| Colon cancer is the third leading cause of cancer-related mortality for men and women in the US, with at least 40% of these cancers expressing the gastrin gene. Gastrin gene products include amidated gastrins (G17, G34) and non-amidated gastrins (G-Gly, PG) which bind different receptors. Therefore, the goal of this study was to determine whether all gastrin peptides exert co-carcinogenic effects in vivo. Based on the absence of carcinogenic effects in transgenic mice that over-express gastrin-17 (INS-GAS mice) and the increased cancer incidence in mice over-expressing progastrin (PG) in the liver (hGAS mice), we hypothesize that amidated gastrins and non-amidated gastrins will have opposing effects on colon carcinogenesis. In order to further examine the co-carcinogenic properties of gastrins, we generated two types of mutant mice: (1) gastrin knockout (GAS-KO) mice which were devoid of all forms of the gastrin peptide and (2) transgenic mice, overexpressing pathophysiological levels of progastrin (PG) in the colon (Fabp-PG mice). Carcinogenesis studies were performed on mutant mice and their wild type (WT) littermates by injection of the carcinogen azoxymethane (AOM). GAS-KO mice developed significantly more aberrant crypt foci (ACF) and tumors than WT mice, indicating that amidated gastrins are protective against colon cancer. Furthermore, male C57Bl/J6 mice are less susceptible to colon carcinogenesis, due to the protective effects of testosterone, which were determined by castration and hormone replacement studies. GAS-KO mice also developed hyperinsulinemia at an early age and obesity (by 10 months of age), which are risk factors for colon cancer development. Finally, ACF and tumor development in Fabp-PG mice were elevated two-fold versus WT mice, due to proliferative and anti-apoptotic effects of PG on colonic cells. In conclusion, our studies with mutant mouse models indicate that amidated gastrins have protective effects against colon carcinogenesis, while non-amidated gastrins promote colon cancer. The opposing actions of these hormones are most likely due to binding of the ligands to different receptor sub-types. It is our hope that a better understanding of the differential effects of these peptides and their receptors will lead to improved treatment modalities and clinical outcomes for colon cancer. |
