big-gastrin and Adenomatous-Polyposis-Coli

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