Progastrin expression predisposes mice to colon carcinomas and adenomas in response to a chemical carcinogen

Processing intermediates of preprogastrin (gly-gastrin and progastrin), termed nonamidated gastrins, are mitogenic for several cell types including colonic epithelial cells. However, presently it is not known if nonamidated gastrins play a role in colon carcinogenesis and if the effects are similar to those of amidated gastrins.

Colon carcinogenesis in response to azoxymethane (AOM) was examined in transgenic mice overexpressing either progastrin (hGAS) or amidated gastrin (INS-GAS), compared with that in wild-type (WT) mice.

In AOM-treated groups, the total number of tumors per colon was significantly higher in hGAS (4.8+/-0.34) than INS-GAS (3.0+/-0.16) and WT (2.7+/-0.35) mice. Total numbers of adenocarcinomas and adenomas per animal colon were also significantly higher in hGAS than INS-GAS and WT mice. The size of the tumors was greater in hGAS mice, resulting in a significantly higher tumor burden per mouse in the hGAS mice than INS-GAS and WT mice. Although >90% of the tumors were located in the distal half of the colon in INS-GAS and WT mice, a significant number (42%) were present at the proximal end of the colon in hGAS mice.

The results suggest that the risk for developing colon carcinomas and adenomas in response to AOM is significantly increased in mice expressing high levels of progastrin, but not amidated gastrins.