Mo1609 Obesity Drives Colon Tumor Development in AOM-Treated Mice

Background/Aims: Obesity is an important risk factor for colon cancer in humans. Numerous studies in experimental animals demonstrated that a high fat diet enhances colon cancer development. A potential mechanism for this increased risk is that adipose tissue, a major source of adipokines, growth factors, and cytokines promotes tumor growth. Alternatively, a high-fat diet causes metabolic changes that can independently enhance tumor growth. Here we determined the independent effects of these factors on colon tumor development. Methods: C57BL/6J male mice were fed regular chow or high fat diet (HFD) for 8 weeks. Half of the animals on high fat diet were switched to regular chow, and half on regular chow were switched to the HFD with the resulting 4 groups being regular (R), HFD (H), regular switched to HFD (RH) and HFD switched to regular (HR). One week after the switch, 5 weekly doses of azoxymethane (AOM) were given to induce colon tumors. Mice were euthanized 1 day after the final dose of AOM to analyze gene expression, proliferation, and apoptosis in the colon or 25 weeks after AOM to analyze numbers of colon tumors and aberrant crypt foci (ACF). Body composition was measured by echo MRI. Results: We previously showed the significantly increased tumor multiplicities in all groups that received HFD (groups H, HR, and RH) relative to animals on regular diet (group R). In this study, an ELISA based array analysis of cytokines and growth factors in serum revealed that obesity was associated with differential expression of molecules involved in insulin-like growth factor (Igf) signaling. Relative to group R mice, group HR mice had ratios 1.5, 0.7, and 0.75 in serum concentrations of Igf-II, Igf binding protein (Igfbp) 5, and Igfbp6, respectively (p = 0.05 for each). These differences were also reflected in mRNA expression patterns in mesenteric adipose tissue, as all obese groups had significantly elevated expression of Igf-I and Igf-II and significantly depressed expression of Igfbp5 and 6. Group HR mice appeared to have a greater toxic response to AOM relative to all other groups as measured by apoptotic index and lengthening of the Ki67-positive proliferative zone in colonic crypts following AOM treatment. Conclusions: We have identified obesity itself as a tumor promoter. A mechanism for the increased tumor responses may involve heightened signaling through the Igf1-receptor due to increased expression of ligands and decreased expression of binding proteins in mesenteric adipocytes. Additionally, the greater tumor response of mice in HFD that were switched to regular diet likely involves a heightened toxic response to AOM. Supported by NIH RO-1 DK60729 (CP); A Pilot and Feasibility Study from CURE: Digestive Diseases Research Center 41301; and the Martin Blinder Fund for IBD Research