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Show 116 Megan Brzenk school of medicine and health sciences Mutations in Apc are essential for colon tumor initiation, and are found in 80% of colon cancers, both fa-milial and sporadic. Interestingly, when similar mutations are modeled in mice, only small intestinal tumors develop. This suggests that additional mutations may be necessary to drive colon tumors to form. Indeed, colon tumors form when one Tcf4 allele (Tcf4het) is deleted in the Apc mutant background (Angus-Hill et al., 2011). These tumors are adenomas that never progress to adenocarcinoma, and it is possible that these mice die from small intestinal tumor load prior to colon tumor progression. Because metastasis of colon cancer is responsible for most colon cancer mortality, our long-term goal is to drive tumor progression in Apcmin Tcf4het animals. The specific aim of my project was to investigate the long-term effects of environmental enrichment in Apcmin Tcf4het and Apcmin mutant mice. Specifically, we will test whether environmental enrichment in-creases lifespan, decreases small intestinal and colon tumor load, and allows for colon tumor invasion and metastasis. Recently, a short-term experiment demonstrated that small intestinal tumor load in Apcmin mutant mice decreases when mice are environmentally enriched over a two-week period (Cao et al., 2010). My project will examine the long-term effects of environmental enrichment on colon tumor initiation and progression. To accomplish this, all mice (male and female) were genotyped and placed in an enriched environment or a control environment by one month of age. Genotyped mice (Apcmin Tcf4het and Apcmin) were divided into two living environments: an enriched environment which consisted of a 15" x 20" x 33" cage with running wheels, tunnels, igloos, huts, crawl balls, and nesting material, or a control environment with a standard sized cage and no developmentally stimulating activities. Males and females were housed separately with five mice in each of our eight control cages, and 20 mice in each of the four environmentally enriched cages. Animals were then collected when they began exhibiting symptoms of cachexia and anemia. All tissue was collected and tumor count and tumor load was determined for both the small intestine and the colon. We found a statistically significant difference between the lifespan of the environmentally enriched and non-environmentally enriched mice. The environmentally enriched Apcmin Tcf4het mutant mice outlived their mutant non-enriched counterparts by an average of 65 days, which implies that environmental enrich-ment promotes long-term survival of these animals. This suggests that the phenotypic effects of the Tcf4 mutation are abrogated by environmental enrichment. Interestingly, both the enriched and non-enriched Apcmin Tcf4het mice had similar tumor load and count upon being collected, suggesting that tumors take longer to develop but ultimately they die of the same tumor burden. Finally, our experiment showed no significant change in the lifespan of Apcmin animals, and contrary to short-term published results we found an increase in colon tumors in Apcmin animals following long-term exposure of animals to an enriched environment compared to the control. Currently, we are conducting further experiments to determine the mechanism behind the increased lifespan of environmentally enriched Apcmin Tcf4het mutant animals. ENVIRONMENTAL ENRICHMENT AND COLON CANCER PROGRESSION IN A MOUSE MODEL OF HUMAN COLORECTAL CANCER Megan Brzenk (Melinda Angus-Hill) Department of Human Genetics University of Utah UNDERGRADUATE RESEARCH ABSTRACTS Melinda Angus-Hill |
