The effects of apc mutation, vitamin d signaling, and colitis on colon crypt dynamics

Robert L Johnson, Purdue University

Abstract

Human colorectal cancer is one of the most common malignancies in humans, particularly in the Western hemisphere. As such, there is an urgent need for research to improve our ability to effectively prevent the disease. The Vogelstein model of colorectal cancer describes the sequential accumulation of genetic mutations that drive the initiation and progression of colorectal cancer from adenoma to carcinoma. The very first step in the Vogelstein model predicts that the biology of normal colonic epithelial cells is modulated by various genetic or environmental factors that place the colonic mucosa at risk for the acquisition of mutations that lead to neoplastic transformation. In order to prevent colorectal cancer, it is imperative that we understand the mechanisms that lead to this "mucosa at risk" and how potential interventions impact this process. In the studies reported here, we used the C57BL/6-Tg( Car1-cre)5Flt transgenic (CAC) mouse model to investigate the effects and interactions between three known colorectal cancer risk factors: Apc mutation, vitamin D signaling, and inflammatory bowel disease. For colorectal cancer, it is becoming clear that mechanisms driving neoplastic transformation are occurring in the stem cells and early progenitor cells found within the proliferative compartment of the colonic crypt. We showed that conditional deletion of vitamin D receptor (Vdr) from large intestinal epithelial cells did not expand the crypt proliferative compartment or DCLK1 positive stem cells. Mutation of a single Apc allele from colonic epithelial cells only expanded the proliferative compartment within normal and mildly dysplastic crypts subjected to an inflammatory environment using the dextran sulfate sodium (DSS) inflammatory bowel disease model. Contrary to our hypothesis, this expansion of the proliferative compartment was accompanied by a decrease in putative intestinal stem cells marked by DCLK1. Finally we showed that feeding a low VD diet to mice with a single Apc allele mutation increased the severity of DSS-colitis and prolonged the recovery of the large intestinal epithelium, which may increase the risk that these epithelial cells will acquire cancer causing mutations.

Degree

Ph.D.

Advisors

Snyder, Purdue University.

Subject Area

Molecular biology|Pathology|Oncology

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