Modulation of intestinal tumorigenesis by dietary carbohydrate and protein sources in APC(Min) mice

Three experiments were conducted to test the hypothesis that diets containing high concentrations of sucrose (vs. cornstarch) promote colon carcinogenesis in APCMin mice by elevating IGF signaling and increasing epithelial cell turnover in colonic crypts. A secondary objective of this research was to assess the impact of dietary protein source (soy vs. casein) on intestinal tumorigenesis in APCMin mice.; In the first experiment, APCMin mice were fed diets containing either sucrose or cornstarch as the primary carbohydrate source for 10 weeks. APCMin mice fed sucrose had significantly more but smaller adenomas in the proximal third of the small intestine when compared to mice fed cornstarch. Dietary carbohydrates did not influence colon tumor development. However, mice consuming sucrose had a significantly greater rate of epithelial cell proliferation in colon compared to mice consuming cornstarch. Serum glucose concentrations and IGF-I mRNA expression in liver were significantly greater in mice consuming high-sucrose diets compared to mice consuming cornstarch. In addition, mice consuming sucrose tended (P = 0.07) to have higher serum insulin levels.; In the second experiment, global gene expression in small intestinal epithelium caused by APC gene mutation and dietary carbohydrate source was assessed using cDNA microarray analysis. Expression of 379 genes was significantly different between APCMin mice and wild-type mice. Among these differentially-expressed genes, 109 were annotated and had expression altered by genotype by more than 50%. Several of these genes were associated with cell growth control and carcinogenesis (APC gene mutation increased expression of Clu, Ccnd2, Ccnb1, Btg4, Anxa1 and Gspt1, and decreased expression of Camk1d, sept2, Lats2, Dab2 and Morf4l1). The expression of 306 genes was significantly influenced by dietary carbohydrate source. Among these genes, 87 were annotated and had expression altered by carbohydrate source by more than 50%. Several of these genes were associated with cell growth control and carcinogenesis (sucrose increased expression of Igf2, Pcna, Cse1l, Idb2 and Camk2g, and decreased expression of Igfbp3, Tia1, Fancg, Bmpr1a and Cul4b). Sucrose feeding increased intestinal expression of IGF2 and decreased expression of IGFBP3, which may result in elevated IGF signaling in the intestinal epithelium.; In the third study, the influence of dietary carbohydrate (sucrose vs. cornstarch) and protein (soy vs. casein) sources on colonic adenoma development in APCMin mice was assessed in using a two by two factorial design. The small intestinal tumorigenesis was retarded by adding sulindac (100 mg/g) to the diets. After a longer duration of dietary treatment (i.e. 16 weeks), APCMin mice consuming sucrose (vs. cornstarch) had significantly greater incidence of colon adenomas, as well as increased epithelial cell proliferation and reduced apoptosis in colonic crypts. Female mice consuming soy flour had significantly greater mammary gland tumor incidence compared with those consuming casein-based diets.