Mediterranean versus Western diet - preventative and interventional effects of dietary lipids on colorectal tumor growth and biology

The purpose of this study was to examine the preventative and interventional effects of different fat sources (lard verses olive oil) and their respective lipid components in a Western-style high-fat diet and Mediterranean-style high-fat diet on tumor biology in vivo in a Cre-lox mouse model called iKAP (inducible Kras, Apc, p53) of colorectal cancer (Boutin et al, Genes & Development 2017, 31:370). Experimental Procedures: At 8-11 weeks of age, mice are randomized to a control lard-based 10% fat diet with high fiber (low-fat diet, LFD), a lard-based 45% fat diet with low fiber (high-fat diet, HFD) or olive oil-based 43% fat Mediterranean diet (MD) with the fiber matched to the LFD control. To measure diet-induced metabolic dysfunction, body composition and glucose tolerance are measured with EchoMRI and glucose tolerance tests (GTT) every three and six weeks, respectively. After 12 weeks post-randomization on diet, mice undergo a submucosal induction with 4-hydroxytamoxifen (4-OHT), which deletes loxP conditional Apc and Trp53 in intestinal cells expressing the Villain promoter, thus causing tumorigenesis. Endoscopies are done every two weeks and tumor growth is measured by percent luminal occlusion - or the percent of the lumen taken up by the tumor over time - until end-of-study (one year or mortality due to tumor burden). In addition to understanding how the two diets affect tumor growth when given before tumor development, an arm of the study aims to understand the effects of an interventional diet post-tumor initiation. To accomplish this, a proportion of mice on LFD or HFD will be assigned to MD two weeks after induction with tamoxifen. Results: At 12 weeks post-randomization with diet, mice on both HFD and MD show evidence of metabolic dysfunction (higher body weight, high fat mass and glucose intolerance) compared to LFD. In addition, mice on HFD and MD consume more chow. Interestingly, preliminary data suggests that systemic cholesterol levels in MD and LFD mice are at similar levels and significantly lower than that of HFD mice. Orthogonal in vitro studies using immunofluorescence, fatty acid oxidation assays and molecular profiling of protein pathways involved in lipogenesis (SREBP1/2, FASN, ABCA1) and cancer cell growth/metabolism (AKT, PI3K, mTOR) are ongoing to understand the influence of different dietary fatty acids (oleic and palmitic acids) and cholesterol/phytosterols in the context of tumorigenesis. Conclusion: Based on preliminary findings, both the Western HFD and MD effectively induce metabolic dysfunction in an iKAP murine model. However, the lipid components of the diets are significantly different; thus, differences in tumor metabolism and growth remain a pertinent question.