Ulcerative colitis and microsatellite instability

Chronic inflammation in ulcerative colitis leads to the development of colorectal cancer. The inflammatory infiltrate creates a hypermutable environment that initiates and drives neoplastic progression. Neutrophils are the predominant cells in this setting, which may penetrate the mucosal barrier and form crypt abscesses. Our lab recently demonstrated that such activated neutrophils lead to replication errors and cause mutations at microsatellites. Such microsatellite instability can be detected in chronically inflamed mucosa and seems to be an early event in the development of colitis-associated cancer. For this project we aim to dissect the culprit factor(s) responsible for microsatellite instability using a coculture system with primary human colonic epithelial cells and certain colitis mouse models that develop microsatellite mutations and cancer. Antagonists will also be tested both in vitro and in vivo.

Ulcerative colitis is characterized by chronic intestinal inflammation with increased risk for the development of colorectal cancer. The inflammatory infiltrate creates an environment in the intestine, which leads to mutations in repetitive DNA sequences, so called microsatellites, in the intestinal mucosa. Microsatellite instability can already be detected in chronic inflamed mucosa (before the onset of cancer) and is considered a key factor for the development of colitis-associated colorectal cancer. Within this project we identified signaling molecules, released by certain immune cells, which lead to mutations in intestinal epithelial cells. Inhibition of these signaling peptides and reactive oxygen species reduced mutations in a culture system of intestinal epithelial cells and granulocytes. To verify our promising results in a mouse model, we created IL-10xMSH2 double knockout (DKO) mice, with a defective mismatch repair system and prone to develop colitis. According to our hypothesis, these IL-10xMSH2 DKO mice developed more colonic tumors compared to single KO mice. Tumors presented mostly right-sided and bacteria were colonizing tumor crypts, an observation characteristic for IL-10 and DKO mice. Using this mouse model we studied the inhibition of signaling molecules for the prevention of colorectal cancer, unfortunately with negative result. The identification of tumor-colonizing bacteria, however, opens the opportunity to study the relationship between intestinal microbiota and colon cancer.