SITE SPECIFICITY OF GASTROINTESTINAL TUMORIGENESIS

DESCRIPTION: (Applicant's Abstract) Mice that inherit a mutant allele of the Apc gene develop tumors principally in the small intestine (SI), unlike patients with familial polyposis (FAP) who develop large bowel cancer. However, the applicant has shown that several mouse models are not refractory to large bowel tumor formation. This application focuses on mechanisms regulating the ability of sulindac, an NSAID to stimulate the formation of large bowel tumors in the Apc1638, ApcMin, and ApcMlh1 mouse models, even though it has an inhibitory effect on tumor formation of the SI. This is similar to reports that patients given sulindac develop rectal tumors. The applicant proposes to utilize the Apc1638, ApcMin, and ApcMlh1 models to determine mechanisms by which probability of tumor formation is modulated at different sites in the intestine by sulindac and celecoxib, a specific Cox-2 inhibitor. A significant aspect of the experimental design is that alterations on a cellular, biochemical and molecular level will be assayed in regions of the intestinal tract undergoing both increases and decreases in tumor formation in the same mouse. Detailed immunohistopathology of tumor formation will include analysis of proliferation and apoptosis in the mucosa and tumors. In addition, Cox-1, Cox-2, arachidonic acid metabolism, and beta-catenin-Tcf signaling will be monitored to determine the role of these pathways in site-specific modulation of tumorigenesis. Lastly, using microarray analyses, the profiles of gene expression that characterize genetic and dietary modulation of risk will be defined.