gastrins and Adenomatous-Polyposis-Coli

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

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

An increase in circulating concentrations of gastrin or gastrin precursors such as progastrin and glycine-extended gastrin has been proposed to promote the development of colorectal carcinomas (CRC). The aim of this study was to investigate whether or not circulating gastrin concentrations were increased in patients with an increased risk of developing CRC.. Patients were divided according to their risk into the five following groups: familial adenomatous polyposis (n = 20), hereditary non-polyposis colorectal cancer (n = 53), cluster of common colorectal cancers (n = 13), personal history and/or family history of adenomatous polyps or CRC (n = 150) and controls (n = 42). Radioimmunoassay with four region-specific gastrin antisera was used to measure progastrin, glycine-extended gastrin (gastrin-gly), amidated gastrin (gastrin-amide), and total gastrin in peripheral blood taken at the time of colonoscopy.. Compared with the control group, familial adenomatous polyposis patients had significantly higher median values of total gastrin (29.8 pM vs 16.9 pM, P = 0.003) and gastrin-amide (17.1 pM vs 12.0 pM, P = 0.015). Patients with a personal or family history of adenomatous polyps or CRC also had higher circulating concentrations of total gastrin (21.8 pM) compared with controls (P < 0.05), while patients from all groups who presented with an adenomatous polyp on the day of colonoscopy had higher concentrations of total gastrin, progastrin, and gastrin-amide than patients without polyps.. Concentrations of gastrin precursors are increased in particular groups with an increased risk of developing CRC.

Topics: Adenomatous Polyposis Coli; Adult; Biomarkers, Tumor; Colorectal Neoplasms; Female; Gastrins; Humans; Male; Middle Aged; Protein Precursors; Radioimmunoassay; Risk; Risk Assessment

Aberrant activation of the beta-catenin/Tcf-4 transcriptional complex represents an initiating event for colorectal carcinogenesis, shifting the balance from differentiation toward proliferation in colonic crypts. Here, we assessed whether endogenous progastrin, encoded by a target gene of this complex, was in turn able to regulate beta-catenin/Tcf-4 activity in adenomatous polyposis coli (APC)-mutated cells, and we analyzed the impact of topical progastrin depletion on intestinal tumor growth in vivo.. Stable or transient RNA silencing of the GAST gene was induced in human tumor cells and in mice carrying a heterozygous Apc mutation (APCDelta14), which overexpress progastrin but not amidated or glycine-extended gastrin.. Depletion of endogenous progastrin production strongly decreased intestinal tumor growth in vivo through a marked inhibition of constitutive beta-catenin/Tcf-4 activity in tumor cells. This effect was mediated by the de novo expression of the inhibitor of beta-catenin and Tcf-4 (ICAT), resulting from a down-regulation of integrin-linked kinase in progastrin-depleted cells. Accordingly, ICAT down-regulation was correlated with progastrin overexpression and Tcf-4 target gene activation in human colorectal tumors, and ICAT repression was detected in the colon epithelium of tumor-prone, progastrin-overexpressing mice. In APCDelta14 mice, small interfering RNA-mediated progastrin depletion not only reduced intestinal tumor size and numbers, but also increased goblet cell lineage differentiation and cell apoptosis in the remaining adenomas.. Thus, depletion of endogenous progastrin inhibits the tumorigenicity of APC-mutated colorectal cancer cells in vivo by promoting ICAT expression, thereby counteracting Tcf-4 activity. Progastrin targeting strategies should provide an exciting prospect for the differentiation therapy of colorectal cancer.

Topics: Adaptor Proteins, Signal Transducing; Adenoma; Adenomatous Polyposis Coli; Animals; Apoptosis; beta Catenin; Cell Cycle Proteins; Cell Line, Tumor; Cell Proliferation; Cell Transformation, Neoplastic; Colorectal Neoplasms; Gastrins; Gene Expression Regulation, Neoplastic; Genes, APC; Humans; Mice; Mice, Nude; Phosphatidylinositol 3-Kinases; Protein Precursors; Random Allocation; Repressor Proteins; RNA, Small Interfering; Signal Transduction; TCF Transcription Factors; Transcription Factor 7-Like 2 Protein; Transcription Factors; Transcriptional Activation; Transplantation, Heterologous

Serum hypergastrinemia promotes the growth of colorectal adenocarcinoma. Some colorectal adenomas express cholecystokinin B/gastrin receptor mRNA, and thus hypergastrinemia may increase progression through the adenoma-carcinoma sequence. This was investigated in the multiple intestinal neoplasia APC(Min-/+) mouse. Serum gastrin levels in APC(Min-/+) mice were elevated 5-6-fold by oral administration of omeprazole (75 mg/kg). Terminal tumor burden was monitored by onset of anemia. A labeling index was generated by immunohistochemical detection of bromodeoxyuridine incorporation. Serum gastrin was neutralized by antigastrin antibodies raised in situ by use of a gastrin immunogen, Gastrimmune. Hypergastrinemia resulted in reduced survival of the APC(Min-/+) mice from a median survival of 13 weeks in the controls to 10 weeks following omeprazole treatment (P < 0.00001, log-rank test). The labeling indices of adenomas from the small and large intestines of omeprazole-treated mice were increased 35 and 29%, respectively (P < 0.05 and P < 0.025, respectively). Gastrimmune immunization reversed both the survival effect and the increased proliferation resulting from serum hypergastrinemia. Hypergastrinemia may promote the progression of existing premalignant colonic lesions by increasing proliferation. Clinical investigations should determine whether this occurs in the human scenario, considering the widespread use of proton pump inhibitors.

Topics: Adenoma; Adenomatous Polyposis Coli; Adenomatous Polyposis Coli Protein; Animals; Bromodeoxyuridine; Cancer Vaccines; Colorectal Neoplasms; Cytoskeletal Proteins; Diphtheria Toxoid; Disease Models, Animal; Disease Progression; Female; Gastrins; Gene Expression Regulation; Heterozygote; Immunization; Intestinal Mucosa; Male; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Omeprazole; Receptor, Cholecystokinin B; Receptors, Cholecystokinin; RNA, Messenger; Survival Rate

Mutations in the adenomatous polyposis coli (APC) tumor suppressor gene occur in most colorectal cancers and lead to activation of beta-catenin. Whereas several downstream targets of beta-catenin have been identified (c-myc, cyclin D1, PPARdelta), the precise functional significance of many of these targets has not been examined directly using genetic approaches. Previous studies have shown that the gene encoding the hormone gastrin is activated during colon cancer progression and the less-processed forms of gastrin are important colonic trophic factors. We show here that the gastrin gene is a downstream target of the beta-catenin/TCF-4 signaling pathway and that cotransfection of a constitutively active beta-catenin expression construct causes a threefold increase in gastrin promoter activity. APC(min-/+) mice overexpressing one of the alternatively processed forms of gastrin, glycine-extended gastrin, show a significant increase in polyp number. Gastrin-deficient APC(min-/+) mice, conversely, showed a marked decrease in polyp number and a significantly decreased polyp proliferation rate. Activation of gastrin by beta-catenin may therefore represent an early event in colorectal tumorigenesis and may contribute significantly toward neoplastic progression. The identification of gastrin as a functionally relevant downstream target of the beta-catenin signaling pathway provides a new target for therapeutic modalities in the treatment of colorectal cancer.

Topics: Adenomatous Polyposis Coli; Animals; Base Sequence; beta Catenin; Cytoskeletal Proteins; Disease Models, Animal; DNA Primers; Female; Gastrins; Gene Expression; Genes, APC; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Mutation; Promoter Regions, Genetic; Signal Transduction; TCF Transcription Factors; Trans-Activators; Transcription Factor 7-Like 2 Protein; Transcription Factors; Transfection

Serum gastrin levels were measured by radioimmunoassay in 62 patients with colorectal neoplasms (40 with adenomatous polyps and 22 with cancer) and 40 controls. Fasting serum gastrin in both the polyp (73.93 +/- 6.5 pg/ml) and the cancer (99 +/- 19.7 pg/ml) groups was significantly higher than those of the control group (42.65 +/- 2.2 pg/ml). These findings suggest that hypergastrinemia may be an etiologic factor in colorectal neoplasia.

Topics: Adenomatous Polyposis Coli; Adenomatous Polyps; Aged; Colorectal Neoplasms; Gastrins; Humans; Middle Aged; Prospective Studies; Radioimmunoassay; Reference Values

An evaluation of the importance of gastrin in the colorectal carcinogenesis in patients with familial adenomatous polyposis was conducted.. Blood samples from 168 family members of 26 families were investigated for circulating gastrin. Blood was drawn from 65 affected patients, 66 clinically unaffected first-degree relatives, and 37 spouses.. We did not find any difference in distribution of serum gastrin among these groups.. Our results seem to exclude gastrin from being relevant in early carcinogenesis in patients with familial adenomatous polyposis.

Topics: Adenomatous Polyposis Coli; Adolescent; Adult; Age Factors; Aged; Anastomosis, Surgical; Biomarkers; Child; Colectomy; Female; Gastrins; Humans; Ileum; Male; Middle Aged; Proctocolectomy, Restorative; Rectum

The article presents data obtained in studying the content of calcium regulating hormone thyrocalcitonin and parathyroid hormone in blood plasma of patients with diffuse polyposis of the colon prior to and after a radical surgical treatment. The content of these hormones was also studied in extracts from colonic polyps. The concentration The concentration of thyrocalcitonin was found to decrease after operation. The elevated concentration of thyrocalcitonin was established in polyp extracts which might suggest its "ectopic secretion" in the polyp tissue in diffuse polyposis. Removal of the colon with polyps is followed by normalization of metabolism in the organism which proves the expediency of early surgical treatment.

Topics: Adenomatous Polyposis Coli; Adolescent; Adult; Calcitonin; Calcium; Gastrins; Humans; Insulin; Insulin Secretion; Parathyroid Hormone; Postoperative Period