Abstract 4374: Plant stanols induce the formation of intestinal adenomas and activate ERK1 signaling in the ApcMin/+ mouse

Abstract

Abstract Introduction The incidence of colorectal cancer (CRC) has been increasing in many Western countries for several decades. Diet rich in plant foods is known to decrease CRC risk, whereas high intake of fat and cholesterol is associated with an increased risk. Plant sterols have been shown to inhibit colon cancer cell growth in vitro (Awad et al. 1996, Choi et al. 2003). The ApcMin/+ mouse carries a heterozygous germ line mutation in the Apc tumour suppressor gene. The homologous gene is mutated in patients with hereditary colon cancer (FAP, familial adenomatosis polyposis). In the ApcMin/+ mouse, the loss of heterozygosity in Apc allele activates the Wnt/Tcf-pathway which leads to accumulation of β-catenin in the cytosol and its translocation to the cell nucleus. β-Catenin acts as a transcription factor for several genes (e.g. cyclin D1, c-myc) and enhances cell proliferation. ApcMin/+ mice develop dozens of adenomas in the small intestine. The aim of this study was to investigate the effect of plant stanol feeding on adenoma formation and cell signaling in ApcMin/+ mice. The sterol composition of the intestinal mucosa was also analyzed. Materials and methods ApcMin/+ mice were fed either a 0.8% (w/w) plant stanol diet (n=14) or a control diet without plant stanols (n=14). Plant stanols were added to the experimental diet in the form of freeze-dried products with plant stanol ester enrichment. The level of cyclin D1, phosphorylated and total ERK1/2 (extracellular signal regulated kinase) were analyzed from the normal appearing intestinal mucosa by Western blot. Cholesterol, plant sterols (sitosterol, campesterol) and stanols (sitostanol, campestanol) were isolated from the intestinal mucosa by direct saponification method and analyzed by gas chromatography. Results The number of small intestinal adenomas was significantly increased by plant stanol feeding (p=0.002). Plant stanols induced adenoma formation by over 60% compared to the control group. No difference in the size of intestinal adenomas was seen. Plant stanol feeding increased the level of activated ERK1 (the ratio of phosphorylated p44 to total p44) and nuclear cyclin D1 in the intestinal mucosa (p=0.024 and p=0.038, respectively). The level of mucosal cholesterol was not affected by plant stanol feeding; however, the level of sitosterol and campesterol were decreased (p<0.001 for both) and sitostanol and campestanol increased (p<0.001 for both) in the intestinal mucosa of plant stanol fed ApcMin/+ mice. The number of intestinal adenomas and the level of mucosal plant sterols appear to have a negative correlation (rs=-0.517; p=0.007). References Awad et al. Anticancer Res 1996;16:2797-2804. Choi et al. Int J Oncol 2003;23:1657-62. 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 4374.