Background

Chronic inflammation in the intestinal epithelium (e.g. inflammatory bowel disease) is a major risk factor for the development of colorectal cancer (CRC). In accordance with this association, regular use of non-steroidal anti-inflammatory drugs (e.g. aspirin) prevents CRC development and promotes regression of established cancers. Moreover, CRCs that do not develop under inflammatory conditions are typically infiltrated with several types of pro-tumorigenic immune cells.

Using genetically engineered mouse models expressing mutant Nras in the intestinal epithelium, our lab has previously found that, although Nras activation does not affect normal homeostasis, it plays a unique role among RAS proteins in protecting it from apoptosis induced by dextran sodium sulfate (DSS - a potent inductor of intestinal cell death, and a pro-inflammatory agent). These results support the hypothesis that NRAS mutations might arise in CRC under circumstances of chronic apoptotic stimulus, such as inflammation. 

Approach

Our goals are: (a) to investigate the effect of N-RAS activation in inflammation-induced colorectal tumorigenesis; and (b) to determine if mutant NRAS is able to promote the transition from an anti-tumorigenic towards a pro-tumorigenic inflammatory response. 

Consistent with our hypothesis, wild-type mice treated with DSS show signs of a high inflammatory response, whereas mutant mice show less signs of inflammation and develop tumors after DSS treatment (the image above shows representative pictures of the normal appearence  of the mouse intestinal epithelium without DSS treatment (left), the highly inflamed and ulcerated epithelium of wild-type mice treated with DSS (middle), and the weak inflammatory reaction and tumor development seen in Nras mutant mice).