Abstract 2866: Western-type diet accelerates intestinal tumorigenesis in APCmin mice

Abstract

Abstract Lifestyle factors contribute to incidence of colorectal cancer (CRC). Western-type diet (WD) containing considerable amounts of saturated fat, sugar and red meat but little dietary fibre, vitamins, minerals and plant-derived nutrients is associated with elevated CRC risk. We have recently started to investigate the mechanisms explaining these observations using APCmin mice, a model of human familial adenomatous polyposis. METHODS: 12 APCmin mice were fed a WD (modified AIN-93G with high fat, low vitamin D and folate) for 10 weeks, starting at the age of 5 weeks. 14 control APCmin mice were fed the unmodified AIN-93G diet. The mice were sacrificed at the age of 15 weeks. The intestines were removed and opened. Number and size of adenomas were measured by blinded observers using a stereomicroscope. Tissue samples were collected from various locations of the small intestines, where the adenomas occur in this model. Epithelial renewal dynamics was analyzed in histologically normal areas of the mucosa. Paraffin tissue sections were immunostained using markers of cycling cells (Ki67 antigen), actually mitotic cells (phospho-histone H3) and apoptotic cells (cleaved caspase 3). The stained sections were analyzed using the ImageJ analysis software. RESULTS: The average number of adenomas in the small intestine was significantly higher in the WD mice (p=0.002). The average size of adenomas was not statistically different between the two diet groups. The heights of the actively cycling cell compartment (measured from the crypt base to the last Ki67-antigen positive cells in the villi) and the numbers of mitotic cells (measured as phospho-histone H3 positive cell count per area of mucosal base cross-section) were similar in both diet groups. The number of apoptotic cells (measured as cleaved caspase 3 positive bodies per area of intestinal tissue section) was also similar between the groups. CONCLUSIONS: In this model, Western-type diet accelerates tumor initiation but does not affect progression. The accelerated tumor initiation is not caused by changes in the general renewal dynamics of the epithelium, as the proliferation and apoptosis rates are not significantly affected. The results suggest that the epithelial stem or progenitor cells are more specifically targeted. To dissect the underlying mechanisms, we are currently analyzing the inflammatory and metabolic status of the intestinal mucosa. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2866.