Title

Understanding the promotional effect of deoxycholic acid during colorectal cancer development

Date of Completion

January 2008

Keywords

Biology, Molecular

Degree

Ph.D.

Abstract

Deoxycholic Acid (DCA) has been linked to colorectal cancer (CRC) in humans and shown to increase tumor number in carcinogen exposed-rodents susceptible to developing CRC. However, the effect of DCA on a strain of mouse not sensitive to carcinogen exposure has been unstudied. To determine whether genetic resistance can be overcome by exposure to a dietary tumor promoter, AOM-exposed AKR/J mice were fed a diet containing 0.25% DCA. Mice placed on the DCA diet developed a significantly higher multiplicity of ACF compared to AOM-exposed mice fed a control diet. Interestingly, increased numbers of ACF were associated with the presence of nuclear β-catenin. In an effort to better understand the promotional role of DCA, the cryptal origins of DCA-exposed ACF were examined. Three ACF were serial-sectioned at 1 μm, followed by three-dimensional reconstruction. Under light microscopy, dysplastic cells protruding from the side of a normal-appearing crypt were observed in all ACF examined, in accordance with the budding model. This cryptal region was also found to harbor cells that stained positive for nuclear β-catenin. It is concluded that DCA promotes dysplasia in a resistant strain, potentially through nuclear β-catenin accumulation, and that the dysplasia originates from the middle of the crypt. ^