| Mutations in the adenomatous polyposis coli (Apc) gene have been identified in human colorectal cancer and in familial adenomatous polyposis. The ApcMin (or Min) mouse carries a germline mutation in the Apc gene and develops adenomas in the small intestine and colon, making it an ideal model for the study of intestinal cancers. The purpose of this dissertation was two-fold: (1) to examine the effects of three dietary treatments (food restriction, feeding a defatted flax/whole-wheat-flour based diet, and feeding a black bean-based diet) on tumor multiplicity and growth in small intestine and colon in the Min mouse; (2) to provide, if possible, a molecular basis for the effects observed. The non-steroidal anti-inflammatory drug (NSAID) sulindac was used as the positive control.; The first study demonstrated that dietary treatments could alter intestinal tumorigenesis. Tumor number in the small intestine decreased (P < 0.05) from 76 ± 5.8 in the casein fed control group to 45 ± 5.3 in the sulindac group (42% decrease), 53 ± 5.5 in the flax/wheat group (30% decrease), 55 ± 5.7 in the black bean group (28% decrease) and 48 ± 9.9 in the diet restricted group (36% decrease). Sulindac reduced average small intestine tumor diameter from 1.3 to 1.0 mm (p < 0.01) while black bean and flax/wheat diets increased tumor diameter (p < 0.05). Colon tumor numbers did not differ significantly among groups, but there was an increase in colon tumor size in mice fed black bean and flax/wheat diets compared to the control group.; Since energy restriction in study one had the most dramatic impact on tumor growth, the second study focused on changes in tumor number and size in Min mice after 3, 6 and 10 weeks of 30% energy restriction. Complimentary DNA arrays were used to determine changes in expression of 1,200 mouse genes in small intestinal tumor tissue from mice fed ad libitum or restricted in energy intake. The results indicate a significant inhibition of tumor multiplicity and size in the small intestine after 3, 6 and 10 weeks of energy restriction (p < 0.05). In the colon, the changes in adenoma number and volume caused by energy restriction were not significant. Of 1,200 genes studies, eight were overexpressed (≥1.6 fold) and 13 were underexpressed (≥1.6 fold) in restricted mice in comparison to control mice. In tumors from the energy restricted mice 30% percent of the underexpressed genes were oncogenes and 50% of the overexpressed genes were immune function proteins.; This research clearly demonstrated that energy restriction will inhibit small intestine tumor growth in Min mice. Furthermore, tumors in mice fed fewer calories had reduced expression of oncogenes and increased expression of genes related to immune function. |
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