EPITHELIAL HOMEOSTASIS IN APC GENE MUTATION

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Mutation of the APC gene is widely recognized as an important early event in colorectal carinogenesis. The availability of humans and mice carrying germline mutations in APC provides a unique opportunity to study both colorectal cancer pathogenesis and tumor prevention. Nonsteroidal antiinflammatory drugs (NSAIDs) can prevent and reverse neoplastic changes in intestinal mucosa affected by APC gene mutation. Some of these neoplastic changes, such as altered levels of enterocyte proliferation and apoptosis, are present even in histologically-normal mucosa from individuals with APC mutation. By studying the mucosa of individuals with APC mutation before and during administration of NSAIDs, we can obtain information concerning the pathogenesis of colorectal cancer, as well as develop useful predictive biomarkers to evaluate cancer chemoprevention strategies. In this proposal, we describe a study of the effect of APC gene mutation upon intestinal epithelial cell turnover time and arachidonic acid metabolism in mice with Apc mutation. Using these measurements of epithelial homeostasis, we will study the effect of several NSAIDs and other related agents upon intestinal carcinogenesis related to Apc mutation. Finally, we will apply this information to a study of NSAID-induced tumor regression in humans with Familial Adenomatous Polyposis, a condition characterized by germline mutation of the APC gene.