograft model, on a possible mode of action being the inhibition of gastrin-induced PKB/Akt phosphorylation through blockade of the CCK-2 receptor. Our results suggest that Z-360 may be a useful adjunct to gemcitabine for the treatment of pancreatic carcinoma and a therapeutic option for patients with advanced pancreatic cancer.

Topics: Adenocarcinoma; Administration, Oral; Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Benzodiazepinones; Cell Line, Tumor; Cell Proliferation; Deoxycytidine; Disease Models, Animal; Female; Gastrins; Gemcitabine; Humans; Mice; Mice, Nude; Pancreatic Neoplasms; Phosphorylation; Proto-Oncogene Proteins c-akt; Receptor, Cholecystokinin B; Survival Rate; Xenograft Model Antitumor Assays

As the hormone gastrin promotes gastrointestinal (GI) cancer progression by triggering survival pathways, regulation of gastrin expression at the translational level was explored. Sequence within the 5' untranslated region of a gastrin transcript expressed in GI cancer cells was investigated, then cloned into a bicistronic vector upstream of firefly luciferase and transfected into a series of GI cancer cell lines. Firefly luciferase activity was measured relative to that of a cap-dependent Renilla luciferase. A gastrin transcript that was different from that described in Ensembl was expressed in GI cancer cells. Its transcription appears to be initiated within the region designated as the gene's first intron. In GI cancer cells transfected with the bicistronic construct, firefly luciferase activity increased 8-15-fold compared with the control vector, and there was a further induction of the signal (up to 25-fold) following exposure of the cells to genotoxic stress or hypoxia, suggesting that the sequence acts as an internal ribosome entry site. These data suggest that the gastrin transcript within GI cancer cells contains an internal ribosome entry site that may allow continued expression of gastrin peptides when normal translational mechanisms are inactive, such as in hypoxia, thereby promoting cancer cell survival.

Topics: 5' Untranslated Regions; Adenocarcinoma; Apoptosis; Cell Survival; Gastrins; Gastrointestinal Neoplasms; Gene Expression Regulation, Neoplastic; HCT116 Cells; Humans; Hypoxia; Luciferases; Luciferases, Renilla; Pancreatic Neoplasms; Protein Biosynthesis; Reverse Transcriptase Polymerase Chain Reaction; Ribosomes; Survival Analysis; Transcription, Genetic; Transfection

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

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

To explore the correlation between the mRNAs and protein expression of gastrin (GAS), somatostatin (SS) and apoptosis index (AI), apoptosis regulation gene Fas/FasL and caspases in large intestinal carcinoma (LIC).. Expression of GAS and SS mRNAs were detected by nested RT-PCR in 79 cases of LIC. Cell apoptosis was detected by molecular biology in situ apoptosis detecting methods (TUNEL). Immunohistochemical staining for GAS, SS, Fas/FasL, caspase-3 and caspase-8 was performed according to the standard streptavidin-biotin-peroxidase (S-P) method.. There was a significant positive correlation between mRNA and protein expression of GAS and SS (GASrs = 0.99, P < 0.01; SSrs = 0.98, P < 0.01). There was significant difference in positive expression rates of GAS, SS mRNAs and protein among different histological differentiation, histological types and Dukes' stage of LIC. The AI in GAS high and moderate expression groups was significantly lower than that in low expression groups (3.75 +/- 2.38 vs 7.82 +/- 2.38, P < 0.01; 5.51 +/- 2.66 vs 7.82 +/- 2.38, P < 0.01), and the AI in SS high and moderate expression groups was significantly higher than that in low expression groups (9.03 +/- 1.76 vs 5.35 +/- 3.00, P < 0.01; 7.44 +/- 2.67 vs 5.35 +/- 3.00, P < 0.01). There was a significant negative correlation between the integral ratio of GAS to SS and the AI (r(s) = -0.41, P < 0.01). The positive expression rate of FasL in GAS high and moderate expression groups was higher than that in low expression group (90.9% and 81.0% vs 53.2%, P < 0.05). The positive expression rates of Fas, caspase-8 and caspase-3 in SS high (90.0%, 90.0% and 100%) and moderate (80.0%, 70.0%, 75.0%) expression groups were higher than that in low expression group (53.1%, 42.9%, 49.0%) (90.0% and 80.0% vs 53.1%, P < 0.05; 90.0% and 70.0% vs 42.9%, P < 0.05; 100.0% and 75.0% vs 49.0%, P < 0.05). There was a significant positive correlation between the integral ratio of GAS to SS and the semiquantitative integral of FasL (rs = 0.32, P < 0.01).. GAS and SS play important roles in the regulation and control of cell apoptosis in LIC, and the mechanism may be directly related to the aberrant expression of Fas/FasL. The GAS and SS will be valuable targets of the biological behavior of LIC.

Topics: Adenocarcinoma; Adult; Aged; Apoptosis; Caspase 3; Caspase 8; Caspases; Colorectal Neoplasms; Fas Ligand Protein; fas Receptor; Female; Gastrins; Gene Expression Regulation, Neoplastic; Humans; Male; Middle Aged; Rectal Neoplasms; Retrospective Studies; RNA, Messenger; Somatostatin

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

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

Topics: Adenocarcinoma; Apoptosis; Barrett Esophagus; bcl-Associated Death Protein; Cyclooxygenase 2; Disease Progression; Esophageal Neoplasms; Gastrins; Gastroesophageal Reflux; Gene Expression Regulation; Helicobacter Infections; Helicobacter pylori; Humans; Incidence; Inhibitor of Apoptosis Proteins; Microtubule-Associated Proteins; Models, Biological; Neoplasm Proteins; NF-kappa B; Prevalence; Survivin

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

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

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

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

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

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

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

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

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

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

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

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

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

The objective of the present study was to determine the influence of cyclooxygenase-2 (COX-2) inhibition by Celecoxib (CLX) in humans with distal colorectal adenocarcinoma (CRC) on serum and tumor levels of progastrin and gastrin and serum levels of proinflammatory cytokines (IL-8, TNF-alpha). In addition, the effects of this CLX treatment on tumor and adjacent mucosa expression of gastrin, its receptors (CCK2), and COX-1 and COX-2, as well as protein expression of the active form of nuclear factor kappa B (NFkappa B) and the apoptotic-related proteins Bcl-2 and survivin, have been examined. Ten distal CRC patients were examined twice, once before and then after 14-day treatment with CLX (200 mg bid). Large biopsy samples were taken from the tumor and intact mucosa 10 cm above the tumor. For comparison, 20 age- and sex-matched healthy controls were enrolled and treated with CLX as CRC patients. Serum levels of IL-8 and TNF-alpha were measured by enzyme-linked immunosorbent assay, and serum levels of amidated gastrins and progastrin, by specific radioimmunoassay. The gene or protein expressions of progastrin, gastrin, CCK2, COX-1, COX-2, Bcl-2, and survivin as well as NFkappa B were determined by RT-PCR or Western blot in biopsy samples of tumor and intact mucosa of CRC patients. Serum IL-8 and TNF-alpha values were severalfold higher in CRC patients than in controls. The increase in serum proinflammatory cytokines was accompanied by increased expression of the active form of NFkappa B. Serum progastrin levels were also found to be significantly higher in CRC than in controls. Treatment of CRC with CLX resulted in a significant decrease in serum levels of progastrin and this was accompanied by an increment in tumor expression of COX-2 with a concomitant reduction in gastrin, Bcl-2, survivin, and NFkappa B expression. We conclude that (1) distal CRC patients show significantly higher serum progastrin levels than matched healthy controls, confirming that this hormone may be implicated in rectal carcinogenesis; (2) CRC patients exhibit significantly higher serum levels of IL-8 and TNF-alpha than healthy controls, probably reflecting more widespread inflammatory reaction in the colonic mucosa in CRC; (3) gastrin, COX-2, Bcl-2, survivin, and NFkappa B were overexpressed in CRC tumor compared to intact mucosa, but treatment with CLX significantly reduced serum levels of progastrin and IL-8 and TNF-alpha, which could mediate the up-regulation of COX-2 in CRC; and

Topics: Adenocarcinoma; Aged; Apoptosis Regulatory Proteins; Base Sequence; Biomarkers, Tumor; Biopsy, Needle; Blotting, Western; Case-Control Studies; Celecoxib; Colorectal Neoplasms; Cyclooxygenase 2 Inhibitors; Cytokines; Female; Gastrins; Glyceraldehyde-3-Phosphate Dehydrogenases; Humans; Immunohistochemistry; Male; Middle Aged; Molecular Sequence Data; Neoplasm Staging; Probability; Prognosis; Pyrazoles; Reverse Transcriptase Polymerase Chain Reaction; Sensitivity and Specificity; Statistics, Nonparametric; Sulfonamides; Survival Rate

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

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

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

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

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

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

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

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

The less processed forms of gastrin have recently been shown to act as trophic factors for both normal and malignant colonic cells. Although incompletely processed forms of gastrin such as glycine-extended gastrin and progastrin are also expressed in human lung cancers, the clinical significance of this expression has not been addressed. Consequently, we investigated the effects of overexpression of glycine-extended gastrin in a mouse strain that is prone to developing lung cancer and also examined the expression of incompletely processed gastrins in primary human lung cancers. We found that transgenic overexpression of glycine-extended gastrin in FVB/N mice resulted in a significant increase in the prevalence and growth of bronchoalveolar carcinoma. In addition, a substantial subset of human lung cancers was found to express progastrin and/or glycine-extended gastrin. Overexpression of glycine-extended gastrin by human lung cancers was associated with a significantly decreased survival. Taken together, these results suggest that glycine-extended gastrin may play a role in the growth and progression of some human lung cancers.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Animals; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Cell Division; Gastrins; Glycine; Humans; Lung Neoplasms; Mice; Mice, Transgenic; Middle Aged; Prognosis; Survival Analysis; Time Factors

Mechanisms by which premalignant Barrett's metaplasia (BM) progresses to esophageal adenocarcinoma are currently being sought. This study investigated the role played by the polypeptide hormone gastrin, specifically its antiapoptotic effects through activation of protein kinase B/Akt (PKB/Akt). In esophageal cell lines with low basal levels of activated PKB/Akt, phosphorylation could be induced by exogenous amidated gastrin. High basal levels of activated PKB/Akt were linked to endogenous gastrin expression and were reduced by treatment with a cholecystokinin-type 2 receptor (CCK-2R) antagonist. Expression of a constitutively active splice variant of the CCK-2R additionally increased basal activation of PKB/Akt. It is proposed that gastrin acting in an autocrine and endocrine manner via a CCK-2R isoform may activate PKB/Akt and that with expression of gastrin and CCK-2R isoforms increasing in BM samples, gastrin may aid progression of BM through amplification of antiapoptotic pathways. Evidence for this proposal was provided through the observed specific up-regulation of PKB/Akt in BM samples.

Topics: Adenocarcinoma; Apoptosis; Barrett Esophagus; Benzodiazepines; Carcinoma, Squamous Cell; Esophageal Neoplasms; Esophagus; Gastrins; Hormone Antagonists; Phosphorylation; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Receptor, Cholecystokinin B; Tumor Cells, Cultured

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

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

The prevalence of esophageal adenocarcinoma in the setting of Barrett's metaplasia continues to increase in Western nations at a rate greater than any other cancer. The trophic properties of gastrin have been documented in gastric, pancreatic and colon cancer cell lines, suggesting a potential role for this regulatory peptide in the growth of these malignancies. The aims of these studies were to identify and characterize the presence of functional cholecystokinin type-2 (gastrin) receptors on the membranes of human esophageal adenocarcinoma cells. Reverse transcriptase-polymerase chain reaction (RT-PCR) demonstrated the presence of cholecystokinin type-2 receptor transcripts in human esophageal adenocarcinoma cell lines. Competitive binding assays revealed specific binding of gastrin in SEG-1 cells (IC50 of 2.4 x 10(-8) M). This finding was confirmed by laser scanning confocal microscopy through internalization of rhodamine green labeled gastrin heptapeptide in SEG-1 cells. Gastrin caused a dose-dependent increase in proliferation of SEG-1 cells when compared to controls. This effect was abolished by co-incubation with L365,260, a CCK-2-specific receptor antagonist. Gastrin-induced phosphorylation of the p44 and p42 mitogen-activated protein kinases was demonstrated by Western blot analysis. In conclusion, the studied human esophageal adenocarcinoma cell lines possess cholecystokinin type-2 (gastrin) receptors. Receptors bind gastrin, resulting in increased proliferation in SEG-1 cells.

Topics: Adenocarcinoma; Benzodiazepinones; Binding, Competitive; Blotting, Western; Cell Proliferation; Esophageal Neoplasms; Gastrins; Humans; Peptide Fragments; Phenylurea Compounds; Phosphorylation; Receptor, Cholecystokinin B; Reverse Transcriptase Polymerase Chain Reaction; Tumor Cells, Cultured

Cyclooxygenase (COX)-2 has been causally implicated in carcinogenesis. The evidence for increased COX-2 in the malignant progression of Barrett's esophagus is contradictory. We hypothesize that COX-2 expression may be causally affected by the gastrin status via the cholecystokinin 2 (CCK(2)) receptor.. COX-2 and prostaglandin E(2) expression were evaluated by Western blotting and enzyme-linked immune assay in samples of squamous esophagus, Barrett's esophagus with varying degrees of dysplasia to adenocarcinoma, and normal duodenum. Differentiation status was evaluated by histopathology and villin expression. A longitudinal case-control study compared COX-2 in patients who progressed to adenocarcinoma with nonprogressors matched for age and length of follow-up. Messenger RNA levels of gastrin and CCK(2) receptor in biopsies and cell lines were evaluated by reverse transcription-PCR, and in vitro gastrin stimulation was conducted with and without inhibitors for CCK(2) (YM022) and COX-2 (NS-398). Cell proliferation was evaluated using minichromosome maintenance protein 2 (Mcm2) and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays.. COX-2 expression is significantly increased in Barrett's esophagus before dysplasia development. Expression is highly variable within Barrett's dysplasia and adenocarcinoma samples independent of differentiation status. In a longitudinal case-control study, the expression levels within patients increased over time, regardless of the degree of malignant progression. Biopsies from nondysplastic Barrett's esophagus expressed increased gastrin mRNA levels compared with other biopsies. Gastrin significantly induced COX-2, prostaglandin E(2), and cell proliferation in biopsies and cell lines. Gastrin-induced proliferation can be inhibited by YM022 and NS-398.. COX-2 is up-regulated early in the Barrett's metaplasia sequence. During carcinogenesis, gastrin is a significant determinant of COX-2 activity levels via the CCK(2) receptor.

Topics: Adenocarcinoma; Adolescent; Adult; Aged; Aged, 80 and over; Barrett Esophagus; Benzodiazepines; Blotting, Western; Case-Control Studies; Cell Differentiation; Cell Line, Tumor; Cell Proliferation; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Female; Gastrins; Gene Expression Regulation, Enzymologic; Humans; Isoenzymes; Longitudinal Studies; Male; Membrane Proteins; Middle Aged; Nitrobenzenes; Prostaglandin-Endoperoxide Synthases; Receptor, Cholecystokinin B; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Sulfonamides; Tumor Cells, Cultured

The gastrin gene is expressed widely in pancreatic adenocarcinomas and the study aimed to assess its role in both the resistance of cancer cells to apoptosis and the sensitivity of cells to chemotherapeutic agents. Two human pancreatic cell lines, PAN1 and BXPC3, expressed gastrin at both the RNA and protein levels and are shown to be representative of human pancreatic adenocarcinomas in terms of gastrin expression. Inhibition of endogenous gastrin production by tumor cells was achieved with neutralizing gastrin antiserum and transfection with a gastrin antisense plasmid. Gastrin antiserum synergized with both taxotere and gemcitabine in inhibiting the in vitro growth of the PAN1 cell line with the inhibitory effect of the antiserum increasing from 12.7% to 70.2% with taxotere (P < 0.05) and 28.6% with gemcitabine (P < 0.01) after controlling for the effects of the cytotoxics. Synergy was only achieved with taxotere in BXPC3 cells with the inhibitory effect of gastrin antiserum increasing from 22.9% to 50.0% (P < 0.005). Cells transfected with gastrin antisense had reduced in vitro growth in low serum conditions and were poorly tumorigenic in nude mice at an orthotopic site. Gastrin antisense-transfected PAN1 cells had increased sensitivity to the antiproliferative effects of both gemcitabine (IC50 of > 100 microg/ml reduced to 0.1 microg/ml) and taxotere (IC50 of 20 microg/ml reduced to < 0.01 microg/ml) when compared with vector controls. The increased sensitivity of PAN1 antisense coincided with increased caspase-3 activity and reduced protein kinase B/Akt phosphorylation in response to both gemcitabine and taxotere. Gastrin gene circumvention may be an optimal adjunct to chemotherapeutic agents, such as taxotere and gemcitabine, in pancreatic adenocarcinoma.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Deoxycytidine; DNA, Antisense; Docetaxel; Gastrins; Gemcitabine; Gene Expression; Genetic Therapy; Humans; Male; Mice; Mice, Nude; Pancreatic Neoplasms; Phosphorylation; Protein Precursors; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Taxoids; Transfection

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

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

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

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

In the Western world, the incidence of oesophageal adenocarcinoma has increased over the last 30 years coinciding with a decrease in the prevalence of Helicobacter pylori. Trends of increasing oesophageal adenocarcinoma can be linked causally to increasing gastro-oesophageal reflux disease (GORD) which can be linked to an increasingly obese population. However, there is no plausible biological mechanism of association between H. pylori, obesity, and GORD. Ghrelin, a peptide produced in the stomach, which regulates appetite, food intake, and body composition, was studied in H. pylori positive asymptomatic subjects.. Plasma ghrelin, leptin, and gastrin were measured for six hours after an overnight fast, before and after cure of H. pylori in 10 subjects. Twenty four hour intragastric acidity was also assessed.. After cure, median (95% confidence intervals) integrated plasma ghrelin increased from 1160.5 (765.5-1451) pg/ml x h to 1910.4 (1675.6-2395.6) pg/ml x h (p=0.002, Wilcoxon's rank sum test), a 75% increase. This was associated with a 14% increase in 24 hour intragastric acidity (p=0.006) and non-significant changes in leptin and gastrin. There was a significant positive correlation between plasma ghrelin and intragastric acidity (r(s) 0.44, p=0.05, Spearman's rank correlation).. After H. pylori cure, plasma ghrelin increased profoundly in asymptomatic subjects. This could lead to increased appetite and weight gain, and contribute to the increasing obesity seen in Western populations where H. pylori prevalence is low. This plausible biological mechanism links H pylori, through increasing obesity and GORD, to the increase in oesophageal adenocarcinoma observed in the West.

Topics: Adenocarcinoma; Adult; Esophageal Neoplasms; Female; Gastric Acidity Determination; Gastrins; Gastroesophageal Reflux; Ghrelin; Helicobacter Infections; Helicobacter pylori; Humans; Leptin; Male; Peptide Hormones; Radioimmunoassay

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

The role of hyper-gastrinaemia in the incidence of colonic cancer remains to be clarified. The aim of this study was to determine whether cholecystokinin-2 (CCK-2) receptor expression predicts the sensitivity of human colonic adenomas to the proliferative effects of serum hyper-gastrinaemia. Gene expression of the classical (74 kDa) CCK-2 receptor in human colonic adenoma specimens and cell lines, was quantified by real-time PCR. Western blotting, using a CCK-2 receptor antiserum, confirmed protein expression. A transformed human colonic adenoma was grown in SCID mice, with hyper-gastrinaemia induced by proton pump inhibitors. CCK-2 receptor blockade was achieved by using neutralising antiserum. Both human colonic adenoma cell lines and biopsies expressed CCK-2 receptor mRNA at levels comparable with CCK-2 receptor transfected fibroblasts and oxyntic mucosa. Western blotting confirmed immunoreactive CCK-2 receptor bands localised to 45, 74 and 82.5 kDa. Omeprazole and lansoprazole-induced hyper-gastrinaemia (resulting in serum gastrin levels of 34.0 and 153.0 pM, respectively) significantly increased the weight of the human adenoma grafts (43% (P=0.016) and 70% (P=0.014), respectively). The effect of hypergastrinaemia on tumour growth was reversed by use of antiserum directed against the CCK-2 receptor. Hyper-gastrinaemia may promote proliferation of human colonic adenomas that express CCK-2 receptor isoforms.

Topics: Adenocarcinoma; Adenoma; Animals; Colonic Neoplasms; Computer Systems; Enzyme Inhibitors; Female; Fibroblasts; Gastric Mucosa; Gastrins; Gene Expression Regulation, Neoplastic; Humans; Introns; Male; Mice; Mice, SCID; Neoplasm Proteins; Neoplasm Transplantation; Omeprazole; Parietal Cells, Gastric; Polymerase Chain Reaction; Protein Isoforms; Protein Processing, Post-Translational; Proton Pump Inhibitors; Receptor, Cholecystokinin B; Receptors, Cholecystokinin; RNA, Messenger; Secretory Rate; Tumor Cells, Cultured

Gastrin is a gastrointestinal peptide that possesses potent trophic properties on both normal and neoplastic cells of gastrointestinal origin. Previous studies have indicated that chronic hypergastrinaemia increases the risk of colorectal cancer and cancer growth and that interruption of the effects of gastrin could be a potential target in the treatment of colorectal cancer. Here we demonstrate that gastrin leads to a dose-dependent increase in colon cancer cell proliferation and tumour growth in vitro and in vivo, and that this increment is progressively reversed by pretreatment with the cyclo-oxygenase-2 inhibitor NS-398. Gastrin was able to induce cyclo-oxygenase-2 protein expression, as well as the synthesis of prostaglandin E2, the major product of cyclo-oxygenase. Moreover, gastrin leads to approximately a two-fold induction of cyclo-oxygenase-2 promoter activity in transiently transfected cells. The results of these studies demonstrate that cyclo-oxygenase-2 appears to represent one of the downstream targets of gastrin and that selective cyclo-oxygenase-2 inhibition is capable of reversing the trophic properties of gastrin and presumably might prevent the growth of colorectal cancer induced by hypergastrinaemia.

Topics: Adenocarcinoma; Animals; Cell Division; Colonic Neoplasms; Cyclin D1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Dinoprostone; DNA Replication; Dose-Response Relationship, Drug; Gastrins; Gene Expression Regulation, Neoplastic; Genes, Reporter; Isoenzymes; Male; Mice; Mice, Inbred BALB C; Neoplasm Proteins; Neoplasm Transplantation; Nitrobenzenes; Proliferating Cell Nuclear Antigen; Promoter Regions, Genetic; Prostaglandin-Endoperoxide Synthases; Receptors, Cholecystokinin; Substrate Specificity; Sulfonamides; Transfection; Tumor Cells, Cultured

New compounds, named nuclear aggregates of polyamines, having a molecular mass of 8000, 4800 and < 1000 Da, were found in the nuclear extracts of several replicating cells. Their molecular structure is based on the formation of ionic bonds between polyamine ammonium and phosphate groups. The production of the 4800 Da compound, resulting from the aggregation of five or more < 1000 Da units, was increased in Caco-2 cells treated with the mitogen gastrin. Dissolving single polyamines in phosphate buffer resulted in the in vitro aggregation of polyamines with the formation of compounds with molecular masses identical to those of natural aggregates. After the interaction of the 4800 Da molecular aggregate with the genomic DNA at 37 degrees C, both the absorbance of DNA in phosphate buffer and the DNA mobility in agarose gel increased greatly. Furthermore, these compounds were able to protect the genomic DNA from digestion by DNase I, a phosphodiesterasic endonuclease. Our data indicate that the nuclear aggregate of polyamines interacts with DNA phosphate groups and influence, more efficaciously than single polyamines, both the conformation and the protection of the DNA.

Topics: Adenocarcinoma; Amino Acids; Caco-2 Cells; Cell Division; Cell Nucleus; Chromatography, High Pressure Liquid; Circular Dichroism; Colonic Neoplasms; DNA; DNA Fragmentation; Electrophoresis, Polyacrylamide Gel; Gastrins; Humans; Magnetic Resonance Spectroscopy; Nucleosomes; Osmolar Concentration; Polyamines; Spectrophotometry

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

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

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

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

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

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

We demonstrated previously, in two different rodent models of pancreatic cancer, that the gastrin receptor is present on malignant pancreatic tumors in spite of the fact that the normal adult rat and mouse pancreas does not express gastrin receptors.. To determine whether gastrin receptors mediate pancreatic growth or promote carcinogenesis or both, we created a transgenic mouse that constitutively expresses gastrin receptors in the exocrine pancreas. The transgene construct contained the full-length rat gastrin receptor cDNA sequence under the control of the rat elastase promoter.. Receptor presence and function on exocrine pancreatic tissue of transgenic but not control mice were confirmed by (125)I-gastrin-I binding studies and by gastrin stimulation of intracellular calcium release. Eighteen-month-old transgenic animals had larger pancreas-to-body weight ratios than their nontransgenic littermate controls (p < 0.001 for females; p < 0.01 for males); however, histopathologic examination revealed no neoplasms or other abnormalities.. In both female and male transgenic mice, the expression of the gastrin receptor in the exocrine pancreas is associated with a significant increase in pancreas weight, but it does not appear to promote the development of spontaneous pancreatic tumors.

Topics: Adenocarcinoma; Animals; Calcium; Female; Gastrins; Gene Expression; Iodine Radioisotopes; Male; Mice; Mice, Transgenic; Pancreas; Pancreatic Neoplasms; Phenotype; Rats; Receptors, Cholecystokinin

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

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

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

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

Topics: Adenocarcinoma; Aged; Case-Control Studies; Cholecystokinin; Female; Gastrins; Humans; Male; Middle Aged; Pancreatic Neoplasms

Colorectal cancers express significant amounts of immature glycine-extended gastrin (G-Gly) and G-Gly is able to stimulate cell proliferation in colonic cell lines and mucosa. Here we wished to investigate whether G17-Gly promote the invasiveness of LoVo human colonic cancer cells, a process which requires degradation of extracellular matrix by proteases and concomitant induction of cell migration. We confirmed that LoVo cells express gastrin and gastrin/CCK-B receptor mRNAs. We showed that these cells secrete matrix metalloproteinase (MMP)-1, -2, and -9. The function of MMP being to degrade components of extracellular matrix, they may thus favor cell migration. As compared to controls, G17-Gly (10(-7) to 10(-12) M) significantly enhanced about two to three times the LoVo cell migration through Matrigel, an artificial basement matrix barrier. Moreover, G17-Gly increased and gastrin/CCK-B receptor antagonists decreased MMP secretion in conditioned culture media of LoVo cells. Our findings show that physiological doses of incompletely processed form of gastrin induce the invasiveness of tumor cells in vitro and suggest a novel potential role for this peptide in the metastatic process of colonic cancers in vivo.

Topics: Adenocarcinoma; Base Sequence; Colonic Neoplasms; Culture Media, Conditioned; DNA Primers; Gastrins; Humans; Matrix Metalloproteinases; Neoplasm Invasiveness; Receptor, Cholecystokinin B; Receptors, Cholecystokinin; Tumor Cells, Cultured

It has been assumed that gastrin stimulates the growth of pancreatic cancer in an autocrine way through co-expression of gastrin and the cholecystokinin-B receptor (CCK-BR). However, pancreatic cancer cell lines established directly from patients have revealed a great heterogeneity in cell proliferation when exposed to CCK, gastrin and their receptor antagonists. The aim of this study was therefore to examine co-expression of CCK-A and CCK-B receptor (CCK-AR and CCK-BR), and gastrin mRNA as well as the secretion of CCK and gastrin peptides in these cell lines.. Fourteen cell lines were established from primary pancreatic cancers or their metastases. Total RNA was isolated from the cell lines and reverse-transcribed into single-stranded cDNA. A PCR technique based on Taq polymerase-antibody interaction and CCK-AR, CCK-BR and gastrin-specific primers, followed by Southern blot analysis, were the methods used. The incubation mediums were analysed for the presence of secreted CCK/proCCK and gastrin/progastrin peptides by specific radioimmunoassays (RIA).. By means of nested Reverse-Transcribed Polymerase Chain Reaction (nested RT-PCR), combined with Southem blot analysis of the PCR amplified products, CCK-AR and gastrin mRNA co-expression was detected in cell lines LPC-6p and LPC-10m, whereas CCK-BR and gastrin mRNA could be detected in cell lines LPC-8p and LPC-12m. A low level of secreted CCK peptides was detected in cell line LPC-6p, which also expressed CCK-AR mRNA. In no other cases were CCK or gastrin peptides detected in the cell culture mediums.. The lack of CCK-BR and gastrin mRNA co-expression, and not detectable levels of secreted CCK and gastrin in culture media, does not lend support to the hypothesis that concomitant gene-expression of CCK receptors and gastrin or CCK are essential to maintaining pancreatic cancer cell proliferation.

Topics: Adenocarcinoma; Adenocarcinoma, Mucinous; Aged; Biopsy; Blotting, Southern; Carcinoma, Ductal, Breast; Carcinoma, Papillary; Cell Division; Cholecystokinin; Gastrins; Gene Expression Regulation, Neoplastic; Humans; Middle Aged; Neoplasm Staging; Pancreatic Neoplasms; Radioimmunoassay; Receptors, Cholecystokinin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Tumor Cells, Cultured

Helicobacter pylori (HP) infection is usually accompanied by an increased plasma level of gastrin, a potent mitogen able to induce cyclooxygenase (COX)-2. This study examined (a) the seroprevalence of HP, its cytotoxic protein, CagA, and cytokines (tumor necrosis factor alpha, interleukins 1beta and 8) in 80 patients with colorectal cancers, before and after the removal of tumor, compared with 160 age- and gender-matched controls; (b) the gene expression of gastrin and its receptors (CCKB-R) in the cancer tissue, (c) the plasma levels and tumor tissue contents of gastrin, and (d) the mRNA expression of COX-1, COX-2, and apoptotic proteins (Bax and Bcl2) in cancer tissue and intact colonic mucosa. Anti-HP IgG, anti-CagA IgG seroprevalence, and cytokine levels were analyzed by enzyme-linked immunosorbent assay tests; gene expressions of gastrin, CCKB-R, COX-1, COX-2, Bax, and Bcl2 by reverse transcriptase polymerase chain reaction; and gastrin by radioimmunoassay. The seroprevalence of HP, especially that expressing CagA, was significantly higher in cancer patients than in controls and did not change 1 week after tumor resection while plasma cytokines were significantly reduced after this operation. Both gastrin and CCKB-R mRNA were detected in the cancer tissue and the resection margin; similarly, COX-2 mRNA was expressed in most of cancers and their resection margin but not in intact colonic mucosa, where only COX-1 was detected. The colorectal cancer tissue contained several folds more immunoreactive gastrin than cancer resection margin and many folds more than the intact colonic mucosa. We conclude that colon adenocarcinoma and its resection margin overexpress gastrin, its receptors, CCKB-R, and COX-2, and that HP infection may contribute to colonic cancerogenesis via overexpression of gastrin and COX-2, which may account for the stimulation of the tumor growth and the reduction in apoptosis as documented by enhanced mRNA expression of anti-apoptotic Bcl2 over proapoptotic Bax proteins.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Antigens, Bacterial; Apoptosis; Bacterial Proteins; Colorectal Neoplasms; Cyclooxygenase 2; Cytokines; Female; Gastrins; Gene Expression; Helicobacter Infections; Helicobacter pylori; Humans; Interleukin-1; Interleukin-8; Isoenzymes; Male; Membrane Proteins; Middle Aged; Prostaglandin-Endoperoxide Synthases; Tumor Necrosis Factor-alpha

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

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

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

To evaluate the value of detection of 4 tumor markers(CEA, CA125, gastrin, and NSE) for histological types in patients with lung cancer and to improve the predicted efficiency of tumor markers for distinguishing between small cell lung cancer(SCLC) and non-small cell lung cancer (NSCLC), these 4 tumor markers in serum were determined in 51 patients (21 cases with SCLC, 30 cases with NSCLC) with confirmed primary diagnosis of lung cancer of different histology by radioimmunoassay. Linear learning machine method, PRIMA method and KNN method were used to classify SCLC and NSCLC. The levels of gastrin and NSE in SCLC were apparently higher than those of gastrin and NSE in NSCLC, but the levels of CEA and CA125 in SCLC were significantly lower than those in NSCLC. Smoking had an effect on the levels of CEA and CA125, but had little effect on those of gastrin and NSE. The total accuracy of the three methods was over 85% in distinguishing SCLC from NSCLC. So combined detection of the four tumor markers in serum might be useful in the prediction of histological types in patients with lung cancer.

Topics: Adenocarcinoma; Aged; Biomarkers, Tumor; CA-125 Antigen; Carcinoembryonic Antigen; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Female; Gastrins; Humans; Lung Neoplasms; Male; Middle Aged; Phosphopyruvate Hydratase

Gastrin is a trophic hormone and promotes growth of gastrointestinal and non-gastrointestinal cancers. Studies both in vitro and in vivo have suggested that pancreatic cancer cells not only have the ability to respond to circulating forms of gastrin but also to respond to the autocrine production of gastrin and its precursors. The aim of this study was to identify the expression of CCK-B/gastrin receptor, progastrin, glycine-extended gastrin and amidated gastrin in both normal pancreas and pancreatic adenocarcinoma.. Tissue sections from patients with normal pancreas (n = 10) and pancreatic cancer (n = 22) were assessed using immunohistochemical methods for CCK-B/gastrin receptor, progastrin, glycine-extended gastrin and amidated gastrin expression.. Normal pancreas showed no expression of receptor or gastrin isoforms except for occasional cells in the islets. Definite expression of CCK-B/gastrin receptor, progastrin, glycine-extended gastrin and amidated gastrin was observed in 95, 91, 55 and 23 per cent of sections from patients with pancreatic cancer respectively.. Pancreatic cancer cells express CCK-B/gastrin receptor and gastrin precursor forms in most patients. Expression of the gastrin precursor forms is probably related to autocrine production. New therapeutic strategies need to be developed for the management of pancreatic cancer. Targeting gastrin and its receptor may provide a novel treatment option.

Topics: Adenocarcinoma; Gastrins; Humans; Immunohistochemistry; Neoplasm Proteins; Pancreatic Neoplasms; Receptors, Cholecystokinin

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

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

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

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

Female inbred cotton rats develop adenocarcinomas in the oxyntic mucosa. Since a female preponderance is typical for enterochromaffin-like (ECL) cell tumors, we examined such tumors for ECL cells. Gastrin plays a decisive role in ECL cell tumorigenesis, so blood gastrin concentration and gastric mucosal pH were measured.. The stomachs from six female cotton rats (6 to 8 months old) were studied histologically, and at euthanasia, gastric mucosal pH was determined. Euthanasia was performed on 15 other female cotton rats of similar age for determination of blood gastrin values by radioimmunoassay (RIA) and gastric mucosal pH. Rats were classified macroscopically to have normal or thick oxyntic mucosa, with or without tumor.. Among the six cotton rats studied histologically, two 6-month-old rats had normal and two others had thick gastric mucosa, whereas two 8-month-old rats had thick mucosa with tumors. The ECL cells were markedly hyperplastic in all rats with thick mucosa, and ECL cells were found in the neoplastic parenchyma. All cotton rats with normal-appearing gastric mucosa had pH <2.5, whereas 14 rats with thick mucosa had pH >3.1 and hypergastrinemia.. Gastrin may play a major role in ECL cell hyperplasia and, perhaps, in adenocarcinoma genesis.

Topics: Adenocarcinoma; Animals; Chromogranin A; Chromogranins; Enterochromaffin Cells; Female; Gastrins; Histidine Decarboxylase; Hydrogen-Ion Concentration; Hyperplasia; Immunoenzyme Techniques; Male; Radioimmunoassay; Rats; Rodent Diseases; Sigmodontinae; Stomach Neoplasms; Synaptophysin

A Mongolian gerbil model was used to clarify whether long-term colonization by Helicobacter pylori is an important risk factor for the development of gastric cancer. Fifty-nine gerbils (3 controls and 56 gerbils inoculated with H. pylori) were killed at various times (average, 23 months) more than 12 months after H. pylori inoculation. In the H. pylori-inoculated group, poorly differentiated adenocarcinoma was observed in the pylorus of 1 gerbil, and carcinoid was observed in the fundus of the stomach in 18 gerbils. No lesions were found in the stomachs of the 3 control gerbils. The results imply that long-term colonization by H. pylori is an important risk factor for the development of gastric adenocarcinoma and carcinoid.

Topics: Adenocarcinoma; Animals; Antibodies, Bacterial; Carcinoid Tumor; Disease Models, Animal; Duodenum; Gastrins; Gerbillinae; Helicobacter Infections; Immunoglobulin G; Intestinal Mucosa; Metaplasia; Stomach Neoplasms; Time

The proximal region of the human gastrin gene promoter contains three GC/GT boxes at positions -140 to -134 bp, -108 to -102 bp and -67 to -61 bp. In this study we have examined the significance of the three elements, and their role in Sp1 and Sp3 mediated gastrin transcription. In AGS cells, mutation of each of the boxes caused a moderate decrease in promoter activity from 33 to 63%, whereas double or triple mutations reduced activity to 3-12%. In Drosophila cells Sp1 activated the promoter, mainly through the distal GC box. Similarly, co-transfection of heterologous promoter constructs revealed that only the distal GC box increased activation by Sp1. The effect of Sp3 was cell-line dependent, since Sp3 inhibited the gastrin promoter activity in AGS cells and caused a synergistic activation of the Sp1 stimulated gastrin promoter in Drosophila cells. Both effects were dependent on the C-terminal DNA binding domain of Sp3. The results indicates that the combined effect of the GC/GT boxes and the ratio between Sp1 and Sp3 are important for gastrin gene expression.

Topics: Adenocarcinoma; Animals; Base Composition; Base Sequence; Chloramphenicol O-Acetyltransferase; Drosophila melanogaster; Gastrins; Genes, Reporter; Humans; Luciferases; Molecular Sequence Data; Promoter Regions, Genetic; Recombinant Fusion Proteins; Stomach Neoplasms; TATA Box; Transcription Factors; Transcription, Genetic; Transfection; Tumor Cells, Cultured

Progastrin-releasing peptide (proGRP) is a specific tumor marker in patients with small cell lung carcinoma (SCLC). It has been reported that serum proGRP levels rarely are elevated in patients with nonsmall cell lung carcinoma (NSCLC); the reported frequency is <3%. The purpose of this study was to examine the clinicopathologic features of NSCLC patients with high serum proGRP levels.. The authors measured serum proGRP levels with a TND-4 kit, a newly developed enzyme-linked immunoadsorbent assay, in 544 NSCLC and 206 SCLC patients. Pathologic features were examined using conventional hematoxylin and eosin staining and histochemical and immunohistochemical staining using polyclonal antibodies to proGRP, chromogranin A, calcitonin, and monoclonal antibody to the neural cell adhesion molecule (NCC-Lu-243).. The serum proGRP levels were elevated in 140 SCLC patients (68.0%) and in 23 NSCLC patients (4.2%). Seven of these 23 NSCLC patients had serum proGRP levels > or = 100 pg/mL. They included two patients with renal dysfunction, one patient diagnosed cytologically with adenocarcinoma without undergoing precise pathologic examination, two patients diagnosed histologically with squamous cell carcinoma with foci of small cell elements, and two patients diagnosed with large cell neuroendocrine carcinoma and poorly differentiated adenocarcinoma, respectively, which showed neuroendocrine differentiation on immunohistologic analysis. The remaining 16 NSCLC patients had serum proGRP levels < 70 pg/mL.. Nearly all NSCLC patients had serum proGRP levels < 100 pg/mL. However, if an NSCLC patient presents with a proGRP level > or = 100 pg/mL, the clinicopathologic features must be examined with regard to the small cell component, neuroendocrine differentiation, and renal dysfunction.

Topics: Adenocarcinoma; Adult; Aged; Biomarkers, Tumor; Carcinoma, Large Cell; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Enzyme-Linked Immunosorbent Assay; Female; Gastrins; Humans; Lung Neoplasms; Male; Middle Aged; Protein Precursors; Renal Insufficiency

Distinguishing between neuroendocrine carcinoma and adenocarcinoma may be difficult.. In the current prospective study blood and tumor tissue from patients with gastric carcinoma were collected. The tissue was fixed in different ways to allow examination for neuroendocrine markers by multiple methods such as various histochemical and immunohistochemical methods and electron microscopy. Blood and tumor homogenates were examined by radioimmunoassay for specific hormones and general neuroendocrine markers.. Based on examination of general neuroendocrine markers such as chromogranin A (by immunohistochemistry, Northern blot analysis, and tissue concentration), neuron specific enolase (immunohistochemistry) as well as electron microscopy, it was possible to conclude that approximately 10% of the tumors were actually neuroendocrine malignant tumors. Among these tumors, the enterochromaffin-like (ECL) cell was the most preponderant cell of origin (Sevier-Munger positive and serotonin negative immunoreactive tumor cells with secretory granules resembling those observed in normal ECL-cells). As reported previously, tumors of the diffuse type (according to the classification of Laurén) most often were reclassified as neuroendocrine carcinomas.. The current study shows that neuroendocrine and particularly ECL cell-derived tumors are more common in the stomach than previously recognized.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Chromogranin A; Chromogranins; Enterochromaffin Cells; Female; Gastrins; Histamine; Humans; Immunohistochemistry; Male; Middle Aged; Neuroendocrine Tumors; Pancreatic Hormones; Prospective Studies; RNA, Messenger; Stomach Neoplasms

Gastrin is trophic for the mucosa of the acid-producing part of the rat stomach, notably the histamine-producing ECL cells. Gastrin is said to stimulate growth also of colonic mucosa and colon cancer. The purpose of the present study was to examine whether endogenous hypergastrinaemia had trophic effects on normal colonic mucosa and transplanted colon adenocarcinoma in rats.. Rats were subjected to fundectomy (surgical removal of the acid-producing part of the stomach) or treatments known to induce endogenous hypergastrinaemia. The treatments included refeeding after 48 h of food deprivation or administration of omeprazole (400 micromol/kg/day, orally). Other operations included colostomy and sham operation. A K12-cell line, originally established from a 1,2-dimethylhydrazine-induced colon adenocarcinoma, was used for transplantation. The rates of cell proliferation were determined in the oxyntic and colonic mucosa and in the tumour by measuring the proportion of the cells that accumulated bromodeoxyuridine in their nuclei, i.e. the labelling index (LI). The thickness of the oxyntic mucosa and the activity of histidine decarboxylase (HDC), the histamine-forming enzyme of the ECL cells, were measured. In addition, the thickness of the colonic mucosa and the weight and volume of the tumour were measured.. Refeeding or treatment with a single dose of omeprazole in fasted rats raised the serum gastrin concentration and the LI and HDC activity in the oxyntic mucosa; refeeding but not omeprazole raised the LI in the colonic mucosa. In fed rats, hypergastrinaemia induced by fundectomy or treatment with omeprazole (for 10 days) failed to affect either the LI or the thickness of the mucosa of the proximal colon and the excluded distal colon of the colostomized rats. Fundectomy failed to stimulate the growth of the tumour transplants.. Endogenous hypergastrinaemia did not induce trophic effects on rat colonic mucosa and did not promote growth of a transplanted colon adenocarcinoma in the rat.

Topics: Adenocarcinoma; Animals; Cell Division; Colon; Colonic Neoplasms; Enzyme Inhibitors; Gastrins; Intestinal Mucosa; Male; Neoplasm Transplantation; Omeprazole; Parietal Cells, Gastric; Rats; Rats, Sprague-Dawley

For more than two decades, our research group has been studying the pancreatic actions of three groups of regulatory peptides: members of the cholecystokinin/gastrin family, bombesin-like peptides and somatostatin. Investigating these peptides, our work has focused on three particularly interesting aspects: peptidergic regulation of pancreatic enzyme secretion and growth in adult rats, peptidergic control of pancreatic enzyme secretion and growth during postnatal development in rats, and peptidergic regulation of proliferation and differential gene expression in pancreatic adenocarcinoma cells. Our data confirmed that the control of the exocrine function of the pancreas is complex, and that it involves peptides such as the cholecystokinin/gastrin-like peptides, bombesin-like peptides and somatostatin. In these investigations, it became evident that selective peptide receptor agonists, antagonists and monoclonal antibodies raised against peptides are useful tools to identify the role of these bioactive peptides in pancreatic exocrine secretion and cell proliferation.

Topics: Adenocarcinoma; Animals; Bombesin; Cell Division; Cholecystokinin; Gastrins; Gene Expression; Pancreas; Pancreatic Neoplasms; Rats; Somatostatin

This study evaluated the effect of gastric acid secretion and serum gastrin response on tumor differentiation for early gastric cancer according to patients' age. We investigated the association between serum gastrin levels, gastric acid secretion and the histologic types of 335 early gastric carcinomas limited to the mucosal and submucosal layers in comparison with 450 gastric and 197 duodenal ulcers. The preoperatively examined basal acid output, maximal acid output and peak acid output after administration of tetragastrin and serum gastrin levels before and after ingestion of a test meal were determined. Patients with differentiated cancer and duodenal ulcer showed a significant negative correlation between gastric acid secretion and age, while the former group also had a significant positive correlation between serum gastrin levels and age. On the other hand, patients with undifferentiated cancer did not show any such correlation between gastric acid and age, but showed a significant positive correlation between serum gastrin, integrated gastrin response and age. Patients with gastric ulcer did not show any such correlations. These data suggest that both low acid secretion and endogenous hypergastrinemia, especially in the elderly, may play an important role in differentiated and undifferentiated gastric carcinomas.

Topics: Adenocarcinoma; Adult; Age Factors; Aged; Aged, 80 and over; Duodenal Ulcer; Female; Gastric Acid; Gastric Mucosa; Gastrins; Humans; Male; Middle Aged; Stomach Neoplasms; Stomach Ulcer

Our objective was to determine whether colorectal cancer tissue synthesizes and secretes biologically active gastrins resulting in a rise of gastrin levels in patients with adenocarcinoma of the colon. Blood samples for gastrin determination were taken from the artery feeding, and from the vein draining colon tumors, from a vein draining an uninvolved colon segment and from a peripheral vein. Tissue gastrin levels were measured in tumor tissues and normal mucosa taken by colonoscopic biopsy from colon cancer patients and healthy controls. The setting was a university hospital research laboratory. We had seventeen patients with colorectal cancer and 23 controls. No significant difference was found in peripheral venous blood gastrin levels between the cancer and the control groups. Serum gastrin concentration was not significantly different in the arterial blood which supplied the tumor area, the venous blood draining the tumor, the "uninvolved" mucosa or the control normal epithelium. Cancer tissue gastrin levels were lower than those measured in biopsies of uninvolved mucosa from cancer patients and normal controls. The present results show no rise of gastrin blood levels in patients with colon cancer, nor any evidence of gastrin-increased synthesis by the tumors.

Topics: Adenocarcinoma; Adult; Aged; Colon; Colorectal Neoplasms; Gastrins; Humans; Middle Aged

Whereas considerable experimental evidence suggests chronic hypergastrinemia can increase the occurrence of colonic neoplasia, the risks in man remain unclear. Zollinger-Ellison syndrome (ZES) is associated with marked plasma elevation of all forms of gastrin and, because of its prolonged course, has been shown to be an excellent model disease to study the effects of chronic hypergastrinemia in man. To determine whether profound chronic hypergastrinemia affects the occurrence of colonic dysplasia and neoplasia, 97 consecutive patients with ZES were studied. All patients underwent colonoscopic examination to the cecum, and the location, size, and type of polyps/tumors were determined. The patients had a mean fasting gastrin level 31 times above normal and a mean disease duration of 10 years; 17/97 (18%) had adenomatous polyps, 67/97 (69%) no adenomatous polyps, and 2/97 (2%) had colonoscopy and/or autopsy studies fo asymptomatic controls. Stratification by age or gender, presence of MEN-I, tumor extent, and duration of degree of hypergastrinemia did not increase prevalence. This study shows that despite prolonged, profound hypergastrinemia, no increased rate of colonic neoplasia (polyps or cancer) was noted. These data suggest that the development of hypergastrinemia secondary to continuous use of H+,K+-ATPase inhibitors for as long as 10 years is unlikely to cause an increased risk of developing colonic neoplasia in man.

Topics: Adenocarcinoma; Adenomatous Polyps; Age Distribution; Chronic Disease; Colonic Neoplasms; Colonic Polyps; Colonoscopy; Fasting; Female; Gastrins; Humans; Incidence; Male; Middle Aged; Risk Factors; Sex Distribution; Zollinger-Ellison Syndrome

The effects of peptide histidine isoleucine (PHI) on the incidence and histology of colon tumors induced by azoxymethane (AOM), and on the labeling index of colon mucosa were investigated in Wistar rats. Rats received weekly s.c. injections of 7.4 mg/kg body weight of AOM for 10 weeks, and of 1.0 or 4.0 nmol/kg body weight of PHI until the end of the experiment in week 35. Administration of PHI at the higher, but not the lower dosage, significantly increased the incidence of colon tumors. PHI had no influence on the histology of colon tumors or adenocarcinomas. It also caused significant increase in the labeling index of colon epithelial cells. These findings indicate that PHI enhances colon carcinogenesis, and that its effect may be related to increasing proliferation of colon epithelial cells.

Topics: Adenocarcinoma; Animals; Azoxymethane; Body Weight; Colon; Colonic Neoplasms; Drug Synergism; Gastrins; Intestinal Mucosa; Peptide PHI; Rats; Rats, Wistar

Studies of transgenic mice have shown that transcriptional control of the gastrin gene exhibits significant species differences. Transfection of the human gastrin promoter in murine cells have depicted proximal Sp1, E-box and CACC elements as the major determinants of transcription. We have examined cis-regulatory elements of the human promoter on a human gastrin expressing cell line and find that a distal -135 to -142 Sp1 element is necessary for maximal activity. Alignment of the mouse and human promoters shows that the proximal human Sp1 and CACC elements are not conserved, whereas the E-box element is retained. The distal Sp1 element is present in mouse but exhibits a C to T transition in the core that is likely to reduce binding affinity of Sp1. We conclude that gastrin gene transcription is regulated by distinct elements in man and rodents.

Topics: Adenocarcinoma; Animals; Base Sequence; Cloning, Molecular; DNA; Gastrins; Humans; Mice; Molecular Sequence Data; Promoter Regions, Genetic; Sequence Alignment; Sequence Analysis, DNA; Sequence Deletion; Sp1 Transcription Factor; Stomach Neoplasms; Transcription, Genetic; Tumor Cells, Cultured

Topics: Adenocarcinoma; Adenomatous Polyps; Aged; Colorectal Neoplasms; Gastrins; Humans; Middle Aged

This study was carried out to develop a scoring system for the diagnosis of gastric adenocarcinoma (GAC). A total of 686 subjects, 150 patients with GAC, 182 with gastric ulcer, 127 with duodenal ulcer, and 227 subjects with negative findings, were enrolled. Analysis of the likelihood ratio (LR) showed that patients with advanced age, ulcer in the stomach, low serum levels of pepsinogen I (PGI), low PGI x gastrin values, and low PGI/gastrin ratio were likely to have GAC. Of these indicators, the serum PGI level had the greatest weight, with a LR of 7.59 for the group with a level < 30 ng/ml. A scoring system combining serum PGI level, Helicobacter pylori seropositivity, and gastric ulcer status was derived, using a logistic regression model. This scoring system was found to be better than any one-parameter criterion for diagnosing GAC after evaluation by the area under the receiver operating characteristic curve (0.84; 95% confidence interval, 0.81-0.88) or by specificity-fixed sensitivity (sensitivity 0.82 at specificity 0.72, sensitivity 0.87 at specificity 0.66, sensitivity 0.96 at specificity 0.44). This scoring system may be potentially useful as a new model for the noninvasive diagnosis of GAC in the future.

Topics: Adenocarcinoma; Adolescent; Adult; Aged; Aged, 80 and over; Female; Gastrins; Helicobacter Infections; Helicobacter pylori; Humans; Male; Middle Aged; Pepsinogens; Radioimmunoassay; Retrospective Studies; Sensitivity and Specificity; Serologic Tests; Stomach Neoplasms

Confirmation of an association between elevated serum gastrin concentrations and presence of colorectal tumors would have important implications with regard to screening procedures and therapeutic strategies.. We compared fasting serum gastrin concentrations of patients with colorectal cancer (n = 91; mean age, 66 (range, 35-87) years), colorectal polyps (n = 89; mean age, 61 (range, 38-86) years), or a normal colonoscopy (n = 101; mean age, 62 (range, 34-82) years) in the period between 1983 and 1992.. Median serum gastrin concentrations were, respectively, 20, 20, and 21 pmol/liter (not significant). We were unable to find a relation with histology of the polyp, presence or severity of dysplasia, and extent of cancer.. This large study fails to show any difference in serum gastrin concentrations among the three studied groups.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Colonic Polyps; Colonoscopy; Colorectal Neoplasms; Female; Gastrins; Humans; Male; Middle Aged; Neoplasm Staging; Retrospective Studies

Endocrine cells (EC) were found in 19 out of 42 cases of the pancreas carcinoma (42.5%). Among them, 4 cases had a positive rate of EC more than 50%. The positive rate of EC in the well differentiated carcinomas (5/20) was lower than that of the poorly-differentiated ones (12/19) or mucinous carcinoma (2/2), and the positive rate in histologic grade I cases (5/18) was significantly lower than that of the grade III cases (7/8). The number of mast cells infiltrating in the matrix in EC positive cases was significantly higher than that of the negative ones. The positive rate of EC in the cases with metastasis (8/14) was higher than that of the non-metastasis cases (7/21). Immunocytochemical staining showed that GN (8), SS(4), HCG(5), CK(12), EMA(13) and CEA(9) were positive in 19 EC positive cases.

Topics: Adenocarcinoma; Adenocarcinoma, Mucinous; Adult; Aged; Female; Gastrins; Humans; Keratins; Male; Middle Aged; Neurosecretory Systems; Pancreatic Neoplasms

Nude mice bearing xenografts of HT-29 human colon cancer cell line were treated for 4 weeks with somatostatin analog (RC-160), bombesin/gastrin releasing peptide (GRP) antagonists (RC-3095 and RC-3440). In three separate experiments somatostatin analog RC-160 (50 micrograms/day) released from microgranules significantly reduced tumor growth. Bombesin/GRP antagonists, RC-3095 and RC-3440 injected subcutaneously (s.c.) twice daily at a dose of 10 micrograms had the greatest and consistently significant inhibitory effect on tumor growth. RC-3095 given once daily s.c. at a dose of 20 micrograms was less effective. RC-3095 also inhibited metastatic tumor growth after intrasplenic injection of HT-29 cells in nude mice. Specific binding sites of somatostatin, bombesin and epidermal growth factor (EGF) were detected on intact HT-29 cells or on the membranes from HT-29 tumor xenografts. The inhibitory effects of bombesin antagonists on tumor growth were consistently linked with a significant down-regulation of EGF receptors. Bombesin/GRP antagonists and somatostatin analogs could be considered for the development of new hormonal therapies for colon cancer.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Bombesin; Colonic Neoplasms; Drug Screening Assays, Antitumor; ErbB Receptors; Gastrin-Releasing Peptide; Gastrins; Growth Hormone; Humans; Insulin-Like Growth Factor I; Liver Neoplasms; Male; Mice; Mice, Nude; Neoplasm Transplantation; Peptide Fragments; Peptides; Radioligand Assay; Somatostatin

The effects of combined administration of bombesin (40 micrograms/kg body weight) and the ornithine decarboxylase (ODC) inhibitor, 1,3-diaminopropane (DAP), on the development of large and small intestinal tumors and the incidence of their metastasis to the peritoneum induced by azoxymethane (AOM, 7.4 mg/kg body weight), the ODC activity of the intestinal wall, and the labeling index of the intestinal mucosa and tumor were investigated in inbred Wistar rats. Rats received weekly s.c. injections of AOM for 10 weeks, s.c. injections of bombesin every other day, and drinking water containing DAP (2.5 g/l) until the end of the experiment at week 40. Administration of bombesin significantly increased the incidence of intestinal tumors at week 40. It had no influence on the location, size, histological features or depth of involvement of intestinal adenocarcinomas, but significantly increased the incidence of their metastasis to the peritoneum. It also resulted in a significant increase in the intestinal ODC activity and labeling index. Administration of DAP with bombesin significantly reduced the enhancement of intestinal carcinogenesis by bombesin. Although the combined use of DAP with bombesin had little or no influence on the location, size, histological features, or depth of involvement of intestinal cancers, the incidence of their metastasis was significantly reduced. DAP significantly attenuated bombesin enhancement of the intestinal ODC activity and labeling index. These findings indicate that ODC inhibition attenuated the enhancement of intestinal carcinogenesis and metastasis to the peritoneum.

Topics: Adenocarcinoma; Animals; Azoxymethane; Body Weight; Bombesin; Cell Division; Diamines; Drug Synergism; Gastrins; Intestinal Mucosa; Intestinal Neoplasms; Male; Neoplasm Metastasis; Ornithine Decarboxylase Inhibitors; Peritoneal Neoplasms; Rats; Rats, Wistar

This report describes an immunohistopathologic analysis characterizing the incidence, pattern of distribution, and hormonal content of neuroendocrine (NE) cells in human benign prostate and prostatic adenocarcinoma.. Formaldehyde-fixed, paraffin-embedded material from 15 benign prostates, 31 primary prostatic adenocarcinomas, 16 metastatic lesions, 21 primary tumors treated with short-course diethylstilbestrol (DES), and 10 specimens from hormone-refractory patients were examined. NE cells were identified using silver histochemistry and a panel of immunohistochemical NE markers (chromogranin-A, serotonin, neuron-specific enolase), and specific peptide hormone antibodies.. NE cells were identified in all benign prostates. NE cells were identified in 77% of primary untreated adenocarcinomas with no significant differences with respect to pathologic stage. NE cells were found isolated and dispersed in the tumor, composing the minority of malignant cells. Double-labeling and serial section immunohistochemistry demonstrated the coexpression of prostate-specific antigen (PSA) in NE cells. In addition to serotonin, some tumors expressed multiple hormone immunoreactivities. NE cells were identified in 56% of metastatic deposits, with a similar pattern of distribution. In DES-treated cases, NE cells were found consistently in the adjacent benign epithelium, whereas 52% of tumors contained NE cells. Hormone-refractory tumors contained NE cells in 60% of cases.. This analysis demonstrates that a significant proportion of primary and metastatic prostatic adenocarcinomas contain a subpopulation of NE cells, the expression of which does not appear to be suppressed with androgen ablation and does not correlate with pathologic stage. Furthermore, NE cells coexpress PSA, suggesting a common precursor cell of origin. The elaboration of biogenic amines and neuropeptides suggests that NE cells dispersed in prostatic carcinoma may play a paracrine growth-regulatory role.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Basement Membrane; Calcitonin; Carcinoma; Cell Differentiation; Chromogranin A; Chromogranins; Cytoplasm; Diethylstilbestrol; Gastrin-Releasing Peptide; Gastrins; Humans; Keratins; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Staging; Neurosecretory Systems; Peptides; Prostate; Prostate-Specific Antigen; Prostatic Neoplasms; Seminal Vesicles; Serotonin; Staining and Labeling; Thyrotropin

Gastrin has been shown to promote the growth of some colonic tumor cell lines. To evaluate the involvement of this hormone in the proliferation of gastric tumors, we studied the effects of gastrin/CCK-receptor antagonists (L365,260 and L364,718), proglumide and C terminal-specific gastrin antibodies on the human gastric adenocarcinoma cell line HGT-1. L365,260, but not L364,718, dose-dependently inhibited cell proliferation (72% after 4 days at 10 nM) and [3H]thymidine incorporation (68% after 2 days at 10 nM) in serum-free medium. No cytotoxic effects of proglumide or L365,260 on this cell line were detected. Proglumide inhibited cell proliferation in serum-free medium (40% and 66.5% after 2 and 4 days of treatment; IC50 = 1.4 mM) and in 5% fetal calf serum (FCS)-supplemented medium (30% and 22% after 2 and 4 days of treatment; IC50 = 3.25 mM). [3H]Thymidine incorporation was also inhibited by proglumide in serum-free medium (IC50 = 2.3 mM) and 5% FCS-supplemented medium (IC50 = 3.35 mM). Gastrin did not induce cell proliferation or increase [3H]thymidine incorporation and no high-affinity gastrin binding sites were observed. However, C terminal-specific gastrin antibodies, even at low concentration, caused a dramatic decrease in both cell number (IC50 = 1:4000 antiserum dilution) and [3H]thymidine incorporation (IC50 = 1:400 antiserum dilution) in the HGT-1 cell line. In addition, immunofluorescence analysis revealed that these antibodies specifically bind HGT-1 cells and radioimmunoassay analysis confirms the presence of gastrin/CCK-like peptide in cell extracts.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adenocarcinoma; Antibodies; Benzodiazepinones; Cell Division; Devazepide; Gastrins; Growth Substances; Humans; Neoplasm Proteins; Phenylurea Compounds; Proglumide; Receptors, Cholecystokinin; RNA, Messenger; RNA, Neoplasm; Stomach Neoplasms; Tumor Cells, Cultured

Topics: Adenocarcinoma; Carcinoid Tumor; Gastric Acid; Gastrins; Helicobacter Infections; Helicobacter pylori; Humans; Peptic Ulcer; Stomach Neoplasms

To assess the value of gastroscopic cancer surveillance of patients with pernicious anaemia, 56 patients were re-endoscoped and biopsied after three years. In addition, changes in the density of fundic mucosal endocrine cells were evaluated morphometrically. Two cases (3.6%) of early gastric cancer and two cases of small gastric carcinoid tumours (3.6%) were detected in addition to the five carcinoids that had been found at the initial endoscopic screening. Nodular argyrophil cell hyperplasia and morphometric density of argyrophil cells were not stable phenomena: nodular hyperplasias regressed in five patients, remained similar in six, and progressed to a small carcinoid tumour in one. Serum gastrin concentrations did not correlate well with changes in the endocrine cell density. Regular endoscopic surveillance for gastric cancer may be beneficial and realistic in young patients with pernicious anaemia while the importance of fundic endocrine cell hyperplasia and that of small gastric carcinoids need further study.

Topics: Adenocarcinoma; Adult; Aged; Anemia, Pernicious; Carcinoid Tumor; Female; Follow-Up Studies; Gastric Fundus; Gastric Mucosa; Gastrins; Gastroscopy; Humans; Hyperplasia; Male; Middle Aged; Stomach; Stomach Neoplasms

To evaluate the hypothesis that gastrin is a local growth factor in colonic carcinomas, the expression of gastrin messenger RNA (mRNA) and peptides were examined in five human colon carcinoma cell lines, 12 solid colon carcinomas, and normal colonic tissue.. Northern analysis, reverse-transcription PCR, and a library of sequence-specific radioimmunoassays were the principal methods.. Cell lines, tumors, and normal tissue all expressed a gastrin mRNA of 0.7 kilobases, and all cell lines contained incompletely processed progastrin (range, 17-54 fmol/10(6) cells). Two cell lines secreted progastrin into the media (LoVo, 25 +/- 3 pmol/L; HCT116; 12 +/- 2 pmol/L). Normal colonic tissue and all the solid tumors also contained progastrin, the concentration being higher in tumors (range, 0.4-2 pmol/g) than in normal tissue (range, 0.1-0.2 pmol/g). Only one tumor contained carboxyamidated gastrins.. Normal and neoplastic colonic mucosa both express the gastrin gene, but the posttranslational phase of expression is attenuated. The incomplete processing and low level of expression suggest that autocrine gastrin secretion has only minor significance for normal adult and most neoplastic colonic tissue.

Topics: Actins; Adenocarcinoma; Blotting, Northern; Colon; Colonic Neoplasms; Colorectal Neoplasms; Exons; Gastric Mucosa; Gastrins; Humans; Oligodeoxyribonucleotides; Polymerase Chain Reaction; Protein Precursors; Rectal Neoplasms; RNA Probes; RNA, Messenger; Tumor Cells, Cultured

Topics: Adenocarcinoma; Animals; Antigens, Viral, Tumor; Carcinoma; Gastrinoma; Gastrins; Genetic Engineering; Hyperplasia; Liver Neoplasms; Mice; Mice, Transgenic; Pancreatic Neoplasms; Pyloric Antrum; Stomach Neoplasms

In this study, determination of gastrin concentration in bronchoalveolar lavage fluid and serum has been detected by radioimmunoassay in 30 cases of lung cancer and 24 cases of non-cancer pulmonary diseases. The results show that the gastrin concentration and its positive rate of lavage fluids from cancer lung are much higher than those from healthy lung and serum in lung cancer patients, and those from serum and both disease and healthy lung in non-cancer pulmonary disease patients (P less than 0.01). The gastrin ratio of lavage fluids from cancer lung to serum is also significantly higher than the ratio of lavage fluid from healthy lung to serum and all the ratios in the non-cancer pulmonary disease group. These results suggest that there is a high gastrin concentration in local tissue of lung cancer, which is signified by the high concentration of gastrin and its high positive rate in lavage fluids from the lung with cancer. Therefore, the gastrin determination in lavage fluids and gastrin ratio of lavage fluids to serum are more reliable in the differential diagnosis of benign from malignant pulmonary diseases than gastrin determination of serum alone.

Topics: Adenocarcinoma; Adult; Aged; Bronchoalveolar Lavage Fluid; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Female; Gastrins; Humans; Lung Diseases; Lung Neoplasms; Male; Middle Aged

Serial changes in serum gastrin level were detected by radioimmunoassay in 58 lung cancer patients before and after operation. In comparing these tests with those of 40 cases of noncancerous thoracic lesions and 151 normal adults, the serum gastrin from lung cancer patients is significantly higher than that of noncancerous thoracic lesions and normal individuals (P less than 0.01). The gastrin level is closely related to stage of cancer, size of primary tumor, presence of lymph node metastasis, and type of histological classification. The serum gastrin was found to decrease gradually after the removal of the tumor and to return to normal on the 14th postoperative day. Those patients whose serum gastrin level can return to normal on the 14th postoperative day will have a good prognosis; if not, their prognosis will be very poor. These results suggest that serum from patients with lung cancer contains a high concentration of gastrin that can help differentiate benign from malignant thoracic lesions and evaluate prognosis of patients with lung cancer. Therefore, the cause of high serum gastrin in patients with lung cancer is likely due to the gastrin-producing property of the lung cancer cells.

Topics: Adenocarcinoma; Adult; Aged; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Female; Gastrin-Releasing Peptide; Gastrins; Humans; Lung Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Staging; Peptides; Postoperative Period; Prognosis; Thoracic Diseases

One hundred and twenty-eight cases of gastric carcinoma were examined with immunohistochemical technic for carcinoembryonic antigen (CEA), human chorionic gonadotropin (HCG), serotonin, gastrin and lysozyme. CEA were observed in 105 cases. Twenty-four cases were positive for HCG, 53 cases for serotonin, 31 cases for gastrin, 89 cases for lysozyme. Sixty-nine cases exhibited more than two hormones or one hormone and lysozyme simultaneously in different cells of the same tumor. Ultrastructurally, sometimes three types of secretory granules were noticed. The electron dense granules in the lysozyme-containing tumor cells were similar to those of Paneth's cells in intestinal metaplasia. The positive rates of the above three hormones, lysozyme and multi-marker expression in diffuse type carcinoma were higher than those in intestinal type, and 42/44 cases of the diffuse type carcinoma were histologically undifferentiated carcinomas or signet-ring cell carcinomas. Lymph node metastasis occurred more frequently in those carcinomas with hormone or lysozyme positivity. These findings suggest that these neoplastic endocrine cells and Paneth's cells have originated from multipotential differentiation of neoplastic stem cells in the stomach, reflecting the state of the gene activity in the tumor cells.

Topics: Adenocarcinoma; Adenocarcinoma, Mucinous; Carcinoembryonic Antigen; Carcinoma; Chorionic Gonadotropin; Gastrins; Humans; Immunohistochemistry; Lymphatic Metastasis; Muramidase; Neoplasm Staging; Serotonin; Stomach Neoplasms

Fifty exocrine pancreatic adenocarcinomas and 57 benign tumors induced in Syrian hamsters by N-nitrosobis(2-oxopropyl)amine (BOP) were examined for the presence of argyrophil cells antiinsulin, -glucagon, -somatostatin, -pancreatic polypeptide (PP), -gastrin/CCK, -vasoactive intestinal polypeptide (VIP), and - neuron-specific enolase (NSE) reactive cells. Argyrophil - and antihormone-reactive cells were found in the normal pancreatic ducts and in the acini, as well as in hyperplastic and atypical ducts/ductules, tubular complexes, benign lesions, and in 80% of ductal adenocarcinomas. Insulin and antiNSE-reactive cells were the most common, followed in decreasing frequency by glucagon, somatostatin, and PP cells. Antigastrin-/CCK-and -VIP-reactive cells were found in two cases. Argyrophil cells were present in about 60% of the tumors with Grimelius staining and in 55% of those with Churukian-Schenk staining. Insulin cells were seen in ductal cancer that had grown into a lymph node and in the lymph node metastases of another cancer. A novel finding was the presence of argyrophil and insulin cells within the lumen of some malignant glandular structures. Coexistence of several peptide cells was found in 52% of the cancers. The presence of argyrophil and hormone-producing cells in induced pancreatic ductal/ductular lesions further strengthens the existence of a close developmental relationship between exocrine and endocrine cells of the pancreas.

Topics: Adenocarcinoma; Animals; Cricetinae; Female; Gastrins; Glucagon; Immunohistochemistry; Insulin; Islets of Langerhans; Male; Mesocricetus; Pancreatic Ducts; Pancreatic Neoplasms; Pancreatic Polypeptide; Phosphopyruvate Hydratase; Silver Staining; Somatostatin; Vasoactive Intestinal Peptide

Two previous studies have shown higher circulating gastrin levels in subjects with colonic neoplasia than in colonoscopy-negative controls. In this much larger study, sera were collected from fasting subjects undergoing colonoscopy. Colonoscopy with biopsy classified participants as having colonic adenomas (N = 139), colon carcinoma (N = 29), or controls without colonic neoplasia (N = 150). Frozen, stored sera were later analyzed for gastrin by radioimmunoassay. Serum gastrin values were no higher in subjects with colonic adenomas or carcinoma than in colonoscopy-negative controls. We conclude that elevated serum gastrin levels play little, if any, role in the initiation of colonic neoplasia.

Topics: Adenocarcinoma; Adenoma; Case-Control Studies; Colonic Neoplasms; Colonoscopy; Female; Gastrins; Humans; Male; Middle Aged; Radioimmunoassay

The effects of bombesin on the incidence, number and histology of colon tumors induced by azoxymethane (AOM), and on their metastases to the peritoneum and/or lymph nodes, were investigated in Wistar rats. Rats received weekly s.c. injections of AOM for 10 weeks, and s.c. injections of bombesin in depot form every other day until the end of the experiment in week 30. Administration of bombesin significantly increased the incidence of colon tumors in week 30. It had no influence on the histological features or depths of involvement of colon adenocarcinomas, but significantly increased the incidence of cancer metastasis to the peritoneum and/or lymph nodes. It also caused a significant increase in the labeling index of the colon epithelial cells. Our findings indicate that bombesin enhances the development and metastasis of colon tumors, and that this effect may be related to its effect in increasing proliferation of epithelial cells of the colon.

Topics: Adenocarcinoma; Animals; Azoxymethane; Bombesin; Colon; Colonic Neoplasms; Gastrins; Male; Neoplasm Metastasis; Norepinephrine; Rats; Rats, Inbred Strains

Plasma gastrin has been reported to be elevated among patients with colorectal cancer. The objectives of the present study were to confirm this observation and, if confirmed, to shed light on the reason for the elevation. Presurgical and postsurgical fasting plasma gastrin levels were compared between 24 patients hospitalized for colorectal adenocarcinoma resection and 25 control patients hospitalized for other surgery. Elevated presurgical gastrin levels in the case group that fell after surgery would be consistent with production of gastrin by the tumor. High presurgical gastrin levels in the case group that did not change following surgery would be consistent with excess gastrin production by G cells. The mean presurgical gastrin levels were 21.9 +/- 3.7 pM (cases) and 45.1 +/- 18.0 pM (controls). The mean postsurgical gastrin levels were 20.5 +/- 3.9 pM (cases) and 43.4 +/- 14.6 pM (controls). These results do not provide support for the hypotheses that gastrin is elevated in colorectal cancer patients or that gastrin is secreted by colorectal tumors in sufficient quantities to be measurable in the plasma.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Case-Control Studies; Colorectal Neoplasms; Female; Gastrins; Humans; Male; Middle Aged

Colonic mucosa and adenocarcinoma are known to possess gastrin receptors. Recent studies have suggested that some patients with large intestinal cancers and polyps have elevated serum gastrin levels and that gastrin may stimulate growth of colonic neoplasms. The aim of the present investigation was to determine whether endogenous hypergastrinemia--induced by the proton pump inhibitor omeprazole--would influence growth in a subcutaneously implanted murine colonic cancer. The results show that despite a fivefold increase in serum gastrin levels (193 pg/ml median value, range 186-252, in the omeprazole-treated group vs 36 pg/ml median value, range 28-37 in controls), there were no differences in tumor size or survival of tumor-bearing animals. Additionally, there were no differences in serum gastrin values between tumor- (29 pg/ml, range 25-38) and non-tumor- (34 pg/ml, range 25-30) bearing, untreated animals. Endogenous elevation of the serum gastrin hormone to five times the normal level does not demonstrate trophic effects on the murine colon tumor MC-26.

Topics: Adenocarcinoma; Animals; Cell Division; Colonic Neoplasms; Gastrins; Liver Neoplasms; Mice; Mice, Inbred BALB C; Neoplasm Transplantation; Omeprazole

The effects of the dopamine agonist 2-bromo-alpha-ergocryptine methanesulfonate (bromocriptine) on the incidence, number and histology of gastric cancer induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) were investigated in Wistar rats. Rats were given 1 or 2 mg kg-1 body weight of bromocriptine subcutaneously every other day in depot form after 25 weeks of oral treatment with MNNG. Prolonged administration of bromocriptine at both dosages every other day resulted in a significant increase in the incidence and number of gastric cancers of the glandular stomach by week 52. Bromocriptine treatment did not influence the histological type of gastric cancer, but caused a significant increase in the labelling index of epithelial cells of the antrum. These findings indicate that the dopamine agonist bromocriptine promotes gastric carcinogenesis, and that this effect may be related to its effect in increasing proliferation of epithelial cells in the antral mucosa.

Topics: Adenocarcinoma; Animals; Bromocriptine; Dopamine; Epinephrine; Gastric Mucosa; Gastrins; Hydrogen-Ion Concentration; Male; Methylnitronitrosoguanidine; Neoplasms, Experimental; Norepinephrine; Rats; Rats, Inbred Strains; Stomach Neoplasms

The effects of ad libitum feeding of synthetic, low-protein diets on the incidence, number and histology of colon tumors induced by azoxymethane (AOM), on the norepinephrine concentration in the colon wall tissue and on the labelling index of colon mucosa were investigated in Wistar rats. Rats received 10 weekly injections of 7.4 mg/kg body weight of AOM and were given synthetic diets of equal calorie content containing 25% casein (normal-protein diet), 10% casein (low-protein diet) or 5% casein (very-low-protein diet). Administration of the low- and very-low-protein diets resulted in significant increases in the incidence and number of colon tumors at week 30. However, it did not affect the histology of the colon tumors. The low- and very-low-protein diets also resulted in significant increases in norepinephrine concentration in the proximal and distal portions of the colon wall and in the labelling indices of both parts of the colon mucosa. Our findings indicate that low- and very-low-protein diets enhance colon carcinogenesis and that this may be related to their effects in increasing the norepinephrine level in the colon wall and in stimulating proliferation of colon epithelial cells.

Topics: Adenocarcinoma; Adenoma; Animals; Azoxymethane; Cell Division; Colon; Colonic Neoplasms; Dietary Proteins; Gastrins; Intestinal Mucosa; Male; Norepinephrine; Rats; Rats, Inbred Strains

The effects of combined administration of bombesin and the ornithine decarboxylase (ODC) inhibitor 1,3-diaminopropane (DAP) on the incidence and number of gastric tumors induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), the ODC activity of the gastric wall and the labelling index of the gastric mucosa were investigated in inbred Wistar rats. Rats were given drinking water containing MNNG (50 micrograms/ml) for 25 weeks and then drinking water containing DAP (2.5 g/l) and/or injections of 40 micrograms/kg body weight of bombesin in depot form every other day. Administration of bombesin alone resulted in significant increases in the incidence of gastric cancers, the ODC activity of the antral portion of the gastric wall and the labelling index of the antral mucosa. Administration of DAP with bombesin significantly reduced enhancement by the latter of gastric carcinogenesis, ODC activity of the antral portion of the gastric wall and the labelling index of the antral mucosa. Our results suggest that ODC inhibition attenuated the enhancement of gastric carcinogenesis by bombesin, and that this enhancement by bombesin was mediated by polyamine biosynthesis.

Topics: Adenocarcinoma; Animals; Bombesin; Diamines; Drug Interactions; Drug Synergism; Gastric Mucosa; Gastrins; Hydrogen-Ion Concentration; Male; Methylnitronitrosoguanidine; Ornithine Decarboxylase Inhibitors; Rats; Rats, Inbred Strains; Stomach; Stomach Neoplasms

Female Syrian golden hamsters with N-nitrosobis(2-oxopropyl)amine-induced pancreatic cancers were treated for 2 months with new pseudononapeptide bombesin receptor antagonist [D-Tpi6,Leu13 psi (CH2NH)-Leu14]bombesin(6-14)(RC-3095), administered s.c. with implanted osmotic minipumps releasing 20 micrograms/day of the analogue. The results were compared to those obtained by treatment with somatostatin analogue RC-160 (35 micrograms/day and 150 micrograms/day) or [D-Trp6]luteinizing hormone-releasing hormone (25 micrograms/day), which inhibited the growth of pancreatic cancers in our previous studies. A new acetylated somatostatin analogue [formula: see text] (30 micrograms/day) also was used for comparison of therapeutic response. All peptide analogues induced tumor inhibition by at least one of the measured parameters. Bombesin antagonist RC-3095 and high dose of RC-160 (150 micrograms/day) had the greatest inhibitory effect on pancreatic cancers: A significant decrease in the number of animals with tumors, reduced pancreatic weight, 87-89% inhibition of tumorous pancreas weight, and a significant diminution in the number of tumor nodules and argyrophilic nucleolar organizer region count in tumor cell nuclei were observed in the groups treated with these regimens. We were able to detect receptors for bombesin in membranes of N-nitrosobis(2-oxopropyl)amine-induced pancreatic tumors and these receptors were not down-regulated after treatment with the bombesin antagonist. In hamsters treated with bombesin antagonists, tumor inhibition might be explained by a significant decrease in the binding capacity of epidermal growth factor receptors in pancreatic cancers. The acetylated somatostatin analogue RC-160-II had a similar inhibitory effect on the tumors as the original analogue RC-160. Our results suggest that the increase in the dose of RC-160 improves the therapeutic response, and this finding should be taken into account in clinical use of this somatostatin analogue. In view of its strong inhibitory effect on experimental pancreatic tumors, the bombesin antagonist RC-3095 might be considered as a possible new agent for the therapy of human exocrine pancreatic cancer.

Topics: Adenocarcinoma; Amino Acid Sequence; Animals; Antineoplastic Agents; Bombesin; Carcinogens; Cell Membrane; Cricetinae; ErbB Receptors; Female; Gastrins; Mesocricetus; Molecular Sequence Data; Nitrosamines; Organ Size; Pancreatic Neoplasms; Peptide Fragments; Receptors, Bombesin; Receptors, Neurotransmitter; Somatostatin

Topics: Adenocarcinoma; Colonic Neoplasms; Colonic Polyps; Gastrins; Humans

Gastrin stimulates the growth of some human colon adenocarcinomas grown in vitro or as xenografts in nude mice. To evaluate the possibility of elevated plasma gastrin levels in patients with adenomatous polyps or colorectal cancer, we carried out a radioimmunoassay in subjects fasting overnight and undergoing colonoscopy. The study included 190 patients who were divided into three groups: controls (n = 65), those with benign adenomas (n = 63), and those with adenocarcinomas (n = 62). The mean values of plasma gastrin in the cancer group (112.71 +/- 16.65 pg/ml) were significantly higher than those of the control group (40.41 +/- 1.88 pg/ml) as well as those of the polyp group. Mean plasma gastrin values in the polyp group (54.27 +/- 5.29 pg/ml) were also significantly higher than those of the control group. In the cancer group, 32 of 62 patients (51.6%) had gastrin levels greater than the control mean +2 SD, as opposed to only 10 of 63 (15.9%) in the polyp group. The number, size, histologic type, and presence of dysplasia in the polyp group and the location or Dukes' stage in the cancer group had no significant influence on gastrin levels in this study. Preliminary results in cancer patients with elevated preoperative gastrin levels show a postoperative reduction in six of seven patients. The exact cause and role of hypergastrinemia in tumor growth in such patients remains to be determined. Measurements taken both before and after colectomy coupled with a systematic search for specific gastrin receptors would be useful.

Topics: Adenocarcinoma; Aged; Colonic Neoplasms; Colonic Polyps; Female; Gastrins; Humans; Male; Middle Aged; Radioimmunoassay; Rectal Neoplasms

We studied the effects of dietary calcium, fat and fiber on serum gastrin in Fischer-344 rats in a full factorial experiment as part of a larger study of diet and colon cancer risk factors. Nine- to 10-wk-old male rats were fed standard or experimental diets for 4 wk. Wheat bran was the sole source of fiber. Wheat bran levels were 0, 2.5, 10 and 20%; fat levels were 1, 5 and 10%; calcium levels were 0.18, 0.52 and 1.04% of diet weight. On d 29 serum was collected and stored at -80 degrees C until analyzed. There was a significant (P less than 0.0001) dose-dependent increase in serum gastrin from 102 to 173 ng/L, with increasing calcium. No other significant changes in serum gastrin were noted with the dietary changes. A long-term change in the level of serum gastrin, caused by dietary modification, will influence the trophic effect that gastrin has on colonic mucosa as well as on colon carcinomas. We speculate that calcium supplementation, although slowing colonic proliferation, might have an undesirable effect on the growth of early undetected colonic tumors.

Topics: Adenocarcinoma; Animals; Calcium, Dietary; Colonic Neoplasms; Dietary Fats; Dietary Fiber; Gastrins; Male; Rats; Rats, Inbred F344; Risk Factors; Triticum; Weight Gain

The effects of gastrin (G-17), proglumide (a gastrin receptor antagonist), and enprostil (a synthetic analog of prostaglandin E2) used alone or in association were studied in colonic cancer Prob and Regb cell growth. The Prob (progressive in BD IX rats) and Regb (regressive) cell lines were cloned from a single chemically-induced rat colonic cancer. After a serum-free period corresponding to one doubling cell time, cells were incubated with 100 to 1,200 pM G-17, 40 or 80 mM proglumide, and 2.5 to 5 micrograms/ml enprostil for 8 h. Cell growth was measured 48 h later by colorimetric MTT assay. Two and four hundred pM G-17 gave a growth stimulation of 17.4 percent and 31 percent for Prob cells respectively or 35.5 percent and 49 percent for Regb cells. Growth stimulation was found to be statistically different (P less than 0.01) for Prob and Regb cells. Proglumide partially inhibited this growth stimulation whereas enprostil inhibited in totally. These results suggest that growth of some colonic cancer cell lines may be G-17 dependent. However the intensity of cell-growth stimulation depends on the level of cell malignancy or differentiation in a single tumor.

Topics: Adenocarcinoma; Animals; Colonic Neoplasms; Dimethylhydrazines; Drug Combinations; Enprostil; Gastrins; Proglumide; Rats; Stimulation, Chemical; Tumor Cells, Cultured

Flow cytometry and immunohistochemical analyses of the human gastric adenocarcinoma cell line MKN45G identified an intracellular peptide recognized by an anti-gastrin-17 (G17) antiserum but not by an anti-cholecystokinin-specific antiserum. Staining was not associated with the parental line MKN45, of which MKN45G is a clonal variant. The MKN45G cell line had elevated in vitro growth in serum-free medium in which the proliferation of MKN45G cells but not MKN45 cells was reduced to 58% of the control value by treatment with a rabbit anti-G17 antiserum. This inhibition of proliferation was reversed by preabsorbing the antiserum with excess G17. Disaggregated primary human gastric and colorectal tumors were screened for gastrin immunoreactivity by flow cytometry, and 6 of 28 colorectal and 8 of 22 gastric tumors had greater than 20% positively staining cells.

Topics: Adenocarcinoma; Animals; Antibodies; Carcinoembryonic Antigen; Cell Division; Cholecystokinin; Colorectal Neoplasms; Flow Cytometry; Gastrins; Gastrointestinal Neoplasms; Humans; Immunohistochemistry; Intracellular Fluid; Rabbits; Stomach Neoplasms; Tumor Cells, Cultured

The effect of tyrosine methyl ester (TME) on the incidence, number, and histological types of gastric cancers induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) was investigated in male Wistar rats. Rats were subcutaneously given TME, 512 mg/kg body weight, every other day after 20 weeks of oral treatment with MNNG. Prolonged alternate-day administration of TME caused a significant increase in the incidence and number of gastric cancers of the glandular stomach by week 52. However, it did not affect the histology of the cancers. TME also caused a significant increase in tissue norepinephrine concentrations in the antral portion of the gastric wall and in the labelling indices of the antral epithelial cells. However, TME had no influence on the serum gastrin level and antral pH. These findings indicate that TME enhances gastric carcinogenesis, and this may be related to its effects on increasing norepinephrine levels in the gastric wall and stimulating proliferation of the antral epithelial cells.

Topics: Adenocarcinoma; Animals; Catecholamines; Drug Synergism; Epinephrine; Gastric Acidity Determination; Gastric Mucosa; Gastrins; Male; Methylnitronitrosoguanidine; Muscle, Smooth; Norepinephrine; Rats; Rats, Inbred Strains; Stomach; Stomach Neoplasms; Tyrosine

To elucidate the biological and clinicopathological significance of endocrine differentiation in gastric adenocarcinoma, an immunohistochemical study was made of 127 cases with ascertained five-year survivals, and of 45 recent cases of bromodeoxyuridine (BrdU) labeling. Endocrine differentiated cancer cells were demonstrated in 37 out of the 127 cases (29.1%) evaluated by chromogranin A (CGA) immunoreactivity, and all CGA-positive tumors were classified as advanced gastric cancer. Analysis of retrospective five-year survival rates revealed the adenocarcinomas with endocrine differentiation to have had significantly longer survival times than those without endocrine immunoreactivity in stage II, but not in stages III or IV. Double immunolabeling for CGA and BrdU in the other 45 adenocarcinoma cases showed only a single CGA-positive cancer cell with BrdU incorporation among a total of 454 CGA-positive cells examined. There was no significant difference between the labeling indices of the general cancer population and the cancer cells adjacent to CGA-positive cells. In conclusion, endocrine differentiation of gastric cancer is not uncommon, particularly in advancing cancer, and it would be a useful marker for a better prognosis in stage II. Probably, endocrine differentiated cancer cells are almost dormant with virtually no DNA synthesizing activity, and their paracrine effect is most unlikely to work in vivo.

Topics: Adenocarcinoma; Bromodeoxyuridine; Cell Differentiation; Cell Division; Chromogranin A; Chromogranins; Gastrins; Glicentin; Glucagon; Glucagon-Like Peptides; Glycoprotein Hormones, alpha Subunit; Hormones; Humans; Immunohistochemistry; Lymph Nodes; Lymphatic Metastasis; Peptide Fragments; Protein Precursors; Serotonin; Somatostatin; Stomach Neoplasms

Topics: Adenocarcinoma; Adrenocorticotropic Hormone; Biomarkers, Tumor; Bombesin; Gastrins; Glucagon; Hormones; Humans; Immunophenotyping; Lung Neoplasms; Male; Middle Aged; Somatostatin; Vasoactive Intestinal Peptide

The effect of enprostil and the somatostatin analogue SMS 201 995 on the growth of a clonal variant of the human gastric adenocarcinoma cell line, MKN45, was studied. The derived cell line grew twice as fast as MKN45 when grown as a xenograft line in nude mice. However, it did not respond trophically to gastrin either in vitro or in vivo (unlike MKN45) although it possessed the same number of gastrin receptors as the parental line. Gastrin production by the cell line during in vitro culture was twice that of MKN45; thus, the cell line was denoted MKN45G. When MKN45G was grown as xenografts in nude mice (n = 10/group), enprostil (20 micrograms/kg/day) significantly inhibited tumour growth when administered continuously by an osmotic mini-pump from day 1 to day 7 of a 20-day experiment, and induced tumour regression when administered from day 7 to day 14. Enprostil reduced postprandial serum gastrin levels when administered from day 7 to day 14 and prevented gastrin release by MKN45 in vitro. SMS 201 995 at doses of 25 and 240 micrograms/kg/day induced tumour regression when administered from day 1 to day 7 and the former dose reduced post-prandial serum gastrin levels at day 5. Gastrin release by MKN45G was not affected by SMS 201 995 in vitro, thus its effect may not be mediated directly via gastrin, requiring interaction between other hormones or growth factors in the in vivo situation.

Topics: Adenocarcinoma; Animals; Cell Line; Drug Evaluation, Preclinical; Enprostil; Female; Gastrins; Humans; Male; Mice; Mice, Nude; Middle Aged; Neoplasm Transplantation; Octreotide; Prostaglandins E, Synthetic; Receptors, Gastrointestinal Hormone; Stomach Neoplasms; Time Factors; Tumor Cells, Cultured

The effects of neurotensin on the incidence, number, size, and histology of colon tumours induced by azoxymethane (AOM) were investigated in Wistar rats. Rats were given 10 weekly injections of AOM (7.4 mg kg-1 body weight) and were also given 200 micrograms kg-1 of neurotensin in depot form every other day until the end of the experiment. In week 40, prolonged alternate-day administration of neurotensin resulted in significant increases in the number and size of colon tumours and the incidence of adenocarcinomas penetrating muscle layer and deeper. However, neurotensin did not influence the incidence of tumour-bearing rats and the histological appearance of colon tumours. Administration of neurotensin caused a significant increase in the labelling index of the colon cancers but not that of colon mucosa. These findings indicate that neurotensin enhanced the growth of colon tumours, possibly related to its effect in increasing proliferation of colon cancer cells.

Topics: Adenocarcinoma; Adenoma; Animals; Azoxymethane; Body Weight; Colonic Neoplasms; Drug Synergism; Gastrins; Male; Neurotensin; Rats; Rats, Inbred Strains

Processing-independent radioimmunoanalysis for progastrin showed that extracts of normal pancreatic tissue from normal subjects (n = 5) and from patients with adenocarcinoma of the papilla of Vater (n = 4) contain progastrin and its products. The concentrations varied from 0.1 to 5.8 pmol/g tissue, of which carboxyamidated bioactive gastrins constituted 0.03-1.9 pmol/g. In histologically normal and nonneoplastic pancreatic tissue from patients with duodenal (n = 3) and pancreatic (n = 2) gastrinomas the expression of gastrin was significantly higher-14.5 pmol/g (median), of which 28% was bioactive amidated gastrins. Gastrin-17 was the main bioactive product, but its immediate precursor, glycine-extended gastrin-17, constituted the predominant part of the preprogastrin product in pancreatic tissue. Proper gastrinoma tissue contained several precursor forms, including intact unprocessed progastrin. Progastrins were also found in high concentrations in plasma from the gastrinoma patients. The results raise the possibility that increased expression of progastrin and its products in non-neoplastic pancreatic tissue is a primary defect predisposing to neoplasia.

Topics: Adenocarcinoma; Ampulla of Vater; Common Bile Duct Neoplasms; Gastrinoma; Gastrins; Gene Expression; Humans; Pancreas; Pancreatic Neoplasms; Protein Precursors; Protein Processing, Post-Translational; Zollinger-Ellison Syndrome

Seventy-six patients with Barrett's esophagus were cared for during a 10-year period. Fifty-six patients (74%) presented with complications of the disease. There were 20 strictures, 7 giant ulcers, 11 cases of dysplasia, and 29 patients with carcinoma. In patients with benign disease, 93% had mechanically defective sphincters and 83% had peristaltic failure of the lower esophageal body. Esophageal pH monitoring showed excessive esophageal exposure to pH less than 4 in 93% and excessive exposure to pH more than 7 in 34% of the patients tested. Ninety-three per cent of patients with excessive alkaline exposure had complications, compared to only 44% with normal alkaline exposure (p less than 0.01). Gastric pH monitoring, serum gastrin levels, and gastric acid analysis supported a duodenal source for the alkaline exposure. Antireflux surgery was performed using Nissen fundoplication in 30, Belsey partial fundoplication in 3, and Collis-Belsey gastroplasty in 2. Six required resection with colon interposition. Good symptomatic control was achieved in 77% after antireflux surgery. Four patients had symptoms and signs of duodenogastric reflux; three required a bile diversion procedure. Fifteen patients had an en bloc curative resection with colon interposition. One patient with high-grade dysplasia on biopsy was found to have intramucosal carcinoma after simple esophagectomy. Five tumors were intramucosal, seven were intramural, and four were transmural. Lymph node involvement occurred only in the latter two. Actuarial survival 5 years after curative resection was 53%. Median survival time for patients after palliative resection or no resection was 12 months. Study of en bloc specimens indicated that extent of resection should be adapted to extent of disease: esophagectomy for intramucosal disease, en bloc esophagectomy with splenic preservation for intramural and transmural disease. Serum CEA was useful in detecting recurrent disease after surgery when the primary tumor stained positively for CEA.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Barrett Esophagus; Carcinoembryonic Antigen; Esophageal Neoplasms; Female; Gastric Acid; Gastric Emptying; Gastrins; Humans; Hydrogen-Ion Concentration; Male; Manometry; Middle Aged; Monitoring, Physiologic; Survival Rate

The effects of the organic calcium channel blocker verapamil and the inorganic calcium channel blocker MgCl2 on gastric carcinogenesis, on caerulein enhancement of gastric carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine, and on the labeling index of gastric mucosa were investigated in inbred Wistar rats. After 25 weeks of treatment with N-methyl-N'-nitro-N-nitrosoguanidine (50 micrograms/ml p.o.), rats received one of the following alternate-day injections: caerulein (2 micrograms/kg body weight, s.c.), MgCl2 (150 mg/kg, s.c.), verapamil (20 mg/kg body weight, i.p.), caerulein (2 micrograms/kg body weight, s.c.) plus MgCl2 (150 mg/kg body weight, s.c.), or caerulein (2 micrograms/kg body weight, s.c.) plus verapamil (20 mg/kg body weight, i.p.). At Week 52, prolonged administration of caerulein had significantly increased the incidence and number of adenocarcinomas in the glandular stomach and the incidence of gastric cancers that penetrated through or beyond the muscle layer. Concomitant administration of MgCl2 significantly attenuated the enhancing effect of caerulein on gastric carcinogenesis. Combined administration of caerulein and verapamil did not affect the incidence and number of gastric cancers but significantly reduced the incidence of cancers penetrating through or beyond the muscle layer. Administration of MgCl2 or verapamil alone had no influence on gastric carcinogenesis. Rats treated with caerulein had a significantly elevated labeling index of the antral mucosa which was significantly decreased by concomitant administration of MgCl2 and/or of verapamil, as compared with the labeling index observed after treatment with caerulein alone. Either MgCl2 or verapamil alone had no influence on the labeling index of the antral mucosa. These findings indicate that caerulein enhances gastric carcinogenesis and that MgCl2 and verapamil attenuate this enhancement. These findings also indicate that calcium may play an important role in caerulein enhancement of gastric carcinogenesis.

Topics: Adenocarcinoma; Animals; Calcium Channel Blockers; Ceruletide; DNA; Gastric Juice; Gastrins; Hydrogen-Ion Concentration; Magnesium Chloride; Male; Methylnitronitrosoguanidine; Rats; Rats, Inbred Strains; Stomach Neoplasms; Verapamil

The effect of oral administration of L-phenylalanine on the incidence and histology of gastric adenocarcinomas induced by N-methyl-N'-nitro-N-nitrosoguanidine was investigated in inbred Wistar rats. Oral administration of 6% phenylalanine after 25 weeks of treatment with the carcinogen significantly reduced the incidence and number of adenocarcinomas of the glandular stomach at experimental week 52. Oral administration of high dose phenylalanine significantly increased the basal serum gastrin level and significantly decreased the norepinephrine concentration in the antral portion of the gastric wall, as well as the labelling indices of antral mucosa. These findings indicate that orally administered phenylalanine inhibits the development of gastric cancers.

Topics: Adenocarcinoma; Administration, Oral; Animals; Gastric Mucosa; Gastrins; Hydrogen-Ion Concentration; Incidence; Male; Methylnitronitrosoguanidine; Norepinephrine; Phenylalanine; Rats; Rats, Inbred Strains; Stomach Neoplasms

The effects of nialamide, a monoamine oxidase inhibitor, on the incidence, number, and histology of gastric cancers induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) were investigated in male Wistar rats. Rats were given subcutaneously 50 mg/kg body weight of nialamide in depot form every other day after 25 weeks of oral treatment with MNNG. Prolonged alternate-day administration of nialamide caused a significant increase in the incidence and number of gastric cancers of the glandular stomach in week 52. However, it did not affect the histology of the cancers. Nialamide also caused a significant increase in tissue norepinephrine concentrations in the gastric wall and in the labeling indices of the gastric mucosae. However, nialamide had no influence on serum gastrin levels in the fasting state and after re-feeding. These findings indicate that nialamide promotes gastric carcinogenesis and that this may be related to its effects in increasing norepinephrine in the gastric wall and stimulating proliferation of gastric epithelial cells.

Topics: Adenocarcinoma; Animals; Gastric Fundus; Gastric Mucosa; Gastrins; Male; Methylnitronitrosoguanidine; Nialamide; Norepinephrine; Pyloric Antrum; Rats; Rats, Inbred Strains; Stomach Neoplasms

Gastric acid secretions and serum gastrin levels have been examined in 128 patients with early gastric cancer and in 98 gastric ulcer patients. Gastric cancer patients were found to have lower acid secretions than did gastric ulcer patients, and those with elevated types of a differentiated adenocarcinoma had lower acid secretions than did those with depressed types of an undifferentiated adenocarcinoma. Gastric acid secretions in patients with both a gastric ulcer and cancer were found to decrease with aging. However, the serum gastrin levels were found to be decreased in patients with a gastric ulcer and to be increased in patients with a gastric cancer. Incidences of a differentiated adenocarcinoma increased with aging. From these observations, it has been speculated that the carcinogenesis of a differentiated adenocarcinoma may be related to increasing endogenous gastrin levels and decreasing gastric acid secretions. These results suggest that a continuous check of the serum gastrin levels might be a good marker for cancer detection and that gastrin antibodies might be useful for treatment.

Topics: Adenocarcinoma; Adenocarcinoma, Mucinous; Adenocarcinoma, Papillary; Adult; Aged; Aging; Biomarkers, Tumor; Female; Gastric Acid; Gastric Mucosa; Gastrins; Humans; Male; Middle Aged; Stomach Neoplasms; Stomach Ulcer

Gastrin and somatostatin-like immunoreactivity (SLI) levels were studied by means of radioimmunoassay in peripheral venous blood of healthy volunteers and patients suffering from gastric adenocarcinoma or duodenal and gastric ulcers. Gastrin and SLI levels were also evaluated in patients in blood drawn from gastric veins during surgery. The elevations of gastrin and SLI levels were found in patients with gastric cancer as compared with healthy people and patients suffering from ulcers. The impairment of the negative feedback between gastrin and somatostatin secretions in patients with gastric cancer was suggested.

Topics: Adenocarcinoma; Adult; Aged; Female; Gastrins; Humans; Male; Middle Aged; Radioimmunoassay; Somatostatin; Stomach Neoplasms; Stomach Ulcer

Topics: Adenocarcinoma; Animals; Cell Division; Cell Line; Colonic Neoplasms; DNA Replication; Gastrins; Glutamine; Humans; Mice; Mice, Nude; Neoplasm Transplantation; Proglumide; Somatostatin; Tumor Cells, Cultured

In view of the trophic action of gastrointestinal hormones on the exocrine pancreas, the effects of secretin, octapeptide of cholecystokinin (CCK-8), and desglugastrin on the growth of hamster pancreatic well differentiated adenocarcinoma were investigated in vitro. Desglugastrin exhibited the greatest effect on thymidine incorporation into these cells after a lag period of 96 h. Doses of desglugastrin in the range from 30 to 270 ng/mL caused a significant and dose-dependent increase in thymidine incorporation. Higher doses of this peptide led to a decreased response. Secretin also increased thymidine incorporation, but the response was less than that induced by gastrin. Prolonged incubation with secretin for 96 h increased tritiated thymidine incorporation in a log-dose fashion in the range of 30 to 270 ng/mL. Doses of CCK-8 in the range of 90 to 810 ng/mL significantly increased thymidine incorporation after 48 h of incubation. Following 72 h of incubation, only the dose of 270 ng/mL continued to exhibit a significant stimulation. Our study suggests that the gastrointestinal hormones could directly increase the growth of pancreatic carcinoma cells, act synergistically with endogenous growth factors, or stimulate the local production of these factors. In any event, our results that gastrin, secretin, and CCK can stimulate the growth of pancreatic ductal tumor cells in tissue cultures, support earlier findings on normal and malignant pancreatic parenchyma.

Topics: Adenocarcinoma; Amino Acid Sequence; Animals; Cell Cycle; Cell Line; Cricetinae; DNA Replication; DNA, Neoplasm; Gastrins; Kinetics; Molecular Sequence Data; Pancreatic Neoplasms; Secretin; Sincalide; Thymidine; Tritium

The effects of cysteamine (2-aminoethanethiol hydrochloride) on the incidence, number and histology of colon tumors induced by azoxymethane (AOM), and on the norepinephrine concentration in the colon wall tissue and the labelling indices of colon mucosa and colon cancers were investigated in Wistar rats. Rats received 10 weekly injections of 7.4 mg/kg body weight of AOM and alternate-day subcutaneous injections of 25 mg/kg of cysteamine in 0.9% NaCl solution until the end of the experiment. At week 40, prolonged administration of cysteamine significantly reduced the incidence and number of colon tumors. Histologically, the adenocarcinomas that did develop in rats treated with cysteamine exhibited high mucin-producing activity. Administration of cysteamine caused significant decreases in the norepinephrine concentration in colon tissue and in the labelling indices of colon mucosa and cancers. Our findings indicate that cysteamine inhibits the development of colon tumors. This action may be related to its effect in decreasing norepinephrine concentration in the colon wall tissues and subsequently in decreasing proliferation of colon cancer cells.

Topics: Adenocarcinoma; Adenoma; Animals; Azoxymethane; Carcinoma; Cell Division; Colon; Colonic Neoplasms; Cysteamine; Gastrins; Male; Norepinephrine; Rats; Rats, Inbred Strains

Two colorectal (HT29, LoVo) and one gastric (MKN45) human tumour cell lines were examined for their in vitro trophic response to human gastrin-17. MKN45 and HT29 responded by increased 75Se selenomethionine uptake to exogenous gastrin (139 +/- 5.5% and 123 +/- 3% of control values respectively) whereas LoVo showed no significant response to this hormone. When these same cell lines were grown as xenografts in nude mice, similar responses were seen to exogenously administered human gastrin-17 (10 micrograms mouse-1 day-1, subcutaneous injection). MKN45 xenografts showed a greater response to continuously administered gastrin (osmotic mini-pumps, (10 micrograms mouse-1 day-1) when compared to the same dose given via a subcutaneous bolus injection. The hormone-treated xenografts had a two-fold increase in tumour cross-sectional area and growth rate when compared to saline-treated controls. Dose-response studies revealed that 0.4 micrograms gastrin mouse-1 day-1 appeared to be the minimally effective dose. As gastric and colorectal tumour cells show a trophic response to gastrin, antagonists of the gastrin receptor may prevent this effect causing tumour stasis. The gastric tumour cell line, MKN45, is gastrin-responsive and would be an ideal model for screening potent receptor antagonists.

Topics: Adenocarcinoma; Animals; Cell Division; Cell Line; Colorectal Neoplasms; Gastrins; Hormones; Humans; Mice; Mice, Nude; Neoplasm Transplantation; Stomach Neoplasms; Tumor Cells, Cultured

To determine the long-term risk for colorectal cancer among patients with pernicious anemia.. Historical cohort study.. Population-based inception cohort of Rochester, Minnesota, residents.. We identified 150 Rochester residents who had the onset of pernicious anemia during the 30-year period from 1950 through 1979, and we followed this cohort for 1664 person-years of observation. The observed risk for subsequent colorectal cancer in the cohort was compared with that expected based on incidence rates of colon and rectal cancer for the local population.. There were 14 cases of colorectal cancer among the 150 patients with pernicious anemia (where 10.5 cases were expected), and 9 of these cases were found after the diagnosis of pernicious anemia was established (where 5.1 cases were expected). The relative risk for colon cancer at any time after the diagnosis of pernicious anemia was 1.8 (CI, 0.8 to 3.3). The relative risk was greatest (4.1; CI, 1.7 to 8.7) in the 5-year period immediately after the diagnosis of pernicious anemia; during this period, 7 cases of colon cancers were observed but only 1.7 were expected (P less than 0.0001).. Although the overall risk does not achieve statistical significance, patients with pernicious anemia may have an increased risk for colorectal adenocarcinoma in the 5 years after diagnosis.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Anemia, Pernicious; Bias; Cohort Studies; Colorectal Neoplasms; Confidence Intervals; Female; Gastrins; Humans; Male; Medical Records; Middle Aged; Risk; Time Factors

Gastrin has been shown to stimulate the growth of carcinogenic-induced colon cancer in animals, and some human colon cancers grown in vitro or as xenografts in nude mice. We determined fasting plasma gastrin levels in control subjects and patients with adenomatous polyps or adenocarcinoma of the colon to determine whether abnormal levels occurred in either patient group. Blood samples were obtained from 73 patients undergoing colonoscopy, primarily for evaluation of Hemoccult-positive stools. Fasting plasma gastrin was significantly greater in patients with adenomatous polyps (24.2 +/- 5.7 pM, N = 25) or colon cancer (84.5 +/- 28.5 pM, N = 20) than in controls (9.9 +/- 0.9 pM, N = 28). Elevations were due to gastrin values greater than control mean + 2 SD in nine patients with polyps (19.5-150.2 pM) and eight with cancer (20.7-403.2 pM). None of the patients had identifiable causes (drugs, prior surgery) for elevated gastrin levels. Our results indicate that elevated plasma gastrin occurs in subgroups of patients with adenomatous polyps or adenocarcinoma of the colon. The cause and potential role of elevated gastrin for polyp and tumor growth in these patients is not known.

Topics: Adenocarcinoma; Aged; Colonic Neoplasms; Colonic Polyps; Fasting; Female; Gastrins; Humans; Male; Middle Aged

The effect of oral administration of cysteamine (2-aminoethanethiol hydrochloride) on the incidence and histology of gastric adenocarcinomas induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) was investigated in inbred Wistar rats. Oral administration of 0.4% cysteamine in food after treatment with MNNG for 25 weeks significantly reduced the incidence and number of adenocarcinomas of the glandular stomach in experimental Week 52. Histological examination showed that adenocarcinomas that did develop in rats fed on cysteamine had high mucin-producing activity. Furthermore, oral administration of cysteamine caused a significant increase in serum gastrin level and significant decreases in the antral mucosal pH and the labeling indices of the antral mucosa. These findings indicate that cysteamine inhibits the development of gastric adenocarcinomas when given orally. This effect may be related to its ability to decrease proliferation of antral mucosal cells.

Topics: Adenocarcinoma; Animals; Cysteamine; Gastric Mucosa; Gastrins; Hydrogen-Ion Concentration; Male; Methylnitronitrosoguanidine; Mitosis; Rats; Rats, Inbred Strains; Stomach Neoplasms

The effects of propranolol and cimetidine on inhibition by cysteamine (2-aminoethanethiol hydrochloride) of gastric carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and on gastric acid secretion, serum gastrin level, and labelling index of the gastric mucosa were investigated in inbred Wistar rats. Rats received alternate-day injections of cysteamine (25 mg/kg body weight) with or without propranolol (dl-propranolol hydrochloride) (2 mg/kg bw) or cimetidine (50 mg/kg bw) in depot form after 25 weeks of oral treatment with MNNG. Prolonged administration of cysteamine significantly reduced the incidence of adenocarcinoma of the glandular stomach. A combination of cysteamine and propranolol significantly accelerated the inhibitory effect of cysteamine on gastric carcinogenesis. However, with concomitant administration of cysteamine and cimetidine, the incidence of adenocarcinoma was slightly but not significantly increased as compared to that after treatment with cysteamine alone. Administration of cysteamine caused a significant increase in gastric acid secretion and serum gastrin level, and a significant decrease in the labelling index of the antral mucosa. A combination of cysteamine and propranolol significantly increased gastric acid secretion by cysteamine alone and significantly decreased the labelling index of the antral mucosa. With this treatment, the serum gastrin level was significantly higher than the basal level, but the stimulated serum gastrin level was significantly lower than observed that after administration of cysteamine alone. In contrast, concomitant administration of cysteamine and cimetidine caused a significant decrease in gastric acid secretion and significant increase in the serum gastrin level as compared to the levels seen after treatment with cysteamine alone, but had no influence on the labelling index of the antral mucosa. These findings indicate that hypersecretion of acid, but not hypergastrinemia associated with hyposecretion of acid or achlorhydria, exerts a protective effect against gastric carcinogenesis, and that this effect may be related to its activity in decreasing proliferation of the antral mucosa.

Topics: Adenocarcinoma; Animals; Cimetidine; Cysteamine; Gastric Acid; Gastric Mucosa; Gastrins; Male; Methylnitronitrosoguanidine; Propranolol; Rats; Rats, Inbred Strains; Stomach Neoplasms

The effect of dietary wheat bran consumption on the anticarcinogenic action of tetragastrin upon colon carcinogenesis induced by azoxymethane was investigated in 122 inbred Wistar rats. Rats were given a control fiber-free diet or the same basal diet plus 20% wheat bran. From week 5, they were given 250 micrograms per kg body weight of tetragastrin in depot form every other day until the end of the experiment at week 45. Prolonged administration of tetragastrin resulted in a significant reduction of the incidence and number of colonic tumors per rat in the group given the fiber-free diet. The adenocarcinomas that did develop in this group had high mucin-producing activity, unlike the cancers produced in controls without tetragastrin. However, administration of tetragastrin had little or no influence on the incidence, number or histology of colonic tumors in the group given basal diet plus wheat bran. Dietary supplementation with wheat bran alone had little or no effect on the development or histology of colonic tumors. Before and during the administration of carcinogens, addition of fiber to the diet resulted in a significant fall in the colonic pH and a significant increase in the crypt column length, but administration of tetragastrin did not have an additive effect on the crypt column length in rats fed diet supplemented with fiber.

Topics: Adenocarcinoma; Animals; Colon; Colonic Neoplasms; Dietary Fiber; Gastrins; Hydrogen-Ion Concentration; Male; Rats; Tetragastrin

The effects of gastrin, proglumide (a gastrin receptor antagonist), and somatostatin on growth of human colon adenocarcinoma cell lines CX1, X56, and HT29 were examined in two experimental models. Nude mice bearing xenografts of colon cancer CX1 or X56 were treated for 14-25 days subcutaneously with saline, pentagastrin (0.5 or 1.0 mg/kg), proglumide (250 or 500 mg/kg), or somatostatin 14 (33, 100, or 300 micrograms/kg) twice daily. Tumor volume, weight, protein, and deoxyribonucleic acid were measured. HT29 cells were grown in vitro and the effects of gastrin 17, proglumide, and somatostatin on growth were evaluated by cell counts or [3H]thymidine incorporation. The larger dose of pentagastrin significantly increased tumor growth in the nude mouse (p less than 0.005) and gastrin induced a biphasic effect on deoxyribonucleic acid synthesis in tissue culture with significant increases of up to 39% (p less than 0.025). Somatostatin alone significantly inhibited tumor growth in two of the cell lines and also inhibited the gastrin-induced growth. Proglumide had no effect by itself but significantly inhibited gastrin-stimulated growth. These findings suggest that growth of some human colon cancers may be hormone-dependent.

Topics: Adenocarcinoma; Animals; Cell Line; Colonic Neoplasms; DNA, Neoplasm; Gastrins; Glutamine; Humans; Mice; Mice, Nude; Neoplasm Transplantation; Neoplasms, Hormone-Dependent; Proglumide; Somatostatin; Tumor Cells, Cultured

One hundred patients with gastric carcinoma resected surgically were studied by PAP immunoperoxidase and ultrastructural method. It was found that the tumor cells were positive for gastrin, serotonin, somatostatin as well as argyrophil particles in 19 patients. In these 19 patients, the quantity of endocrine tumor cells surpassed half of its total cancer cells in 4, leading to a separate entity of neuroendocrine gastric carcinoma. The authors hope to introduce this new subtype into the classification of gastric carcinoma. Among the 100 cases, 50 patients with undifferentiated carcinomas contained the NE cells in 16 (32%), the remains for high differentiated adenocarcinomas had the NE cells in 3 (6%) only. It was suggested that the appearance of NE tumor cells was closely correlated to differentiation of gastric carcinoma. This study theoretically demonstrated the heterogenicity of gastric carcinoma and supported the theory that different kinds of tumor cells (endocrine and nonendocrine) may have a common origin and are derived from the endoembryogenetic immature precursor cells.

Topics: Adenocarcinoma; Carcinoma; Gastrins; Humans; Immunohistochemistry; Neurosecretion; Serotonin; Somatostatin; Stomach Neoplasms

The effects of combined administration of cimetidine and tetragastrin on gastric acid secretion, the labeling index of the gastric mucosa, and the incidence of gastric adenocarcinomas induced by N-methyl-N'-nitro-N-nitrosoguanidine were investigated in inbred Wistar rats. Prolonged administration of tetragastrin in depot form after treatment with N-methyl-N'-nitro-N-nitrosoguanidine resulted in a significant increase in gastric acid secretion, a significant decrease in the labeling index of the antral mucosa, and a significant decrease in the incidence of adenocarcinomas of the glandular stomach. Administration of cimetidine at 20 mg, but not 10 mg, per kg body weight with tetragastrin significantly reduced the gastric acid secretion induced by tetragastrin alone but did not influence the labeling index of the antral mucosa or the inhibitory effect of tetragastrin on gastric carcinogenesis. These findings indicate that gastric acid secretion has no influence on the development of gastric adenocarcinomas and that the inhibitory effect of tetragastrin on gastric carcinogenesis may be related to its effect in decreasing proliferation of cells in the antral mucosa.

Topics: Adenocarcinoma; Animals; Cimetidine; DNA; Gastric Acid; Gastric Mucosa; Gastrins; Hyperplasia; Male; Methylnitronitrosoguanidine; Rats; Rats, Inbred Strains; Stomach Neoplasms; Tetragastrin

The heterogeneity of gastrin-containing G cells present in human gastric mucosa has been examined immunohistochemically. Calcitonin gene-related peptide (CGRP), calcitonin and human chorionic gonadotropin (hCG)-immunoreactivity were detected in about 500, 20 and 10 cells pro 1,000 G cells, respectively, these findings supporting the "one cell, multi-hormone theory". Gastrin, calcitonin immunoreactive tumor cells were demonstrated in 13%, 3% of the antral adenocarcinomas and 17% and 10% of antral endocrine tumors, but they were not found in fundic adenocarcinomas and endocrine tumors. Cell hybridization between the tumor cell and the G-cell might be a possible mechanism for the occurrence of gastric and calcitonin in the gastric tumors. HCG-immunoreactive tumor cells were detected in 27% of antral adenocarcinomas, and in 24% of the fundic adenocarcinomas, and the production of hCG by gastric tumor cells might be based on the gene expression during carcinogenesis, regardless of the tumor localization.

Topics: Adenocarcinoma; Calcitonin; Calcitonin Gene-Related Peptide; Carcinoma; Chorionic Gonadotropin; Duodenal Ulcer; Gastric Mucosa; Gastrins; Humans; Immunochemistry; Neuropeptides; Pyloric Antrum; Stomach Neoplasms

The effects of combined administration of propranolol and tetragastrin on gastric acid secretion and the incidence and histological types of gastric adenocarcinomas induced by N-methyl-N'-nitro-N-nitrosoguanidine were investigated in inbred Wistar rats. Prolonged administration of tetragastrin, 1 but not 0.2 mg/kg body weight in depot form after treatment with N-methyl-N'-nitro-N-nitrosoguanidine significantly reduced the incidence of adenocarcinoma of the glandular stomach. The adenocarcinomas that did develop in rats treated with the higher dose of tetragastrin had high mucin-producing activity and showed little or no typical glandular structure. A combination of propranolol (2 mg/kg) and tetragastrin (1 mg/kg) did not influence the inhibitory effect of gastrin on gastric carcinogenesis. However, concomitant administration of propranolol (2 mg/kg) and tetragastrin (0.2 mg/kg) caused a significant increase in gastric acid secretion and a reduction in the incidence of gastric carcinomas. With this treatment, the incidence of adenocarcinoma was similar to that of treatment with tetragastrin (1 mg/kg). Histological examinations showed that like the cancers in control rats, the adenocarcinomas induced in these rats were all highly differentiated.

Topics: Adenocarcinoma; Animals; Drug Synergism; Gastric Acid; Gastric Mucosa; Gastrins; Hyperplasia; Male; Methylnitronitrosoguanidine; Propranolol; Rats; Rats, Inbred Strains; Stomach Neoplasms; Tetragastrin

Fifteen neuroendocrine carcinomas of the skin (Merkel cell tumors) were stained within the constraints of tissue availability by the Grimelius method and immunohistochemically for keratin, neuron-specific enolase (NSE), carcinoembryonic antigen (CEA), S-100, common leukocyte antigen (CLA), met-enkephalin, bombesin, calcitonin, ACTH, gastrin, and somatostatin. Focal argyrophilia was present in 5 of 12 tumors. All tumors tested demonstrated immunoreactivity for NSE and 5 tumors were positive for keratin. One tumors appeared to demonstrate focal ACTH-like immunoreactivity, but otherwise no immunoreactivity for the above mentioned polypeptide hormones was noted in 11 completely studied tumors. One tumor contained histologically obvious areas of squamous differentiation in addition to areas of Merkel cell tumor. In various tumors, keratin immunoreactivity was present either in areas of histologically obvious squamous differentiation, in randomly scattered single cells not histologically identifiable as squamous, or in a paranuclear dot-like distribution. Immunoreactivity for CEA, S-100 and CLA was not present in any tumors. The lack of met-enkephalin and the presence of squamous differentiation in these tumors indicates multidirectional differentiation in a fashion not phenotypically typical of Merkel cells.

Topics: Adenocarcinoma; Adrenocorticotropic Hormone; Bombesin; Calcitonin; Carcinoembryonic Antigen; Enkephalin, Methionine; Gastrins; Histocompatibility Antigens; Humans; Immunoenzyme Techniques; Keratins; Leukocyte Common Antigens; Phosphopyruvate Hydratase; Skin Neoplasms; Somatostatin

This study evaluated the dose-related trophic effects of glutamine, gastrin, and somatostatin on the in vitro growth of human gastric cancer cells and normal human gastric mucosal cells. Quadruplicate cell cultures were seeded into growth medium with or without glutamine, gastrin, or somatostatin. After 72 hours' incubation, cells were counted and their numbers compared with those of controls. Glutamine and gastrin stimulated the growth of both normal and malignant gastric mucosal cells. Compared with normal cells, the malignant cells responded to these growth factors at lower concentrations. Somatostatin enhanced growth of gastric cancer cells at all concentrations and inhibited growth of normal cells at high concentrations. Further studies on the responsiveness of gastric adenocarcinoma to gastrointestinal tract hormones may elucidate mechanisms of oncogenesis and suggest new therapeutic avenues for patients with gastric cancer.

Topics: Adenocarcinoma; Cells, Cultured; Dose-Response Relationship, Drug; Drug Evaluation; Gastric Mucosa; Gastrins; Glutamine; Humans; In Vitro Techniques; Somatostatin; Stomach Neoplasms

Gut endocrine cells in a total of 18 gastric adenocarcinomas in inbred Wistar rats induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and gastrin or serotonin, were examined histologically, ultrastructurally, and immunohistochemically for gastrin, somatostatin, calcitonin, glicentin, and serotonin. A large number of argyrophil cells were observed in 17 tumors (94.4%) and 14 tumors (77.8%) had argentaffin cells. Immunohistochemically, C-terminal fragment of gastrin (G17) immunoreactivity was observed in 15 (82.2%) out of the 18 tumors, but 3 G17-positive tumors had no G 34 immunoreactive cells in rats treated with MNNG plus gastrin. Serotonin immunoreactivity was detected in 14 tumors (77.8%). Somatostatin immunoreactivity was detected in 7 of the 11 tumors (63.6%) in rats treated with MNNG plus gastrin whereas no tumor in rats treated with MNNG plus serotonin had somatostatin, the difference of the incidence being significant (P less than 0.05). One endocrine cell carcinoma which consisted mainly of serotonin-producing cells was observed in a rat treated with MNNG plus serotonin. Calcitonin and glicentin immunoreactivity was not demonstrated in any tumors. Ultrastructurally, three types of endocrine granule were found in the tumor cells. These data suggest that hormonal environment in stomach carcinogenesis may influence the expression of endocrine cells within the tumors.

Topics: Adenocarcinoma; Animals; Calcitonin; Chromaffin System; Enterochromaffin Cells; Female; Gastrins; Glucagon; Histocytochemistry; Male; Methylnitronitrosoguanidine; Microscopy, Electron; Proglucagon; Protein Precursors; Rats; Serotonin; Somatostatin; Stomach Neoplasms; Time Factors

The localization of peptide hormones and serotonin in ovarian mucinous and endometrioid tumors with argyrophil cells was examined by immunohistochemistry. All of the 15 mucinous tumors had argyrophil cells which resemble the enterochromaffin cells seen in the gastrointestinal tract, and peptide hormones such as gastrin and somatostatin were found in 3 of 5 benign, in 3 of 5 borderline, and in all of 5 malignant tumors. Serotonin was found in 4 benign, 3 borderline and 2 malignant tumors. Of 19 endometrioid adenocarcinomas, type I argyrophil cells which resemble enterochromaffin cells were found in 4 tumors, type II argyrophil cells which contain argyrophil granules mainly in the apical portion or throughout the whole cytoplasm were found in 14, and mixed type cells were found in one. Somatostatin-positive cells were found only in type I cells of a tumor with mixed type argyrophil cells. Serotonin-positive cells were found in 3 tumors containing type I cells. The results obtained were discussed in the comparison with those of cervical and endometrial adenocarcinomas of the uterus. In conclusion, the present study suggests that type I or similar argyrophil cells in ovarian tumors may have endocrine activity.

Topics: Adenocarcinoma; Adenocarcinoma, Mucinous; Antibodies, Monoclonal; Endometriosis; Female; Gastrins; Glucagon; Histocytochemistry; Humans; Ovarian Neoplasms; Serotonin; Somatostatin

Tumours of the glandular stomach and upper small intestine were induced in rats by oral administration of MNNG. In most cases the lesions were identified histologically as adenocarcinomas and their prestages, such as polypeous and downward growing adenomatous hyperplasias. Out of 48 adenomatous hyperplasias and adenocarcinomas of the stomach and 24 well differentiated adenocarcinomas of the small intestine, we observed argyrophilic cells in nearly the half of the cases. Endocrine cells were also identified by electron microscopy. The frequency of endocrine cells was reduced with decreasing degree of tissue differentiation. In poorly differentiated carcinomas, including signet ring cell carcinomas, no argyrophilic cells were found. Out of 10 adenomatous hyperplasias and tumours of the stomach investigated immunohistochemically, 5 cases showed gastrin producing cells. Most of these animals were radioimmunologically characterized by strongly elevated serum gastrin levels. Derivation and potential relevance of the endocrine cells in tumours are discussed.

Topics: Adenocarcinoma; Administration, Oral; Animals; Duodenal Neoplasms; Endocrine Glands; Fluorescent Antibody Technique; Gastrins; Histocytochemistry; Male; Methylnitronitrosoguanidine; Microscopy, Electron; Precancerous Conditions; Rats; Rats, Inbred Strains; Stomach; Stomach Neoplasms

The effects of tetragastrin and histamine on the incidence and histology of tumors induced in the small intestine by N-methyl-N'-nitro-N-nitrosoguanidine [(MNNG) CAS: 70-25-7] were investigated in male W rats. Animals were given MNNG at 150 micrograms/ml in their drinking water for 25 weeks and then 300 micrograms tetragastrin or 4 mg histamine dihydrochloride sc per day in depot form. Administration of tetragastrin or histamine after MNNG treatment resulted in a significant increase in gastric acid secretion and a significant reduction in the incidence of tumors in the duodenum; however, only histamine decreased the incidence of tumors in the jejunum. Histologically, the tumors induced in the small intestine were mostly adenocarcinomas, and their histologic type was not affected by either tetragastrin or histamine.

Topics: Adenocarcinoma; Animals; Drug Antagonism; Duodenum; Gastric Acidity Determination; Gastrins; Histamine; Intestinal Neoplasms; Jejunum; Male; Methylnitronitrosoguanidine; Rats; Stomach Neoplasms; Tetragastrin

The effects of coffee on exocrine pancreatic secretion are unknown but may be important, because a link between chronic stimulation of pancreatic secretion and experimental chemical carcinogenesis and an association between coffee drinking and human pancreatic adenocarcinoma have been reported. We measured exocrine pancreatic trypsin and gastric acid secretions collected through orogastroduodenal tubes and serum gastrin in eight non-coffee drinkers and eight coffee drinkers. During fasting, after one interdigestive cycle control period, one of four 250-ml samples [plain water, water plus caffeine (4.6 mg/kg), decaffeinated coffee (127.9 mg/kg), caffeinated coffee (127.9 mg/kg)] was administered through the orogastric tube. Caffeinated and decaffeinated coffee (p = 0.008), caffeine (p = 0.03), and an unidentified substance(s) in coffee other than caffeine (p = 0.008) were associated with increased interdigestive exocrine pancreatic trypsin secretion. In addition, we also confirmed that coffee and caffeine stimulated gastric acid secretion (p = 0.02) and decaffeinated coffee raised serum gastrin concentrations (p = 0.005). If an association between coffee and pancreatic carcinogenesis exists, chronic stimulation of the exocrine pancreas by secretagogues could result in a gland susceptible to carcinogenesis.

Topics: Adenocarcinoma; Adult; Caffeine; Coffee; Fasting; Female; Gastric Acid; Gastrins; Humans; Male; Middle Aged; Pancreas; Pancreatic Neoplasms; Trypsin

In an attempt to elucidate histogenesis of stomach cancer, quantitative analysis and measurement of DNA contents of various atypical lesions were sequentially made in the process of gastric carcinogenesis of Wistar strain of rats. Along with this, the effect of vagotomy on the development of atypical or neoplastic lesions were studied. A variety of focal lesions in the glandular stomach were seen in the middle or 4 and 12 weeks after the oral administration of N-methyl-N'-nitrosoguanidine (MNNG, 83 mg/l in drinking water) for 25 weeks. Both upward and downward growth was found in the intramucosal atypical lesions as well as frank carcinoma; the former lesions were histologically classified into 3 (Type I--Type III). On the basis of DNA distribution pattern, Type III lesions were considered to be intramucosal carcinoma and Type II to include precancerous state in some instances. In a group of rats vagotomized 1 week prior to the start of MNNG administration, there were significantly more lesions than in a group of MNNG alone. In contrast to the latter group which developed lesions in an uniform distribution pattern along the lesser curvature in the pyloric region, lesions in the former were characterized by random distribution pattern.

Topics: Adenocarcinoma; Animals; Body Weight; DNA, Neoplasm; Gastric Mucosa; Gastrins; Male; Methylnitronitrosoguanidine; Rats; Rats, Inbred Strains; Stomach Neoplasms; Vagotomy

The trophic effects of the hormone gastrin-17 were examined on a human colon cancer cell line. LoVo cells were obtained from the American Type Culture Collection and grown in minimal essential medium in the presence of 10% bovine fetal serum. To demonstrate the trophic effect of gastrin, synchronization was necessary. The effect of gastrin was optimal after 26-h exposure to 0.6 mM thymidine. In the presence of serum the optimal dose of gastrin for stimulation of DNA synthesis was 7.2 X 10(-10) M. Under these conditions gastrin caused a 220% increase in [3H]thymidine incorporation. In the absence of serum the optimal dose of gastrin (3.6 X 10(-9) M) increased DNA synthesis approximately 200%. Twenty-four hours after gastrin treatment (1.8 X 10(-10) M gastrin 17) cell numbers increased 50.8% compared with control. At 48 h this increase was maintained at 44%. Maximum stimulation by gastrin occurred 7-8 h after release from synchronization and exposure to gastrin. This corresponded to the S phase of the cell cycle. Significant stimulation occurred a second time at 22-24 h, presumably during the second S phase in a still synchronous or partially synchronous cell population. These data demonstrate that physiological concentrations of gastrin-17 can stimulate the growth of a human cancer cell line and that some degree of synchronization may be necessary to demonstrate similar effects in other cell lines. Such cell lines may provide a source of rapidly growing cells in which the mechanisms of the trophic effect of gastrin can be examined.

Topics: Adenocarcinoma; Blood; Cell Division; Cell Line; Colonic Neoplasms; Culture Media; DNA; Gastrins; Humans

Gastrin is trophic for normal gastric and colonic mucosa. We examined the potential trophic effects of chronic gastrin administration on the growth of mouse colon adenocarcinoma (MC-26). Thirty-three mice bearing transplantable MC-26 colon cancers were treated with varying doses (125, 250, or 500 micrograms/kg/day) of pentagastrin. Significant increases in tumor weight and DNA content were observed. Fundic mucosal weight and DNA content in these mice showed a dose-related trophic response. The weight of control fundic mucosa was 10 mg and rose to 20, 45, and 65 mg with increasing doses of gastrin. The DNA content of control fundic mucosa was 155 micrograms and rose to 220, 340, and 480 micrograms as the dose of gastrin was increased. Pentagastrin stimulated growth of the MC-26 colon cancer, but the threshold for gastrin-stimulated tumor growth was different from that of normal mucosal growth. The hyperplastic response of the fundic mucosa was increased by increasing gastrin doses; whereas, colon cancer hyperplasia was maximal at the lowest dose tested (125 micrograms/kg/day) and did not increase further with increasing doses of hormone. Mice bearing gastrin-stimulated tumors died at a significantly greater rate than did mice with untreated tumors (80% of control mice and none of the treated mice were alive at day 55). The effects of gastrin treatment on the growth of MC-26 colon cancer persist after treatment is discontinued; mice with tumors that were treated with gastrin for either 7 or 14 days and in which the treatment was stopped were all dead by 35 or 28 days, respectively, after the end of treatment.

Topics: Adenocarcinoma; Animals; Colon; Colonic Neoplasms; DNA, Neoplasm; Gastrins; Intestinal Mucosa; Male; Mice; Mice, Inbred BALB C; Neoplasm Transplantation; Pentagastrin; Stimulation, Chemical

Examples of mucinous tumors from retroperitoneum (2) and pancreas (1) were studied. These tumors share many morphological similarities with ovarian mucinous tumour and adenoma malignum of uterine cervix. They have a similar spectrum of endocrine cells; serotonin, somatostatin, gastrin and pancreatic polypeptide cells were characterized. In nonproliferative areas was found a well-differentiated mucinous columnar epithelium with scarce endocrine cell. In more proliferative areas were found either a mucinous columnar lining with infolds and secondary glands or a less well-differentiated intestinal-type epithelium with papillary formations; both linings were well supplied in endocrine cells.

Topics: Adenocarcinoma; Adult; Endocrine Glands; Epithelium; Female; Fluorescent Antibody Technique; Gastrins; Histocytochemistry; Humans; Ovarian Neoplasms; Pancreatic Neoplasms; Pancreatic Polypeptide; Retroperitoneal Neoplasms; Serotonin; Somatostatin; Uterine Cervical Neoplasms

The effect of hydrochlorhydria caused by vagotomy on carcinogenesis in the glandular stomach of male rats was studied. Group A (35 rats): After N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) 80 mg/l solution was orally administered during the first 15 weeks of life, vagotomy was performed. Group B (35 rats): After the oral administration of MNNG 80 mg/l solution during the first 15 weeks of life, laparotomy was done. Group C (10 rats): As the control, vagotomy was undertaken at the 15th week of life. Group D (10 rats): As the control, laparotomy was done at the same time. At the 52nd week, all surviving rats were autopsied, and gastrin cell counts and body weight were ascertained. The incidence of adenocarcinoma was 62% in Group A, 32% in Group B (p less than 0.05) and nil in Group C and D. These results strongly support the view that the hypochlorhydria plays the role of a promoting factor in producing gastric carcinoma.

Topics: Adenocarcinoma; Animals; Gastric Acidity Determination; Gastrins; Histamine H2 Antagonists; Male; Methylnitronitrosoguanidine; Rats; Rats, Inbred Strains; Stomach Neoplasms; Vagotomy

Some tumors are responsive to hormone manipulation. Some gastric and colonic adenocarcinomas from both humans and animals have specific gastrin receptors. A transplantable mouse colon adenocarcinoma cell line (MC-26) contains gastrin receptors; growth of MC-26 colon cancer in vivo is stimulated by pentagastrin (PG). The purpose of this study was to determine whether a gastrin-receptor antagonist, proglumide (PGL), would inhibit growth of MC-26 colon cancer and prolong survival in tumor-bearing mice. Subcutaneous tumors were induced by injecting single-cell suspensions of MC-26 cells into 50 mice divided into 10/group. In Experiment 1, all mice received 1 X 10(5) tumor cells and treatment groups were divided as follows: Group A received intraperitoneal (IP) saline (0.2 ml tid beginning on day 1); B, IP, PGL (250 mg/kg tid) from day of tumor cell inoculation; and C, IP PGL (250 mg/kg tid) from day 7 after tumor implantation. In Experiment 2, mice were inoculated with half the number of tumor cells. Group I mice received saline and Group II received PGL in the same manner starting on day 1. Tumors were measured and all mice were sacrificed on day 23. In Experiment 1, mean tumor area in Group B (PGL-treated) was significantly smaller than Group A on days 11, 14, 17, and 21. Tumors of Group C were significantly smaller than controls on day 21. Survival of PGL-treated mice was significantly prolonged. In Experiment 2, mean tumor area, mean tumor weight, and tumor DNA and RNA content were significantly less in the PGL-treated group than control. It was concluded that growth of a gastrin-responsive colon cancer was inhibited and host survival was enhanced by treatment with a gastrin-receptor antagonist. Hormone manipulation may be a useful treatment for gastrointestinal cancers.

Topics: Adenocarcinoma; Animals; Body Weight; Cell Division; Cell Line; Colon; Colonic Neoplasms; Gastric Fundus; Gastrins; Glutamine; Mice; Organ Size; Pancreas; Proglumide; Receptors, Cell Surface

The effects of ad libitum feeding of a chemically defined diet in liquid form on the incidence and histology of colon cancer induced by 10 weekly sc injections of 7.4 mg/kg of azoxymethane [(AOM) CAS: 25843-45-2] were investigated in W-rats. The chemically defined diet was adjusted once every 24 hours from 4 weeks before injection of the carcinogen to the end of the experiment at week 40. Oral administration of the defined diet resulted in significant increase in the incidence of colon cancer at week 40. Histologic examination showed that unlike adenocarcinomas with high mucin-producing activity, which were common in rats on pellet diet, most of the adenocarcinomas that developed in rats fed on defined diet were highly or well differentiated, with a typical glandular pattern. Administration of the chemically defined diet also resulted in marked colon mucosal hypoplasia and reduced gastrin levels in the serum at weeks 4 and 40.

Topics: Adenocarcinoma; Animals; Colonic Neoplasms; Dietary Fiber; Food, Formulated; Gastric Mucosa; Gastrins; Male; Rats; Rats, Inbred Strains

The effects of prolonged administration of tetragastrin from the beginning of intrarectal instillation of 1 ml of 0.25% N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and after MNNG-treatment on the incidence and histology of colonic tumors were compared in inbred Wistar rats. In week 35 prolonged administration of testragastrin in depot form from the beginning of MNNG-treatment resulted in a significant reduction in the incidence of colonic tumors and a significant increase in the incidence of mucinous adenocarcinoma, unlike the well-differentiated adenocarcinoma produced in controls without gastrin. In contrast, prolonged administration of tetragastrin after MNNG-treatment had little or no influence on the incidence, size or histology of colonic tumors. Thus tetragastrin had no promoting effect on colonic tumors.

Topics: Adenocarcinoma; Animals; Cocarcinogenesis; Colonic Neoplasms; Drug Administration Schedule; Gastrins; Male; Methylnitronitrosoguanidine; Neoplasm Metastasis; Rats; Rats, Inbred Strains; Tetragastrin

This was a study of the effects of gastrin on gastric mucosal cyclic-adenosine 3':5'-monophosphate (cAMP)-dependent protein kinase activity and DNA synthesis in rat stomach carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) in order to clarify the mechanism of the enhanced effect of gastrin on the early stage of stomach carcinogenesis. Inbred Basel-Wistar rats received MNNG in drinking water (50 micrograms/ml for 32 weeks) and were treated with s.c. injections of pentagastrin (300 micrograms/kg twice daily for 4 weeks) beginning with the fourth and eighth weeks after the initiation of MNNG treatment. The incidence of gastric adenocarcinoma in fourth-week gastrin-treated rats and of gastric carcinoid in eighth-week gastrin-treated rats was higher than that in rats treated with MNNG alone. The former tumors developed in the antrum and most of the latter tumors in the fundus. In the early stage of carcinogenesis the labeling index [( 3H]thymidine-labeled nuclei/one gland) in both the antrum and fundus was the same in MNNG-plus-gastrin-treated groups and in the MNNG-only-treated group. With regard to the distribution of cAMP-dependent protein kinase isoenzyme in fourth-week gastrin-treated rats, the proportion of type I cAMP-dependent protein kinase significantly increased in the antrum during the eighth week after the initiation of MNNG treatment (P less than 0.01). The increased type I activity in the antrum of the gastrin-treated rats agreed with the high incidence of gastric adenocarcinoma in the antrum. Type I isoenzyme clearly increased in gastric adenocarcinoma. These results suggest that type I cAMP-dependent protein kinase can play an important role in the enhanced effect of gastrin on rat stomach carcinogenesis induced by MNNG.

Topics: Adenocarcinoma; Animals; DNA; Drug Synergism; Gastric Mucosa; Gastrins; Isoenzymes; Methylnitronitrosoguanidine; Protein Kinases; Rats; Rats, Inbred Strains; Stomach Neoplasms

Topics: Adenocarcinoma; Aged; Animals; Colonic Neoplasms; Female; Gastrins; Humans; Leucine; Male; Mice; Mice, Nude; Middle Aged; Neoplasm Proteins; Secretin; Stomach Neoplasms

This study deals with the growth effect of gastrin on two xenotransplantable human gastric carcinomas (SC-6-JCK, poorly differentiated adenocarcinoma; and St-15, mucinous adenocarcinoma) and on one colonic carcinoma (Co-3, well-differentiated adenocarcinoma). In SC-6-JCK, the treatment with s.c. injection of pentagastrin at a dose of 10 micrograms/mouse once daily for 25 days promoted the growth of the tumor transplanted in nude mice, but gastrin had no effect at all on St-15 and Co-3. In SC-6-JCK, the weight, size, and labeling index of [3H]thymidine of the tumor were significantly increased in comparison with those of the control (p less than 0.05). In SC-6-JCK, cyclic adenosine 3':5'-monophosphate (cAMP) in the tumor was increased by a single i.p. injection of pentagastrin at a dose of 20 micrograms/mouse in nude mice, but such an increase was not observed in St-15 and Co-3. Cyclic guanosine 3':5'-monophosphate in SC-6-JCK was slightly increased by gastrin treatment but was not affected in the other tumors. In SC-6-JCK, at 30 min after gastrin treatment when cAMP showed a maximum increase, the activity ratio of cAMP-dependent protein kinase in the tumor was also elevated. In vitro also, gastrin stimulated cAMP production and cAMP-dependent protein kinase activation. The data suggest that some human gastric carcinomas may have receptor for gastrin.

Topics: Adenocarcinoma; Adult; Animals; Cell Division; Cell Line; Colonic Neoplasms; Cyclic AMP; Cyclic GMP; Female; Gastrins; Humans; Kinetics; Male; Mice; Mice, Nude; Middle Aged; Neoplasm Transplantation; Protein Kinases; Stomach Neoplasms; Transplantation, Heterologous

Thirty patients with cervical adenocarcinoma were analyzed clinicopathologically with special reference to argyrophil cells. In contrast to argyrophil small cell carcinoma of the cervix, four adenocarcinomas with argyrophil cells were not more aggressive than the remaining 26 usual ones. One or two peptide hormones were demonstrated in three out of four tumors with argyrophil cells which were examined by immunohistochemistry. Somatostatin- and gastrin-containing cells were found in one tumor, but were located differently from each other. Either gastrin- or adrenocorticotropic hormone (ACTH)-containing cells were detected in two other tumors. They all corresponded to argyrophil cells, but were less numerous.

Topics: Adenocarcinoma; Adult; Enterochromaffin Cells; Female; Gastrins; Histocytochemistry; Humans; Immunoenzyme Techniques; Middle Aged; Peptides; Somatostatin; Uterine Cervical Neoplasms

A total of 87 surgical cases of gastric carcinoma including 3 carcinoid tumors were investigated with the methods of silver reaction and immunoperoxidase stain for 8 different brain-gut hormones. Argyrophil (AP) cells were demonstrated in 38 cases (44%), argentaffin (AF) cells in 18 (21%) and endocrine cells in 13 (14%). The occurrence of endocrine cells had no relation with histological types. Glicentin cells were demonstrated in 10 cases, somatostatin in 7, motilin in 3, beta-endorphin in 2 and gastrin in one. Endocrine cells appeared generally in small numbers except one carcinoid tumor which had numerous somatostatin cells. No single cell positive for more than two kinds of hormones could be demonstrated. Two undifferentiated carcinomas looking like carcinoid tumors had argyrophil cells and endocrine cells of either somatostatin or beta-endorphin. These results suggest that carcinoid-like carcinoma or endocrine cell carcinoma may lie on the intermediate state between carcinoma and carcinoid tumor.

Topics: Adenocarcinoma; Adenocarcinoma, Mucinous; Adult; Carcinoid Tumor; Endorphins; Female; Gastrins; Gastrointestinal Hormones; Glucagon; Histocytochemistry; Humans; Male; Microscopy, Electron; Middle Aged; Motilin; Proglucagon; Protein Precursors; Somatostatin; Stomach Neoplasms; Vasoactive Intestinal Peptide; Vasopressins

Sixty-eight endometrial carcinomas were examined histochemically and immunohistochemically for the presence of amine-containing or neurohormonal peptide-containing cells, particularly in relation to argyrophil cells. Argyrophil cells, detected in 43 of the 68 endometrial carcinomas by the Grimelius method, were subgrouped into two types according to the distribution of argyrophil granules and the shape of the tumor cells. Type I was found in 7 tumors and type II in 39; 3 tumors contained both cell types. The argyrophilia of type II cells was diminished in varying degrees in some tumors by diastase digestion, although it was unchanged in type I argyrophil cells. Indoleamine was detected by the formaldehyde-induced fluorescence method in type I argyrophil cells of four carcinomas. Immunohistochemically, somatostatin-reactive cells were found in two well-differentiated adenocarcinomas with argyrophilia; many of these cells corresponded to some of the type I argyrophil cells, although some were non-argyrophilic. Two adenosquamous cell carcinomas with type II argyrophil cells also contained cells that were immunoreactive with antisera against gastrin; however, they were non-argyrophilic.

Topics: Adenocarcinoma; Adult; Carcinoma, Squamous Cell; Enterochromaffin Cells; Female; Fluorescence; Gastrins; Histocytochemistry; Hormones; Humans; Immunoenzyme Techniques; Middle Aged; Somatostatin; Uterine Neoplasms

A total of 44 extrahepatic bile duct carcinomas comprising 13 well-differentiated adenocarcinomas, 25 moderately differentiated adenocarcinomas, and 6 poorly differentiated adenocarcinomas were examined histologically and immunohistochemically for somatostatin, gastrin, and glicentin. Argyrophil cells, argentaffin cells, and somatostatin- and gastrin-immunoreactive cells within the tumor were detected in 46.2%, 15.4%, 23.1%, and 15.4% of well-differentiated adenocarcinomas, and in 16.0%, 8.0%, 12.0%, and 4.0% of moderately differentiated adenocarcinomas, respectively. No tumor tissues of poorly differentiated adenocarcinomas contained endocrine cells. A statistically significant difference in the frequency of argyrophil cells was observed between well and poorly differentiated adenocarcinoma. The incidence of argyrophil cells and somatostatin-immunoreactive cells in nonneoplastic mucosa adjacent to well-differentiated adenocarcinoma was higher than in that adjacent to poorly differentiated adenocarcinoma. Glicentin-immunoreactive cells could not be demonstrated either in tumor tissue or in nonneoplastic mucosa of the extrahepatic bile duct. With reference to the histogenesis of extrahepatic bile duct carcinoma, it was assumed from these results that the development of well-differentiated adenocarcinoma might be closely related to the occurrence of endocrine cells and that poorly differentiated adenocarcinoma might develop from ordinary mucosa.

Topics: Adenocarcinoma; Bile Duct Neoplasms; Endocrine Glands; Enterochromaffin Cells; Female; Gastrins; Glucagon; Histocytochemistry; Humans; Immunoenzyme Techniques; Male; Middle Aged; Mucous Membrane; Neoplasm Staging; Proglucagon; Protein Precursors; Somatostatin

A primary endometrial adenocarcinoma is reported that showed abundant foci suggestive of pathologically differentiated intestinal epithelium. The tumor epithelium was composed of four main cell types. Columnar cells resembled absorptive intestinal cells and displayed glycocalyceal carcinoembryonic antigen immunostaining; mucin-producing cells and a few Paneth-like lysozyme-rich cells were irregularly distributed; a massive quantity of argyrophil cells including a few amphicrine (muco-argyrophil) ones, were detected by Grimelius-Alcian blue method. Immunocytochemical evidence was obtained for the storage of serotonin, somatostatin and gastrin/cholecystokinin in some of the endocrine cells. These findings suggest that the tumor arose from a pluripotential stem cell of the glandular epithelium.

Topics: Adenocarcinoma; Aged; Cholecystokinin; Female; Gastrins; Histocytochemistry; Humans; Immunochemistry; Somatostatin; Uterine Neoplasms

Topics: Adenocarcinoma; Adult; Aged; Female; Gastric Mucosa; Gastrins; Gastrointestinal Diseases; Humans; Male; Middle Aged; Peptic Ulcer; Peptide Fragments; Protein Precursors; Pyloric Antrum; Stomach Neoplasms

Gut endocrine cells in a total of 122 intestinal-tract adenocarcinomas induced in inbred Wistar rats by 1,2-dimethylhydrazine dihydrochloride were examined histologically, ultrastructurally, and immunohistochemically for gastrin, somatostatin, vasoactive-intestinal polypeptide (VIP), and glicentin (enteroglucagon). Of the 122 tumors, argyrophil cells were detected in 42 tumors (34.3%) comprising 15 tumors of the well differentiated type and 27 tumors of the poorly differentiated type, including signet-ring-cell carcinomas. Of the 27 tumors of the poorly differentiated type, 12 were regarded as endocrine-cell carcinomas composed of numerous argyrophil or argentaffin cells and mucus-containing cells. Immunohistochemically, 7 of the 12 tumors had glicentin and two of these seven tumors also had gastrin and argentaffin cells synchronously. None of the tumors showed immunoreactivity for somatostatin and VIP. Nine of the 12 tumors metastasized to the lung, pancreas, liver, mesenterium, omentum, and lymph nodes. The metastatic foci of these tumors were also shown to have glicentin and argentaffin cells. Ultrastructurally, four types of endocrine granule were found in the tumor cells and amphicrine cells containing endocrine granules and mucous granules were noted. These endocrine-cell tumors were assumed to develop from totipotent immature cells of endodermal origin.

Topics: 1,2-Dimethylhydrazine; Adenocarcinoma; Animals; Carcinogens; Chromaffin System; Dimethylhydrazines; Enterochromaffin Cells; Female; Gastrins; Glucagon-Like Peptides; Intestinal Neoplasms; Male; Microscopy, Electron; Neoplasm Metastasis; Neoplasms, Experimental; Rats; Rats, Inbred Strains; Somatostatin; Vasoactive Intestinal Peptide

The present study includes a histopathological and immunohistochemical study of 4 cases of diffuse hyperplasia of gastric argyrophil cells. The mode of proliferation of these cells and the production of hormone by these cells have been documented. The distribution of microacinar nests composed of argyrophil cells was thought to be related to chronic gastritis in which there are atrophy of mucosa and intestinal metaplasia. In the case in which these nests were found only in the corpus ventriculi, there was intestinal metaplasia throughout the stomach. On the other hand, in the case in which these nests appeared only in the pyloric area, atrophy of the mucosa with mild intestinal metaplasia was observed only in the pyloric area. The microacinar nests composed of argyrophil cells were distributed in the deep mucosa at the basal portion of the glands in the area with intestinal metaplasia. Serial sections revealed a sprout composed of argyrophil cells budding from the gland with intestinal metaplastic changes. The sprout buds out from the growth zone of glands with intestinal metaplasia and then becomes isolated and gives rise to reactive hyperplasia. The peptide hormone contained in these cells differs according to the mucosal environments. Cells containing gastrin were observed in the pyloric area, but not in the corpus ventriculi where there was marked intestinal metaplasia. The cells in this area were assumed to contain other hormones.

Topics: Adenocarcinoma; Adult; Chromaffin System; Enterochromaffin Cells; Female; Gastrectomy; Gastric Mucosa; Gastrins; Humans; Hyperplasia; Immunoenzyme Techniques; Male; Middle Aged; Somatostatin; Stomach Neoplasms

A rare case with gastrin-producing carcinoid, adenocarcinoma and xanthoma of the stomach is presented. A 69-year-old male underwent total gastrectomy with splenectomy and distal pancreatectomy. The histological type of the carcinoid was poorly differentiated (type D), and argyrophil cell carcinoma. Immunoperoxidase staining of the carcinoid was positive for gastrin and negative for glucagon, somatostatin or insulin. The histological findings of the carcinoma were tub 2, medullary, INF alpha, se, ly 2, v 1, ow(-), aw(-), n 1. Histologically, the xanthoma consisted of foamy macrophages accumulated in the lamina propria.

Topics: Adenocarcinoma; Aged; Carcinoid Tumor; Gastrins; Humans; Male; Neoplasms, Multiple Primary; Stomach Diseases; Stomach Neoplasms; Xanthomatosis

The effects of gastrointestinal hormones on gastric carcinomas were examined in vitro and in vivo. In five of seventeen cases of human gastric carcinomas, the uptake of 14C-leucine into the tumor tissue in organ culture was enhanced by 10 micrograms/ml of gastrin. Also, in four of thirteen cases of human gastric carcinomas, the production of 14C-labelled proteins in medium was increased by gastrin. All the cases in which protein synthesis was enhanced by gastrin were histologically poorly differentiated adenocarcinomas. The effects of gastrin and secretin on the growth of gastric carcinoma, which was serially transplanted in athymic mice, were examined. The doubling time of the tumor was 7.1 days. The doubling time was shortened to 4.1 days by daily administration of 250 micrograms/kg of gastrin. This topic effect of gastrin on gastric carcinoma was inhibited by 100 U/kg of secretin. These results showed that the growth and protein synthesis of gastrointestinal tumor may be regulated by gastrointestinal hormones.

Topics: Adenocarcinoma; Animals; Carcinoma; Cell Division; Gastrins; Humans; Leucine; Mice; Mice, Nude; Neoplasm Proteins; Neoplasm Transplantation; Secretin; Stomach Neoplasms

The effect of tetragastrin on the incidence and histology of colonic tumors induced by intrarectal instillation of N-methyl-N'-nitro-N-nitrosoguanidine was investigated in Wistar rats. Prolonged administration of tetragastrin in depot form during and after treatment with N-methyl-N'-nitro-N-nitrosoguanidine resulted in a significant reduction in the incidence of colonic tumors in Experimental Week 35. Histological examinations showed that, unlike the well-differentiated adenocarcinomas with a typical glandular pattern in control groups, the adenocarcinomas that developed in rats treated with tetragastrin had high mucin-producing activity.

Topics: Adenocarcinoma; Adenoma; Animals; Colonic Neoplasms; Gastrins; Injections, Subcutaneous; Male; Methylnitronitrosoguanidine; Neoplasms, Experimental; Rats; Rats, Inbred Strains; Sarcoma; Tetragastrin

Topics: Acromegaly; Adenocarcinoma; Adolescent; Adult; Chromaffin System; Enterochromaffin Cells; Gastrins; Humans; Hyperplasia; Male; Middle Aged; Pyloric Antrum; Stomach Neoplasms; Stomach Ulcer

Eighteen argyrophil cell carcinomas in 101 early gastric carcinomas were explained histologically, ultrastructurally, and immunohistochemically for polypeptides, carcinoembryonic antigen (CEA), lysozyme, and human chorionic gonadotrophin (hCG). Seven of these 18 tumors had gastrin, and two of seven tumors also contained somatostatin. In all of these 18 tumors CEA were demonstrated. Seven had lysozyme and five of seven tumors also contained gastrin; hCG were present in four of the 18 tumors and two of four tumors had gastrin, CA, mucin, and lysozyme simultaneously. Argentaffin cells were found in seven of 18 tumors. Of the above seven tumors containing gastrin, three had argentaffin cells. Ultrastructurally, several types of secretory granules were noted and tumor cells resembling D1- or P cells were present in nine of the 18 tumors. Macroscopically, many of the tumors showed IIc or IIc + III type. Histologically, the 18 tumors consisted of six well differentiated adenocarcinomas and 12 poorly differentiated adenocarcinomas including signet-ring cell carcinoma. These 12 tumors frequently developed in the stomach of young females. In view of our previous investigations, it was suggested that the IIc-type argyrophil cell carcinoma histologically showing poorly differentiated adenocarcinoma may be related to scirrhous carcinoma of the stomach.

Topics: Adenocarcinoma; Adenocarcinoma, Scirrhous; Adult; Aged; Carcinoembryonic Antigen; Chorionic Gonadotropin; Female; Gastrins; Histocytochemistry; Humans; Male; Microscopy, Electron; Middle Aged; Silver; Staining and Labeling; Stomach Neoplasms

The effects of gastrin on the histopathology of the glandular stomach and on the incidence of gastric carcinoma induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) were investigated in inbred Wistar (W) rats. Prolonged administration of gastrin after treatment with MNNG significantly reduced the incidence of adenocarcinomas of the glandular stomach. In addition, atypical glandular proliferations were significantly less frequent and were smaller, and the incidence of marked mucosal atrophy was significantly reduced in both the antral and oxyntic gland mucosae. Both atypical glandular hyperplasia and mucosal atrophy are precursors of gastric cancers; prolonged administration of gastrin to rats after treatment with MNNG suppressed development of precursors of gastric cancer and so prevented development of gastric cancers.

Topics: Adenocarcinoma; Animals; Atrophy; Delayed-Action Preparations; Drug Interactions; Gastric Mucosa; Gastrins; Male; Methylnitronitrosoguanidine; Rats; Rats, Inbred Strains; Stomach; Stomach Neoplasms

A histological and immunohistological investigation was performed on biopsy specimens from ten patients 3 to 35 years after antrectomy, to study the type of epithelium and the possible occurrence of gastrin-producing cells (G cells) in the distal stump of the stomach remnant. The study showed that parietal cells were present in all patients, whereas G cells could not be demonstrated, although areas of pyloric-type epithelium (pseudopyloric metaplasia, were seen in eight. We conclude that the pyloric-type metaplasia, which occurs in the fundic mucosa after antrectomy, does not involve the G cells. It is suggested that the normal levels of fasting serum gastrin in these patients originate from outside the gastric mucosa, presumably from the duodenal bulb.

Topics: Adenocarcinoma; Biopsy; Epithelium; Fibrosis; Follow-Up Studies; Gastrectomy; Gastric Acid; Gastrin-Secreting Cells; Gastrins; Gastritis, Atrophic; Gastroscopy; Humans; Postoperative Period; Pyloric Antrum; Radioimmunoassay; Stomach Neoplasms; Stomach Ulcer; Time Factors

Topics: Adenocarcinoma; Gastrins; Gastritis; Humans; Peptic Ulcer; Radioimmunoassay; Stomach Neoplasms

Topics: Adenocarcinoma; Adult; Aged; Animals; Dogs; Fasting; Female; Gastrectomy; Gastrins; Humans; Male; Middle Aged; Postoperative Period; Stomach Neoplasms

Topics: Adenocarcinoma; Animals; Gastrectomy; Gastric Juice; Gastrins; Intestinal Polyps; Male; Methylnitronitrosoguanidine; Neoplasms, Experimental; Rats; Stomach Neoplasms; Stomach Ulcer

Topics: Adenocarcinoma; Animals; Gastrins; Histamine; Male; Methylnitronitrosoguanidine; Rats; Stomach Neoplasms

A 61-year-old man with a 20-year history of recurrent gastric peptic ulcerations had an adenocarcinoma of the esophagus resected. The carcinoma was associated with columnar cell-lined (Barrett's) esophagus with carcinoma in situ. The patient had hypergastrinemia (gastrin level, 1,000 pg/dl), and at autopsy two months after the operation, a 3-mm pancreatic adenoma was discovered. In addition to the rarity of this clinical constellation, the case is of interest in suggesting that hypergastrinemia does not protect against peptic esophagitis and its sequelae.

Topics: Adenocarcinoma; Esophageal Diseases; Esophageal Neoplasms; Esophagitis, Peptic; Gastrins; Humans; Male; Middle Aged; Zollinger-Ellison Syndrome

In a consecutive material consisting of 24 stomachs resected due to adenocarcinoma, intestinal metaplasia occurred in 21. Gastrin-producing cells (G-cells) were found to be distributed in a sporadic manner in antra with intestinal metaplasia. Not a single G-cell could be demonstrated in areas with metaplasia, while in the nonmetaplastic areas the distribution of the G-cells corresponded to that of the middle part of the mucosa. This means, that an error can occur when determining the quantity of G-cells, and can explain the previous controversial results regarding the density of G-cells. Enteroglucagon containing cells (GLI-cells) on the contrary were demonstrated in areas with intestinal metaplasia in antra of 19 of the stomachs showing intestinal metaplasia but never in the nonmetaplastic mucosa. This indicated that metaplasia also includes the endocrine cells. The identification of the G-cells and the GLI-cells was carried out by means of indirect immunoperoxidase technique combined with alcian blue pH 2,6-PAS staining.

Topics: Adenocarcinoma; Cell Count; Gastrins; Glucagon-Like Peptides; Humans; Metaplasia; Pyloric Antrum; Stomach Neoplasms

The effects of gastrin on gastric acid secretion and on the incidence of gastric carcinoma induced by N-methyl-N'-nitro-N-nitrosoquanidine were investigated in rats. At Week 50 after the start of the experiment, it was found that prolonged administration of gastrin after treatment with N-methyl-N'-nitro-N-nitrosoquanidine resulted in a significant increase in gastric acid secretion and a significant reduction in the incidence of adenocarcinomas of the glandular stomach. The administration of gastrin did not influence the histological appearance of the few gastric adenocarcinomas that did develop.

Topics: Adenocarcinoma; Animals; Drug Administration Schedule; Gastric Juice; Gastrins; Male; Methylnitronitrosoguanidine; Neoplasms, Experimental; Rats; Stomach Neoplasms

With better methods of diagnosis, patients will be identified earlier in the course of their disease and will often have atypical and borderline manifestations of the syndrome. Serum gastrin measurements with calcium and especially with secretin challenge will be the most important method of diagnosis. Any patient with acid hypersecretion who has a high serum gastrin level that does higher on secretin infusion should be considered to have the Zollinger-Ellison syndrome. A firm diagnosis of the Zollinger-Ellison syndrome should be made, if at all possible, prior to operation. At operation, a thorough search of the pancreas, duodenum, stomach, greater and lesser omentum and liver should be made for primary and secondary gastrinomas. If the preoperative data firmly establish the diagnosis of the Zollinger-Ellison syndrome, a total gastrectomy should be carried out even if no primary tumor is found. Similarly, a total gastrectomy should be done even if there are massive hepatic metastases. If total gastrectomy is not performed, the patient is apt to die of complications of acid hypersecretion. The only possible exceptions to the rule of always performing a total gastrectomy are in asymptomatic patients with easily excisable tumors or patients with tumors of the duodenum that are easily excisable, providing that in both instances after the excision of the tumor the output of gastric acid as measured at operation is immediately halted. All possible metastatic tumor tissue should be removed. The more tumor tissue removed, the longer the patient will survive. Metastases should be treated aggressively. They do not disappear after total gastrectomy in our experience, and they may kill patients. Patients should be followed after operation with serial measurements of serum gastrin concentrations and by hepatic scintillation scans and hepatic angiography. If hepatic metastases develop, intrahepatic artery infusions of 5-fluorouracil may slow tumor growth.

Topics: Adenocarcinoma; Adult; Aged; Angiography; Calcium; Endoscopy; Female; Gastrectomy; Gastrins; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Pancreatic Neoplasms; Peptic Ulcer; Postoperative Complications; Preoperative Care; Radioimmunoassay; Secretin; Zollinger-Ellison Syndrome

Topics: Adenocarcinoma; Adenoma, Islet Cell; Calcium; Child; Duodenal Diseases; Gastric Juice; Gastrins; Humans; Lymphatic Metastasis; Male; Pancreatic Neoplasms; Radiography; Zollinger-Ellison Syndrome

Although histochemical, immunohistochemical, and electron microscopic methods have led to the identification of a large variety of endocrine cells in the upper gastrointestinal mucosa, no conventional light microscopic technique capable of the simultaneous identification of these cells has been reported. Such a staining method would be of considerable value to the pathologist as the malfunction of the endocrine cells of the gut, which produce numerous digestive hormones and biogenic amines, is closely related to a number of clinical conditions afflicting man. In this work, after testing three different polychrome staining methods, it has been concluded that a slightly modified Herlant's tetrachrome in tissues fixed in Zenker-formol is the procedure of choice. This method allows the distinction of several different cell types in the upper gastrointestinal mucosa of man and dog and permits the easy identification of the gastrin-producing cells on a routine basis. This identification has been confirmed in the case of two patients with gastrin cell hyperplasia, seen by both light and electron microscopy. Herlant's tetrachrome has proven valuable in the screening of human as well as experimental gastrointestinal tissues and it has been found to be very suitable for recognizing gastrin-producing cell hyperplasias. The usefulness of this method is expected to increase with the establishment of further correlations between the light and electron microscopy of the endocrine cells of the gut.

Topics: Adenocarcinoma; Animals; Chromates; Dogs; Duodenal Ulcer; Duodenum; Gastric Mucosa; Gastrins; Humans; Hyperplasia; Intestinal Mucosa; Methods; Microscopy, Electron; Peptic Ulcer; Staining and Labeling; Stomach Neoplasms

Topics: Adenocarcinoma; Adenoma; Aortography; Diagnosis, Differential; Diarrhea; Gastrectomy; Gastric Juice; Gastrins; Gastrointestinal Hemorrhage; Gastrointestinal Motility; Humans; Hyperplasia; Intestine, Small; Peptic Ulcer; Zollinger-Ellison Syndrome