Cancer is known to result from accumulation of non-lethal mutations and changes in gene regulation that affect cell growth, genomic stability, and allow continuous self-renewal. Although the oxidative stress generated by inflammation within the colon can clearly enhance the rate of mutation accumulation, this alone appears to be insufficient to explain the extremely high risk of colorectal cancer in patients with inflammatory bowel disease (IBD). This application is designed to determine the molecular and cellular mechanisms by which patients with IBD has increased risk for developing colorectal cancer and to explore how these connections can be exploited to develop novel preventive or therapeutic strategies (NCI's provocative question 6). Recent research has shown that the expression of the mutation-inducing enzyme activation-induced cytidine deaminase (AID) is induced by colon inflammation and that AID expression can enhance the acquisition of p53 mutations by colon epithelial cells. Based on very recent data indicating that AID can also affect "stemness" (self-renewal properties) via its effects on gene methylation, we hypothesize that induction of AID expression within colon epithelial cells causes a "perfect storm" that can rapidly lead to development of colon cancer by simultaneously increasing mutation rates, decreasing genome stability, and conferring the self-renewal properties that are a hallmark of cancer. For this study we will determine how the ability to induce AID affects the incidence of colorectal neoplasia in a novel murine model of IBD that very closely resembles human ulcerative colitis in both clinical presentation and cancer susceptibility. Acquisition of mutations and/or dysregulation in genes and pathways that are known to be critical drivers of colorectal neoplasia will be assessed in both neoplastic lesions and adjacent normal-appearing mucosa as a function of colitis duration. Results will enhance our understanding of molecular signaling pathways that are relevant to the development and progression of inflammation-associated colorectal cancer. Importantly, they will identify critical biomarkers that will allow earlier and/or non-invasive methods of diagnosis and will lay the foundation for development of drugs to decrease risk of inflammation-associated and sporadic colorectal cancers.
Colorectal cancer is the 3d most common cancer in the United States. Patients with inflammatory bowel disease (IBD) experience chronic colon inflammation that increases their colon cancer risk by as much as 20-fold above that of the general population. Development of safe and effective strategies to decrease the development of inflammation-associated colon cancer would thus be of particular benefit to IBD patients but, since inflammation may also play a role in the development of sporadic colon cancers, would benefit the rest of population as well.