Unique histopathological features of dextran sulfate sodium-induced colonic lesions in p53 deficient mice

Proc Amer Assoc Cancer Res, Volume 46, 2005 6067 Ulcerative colitis (UC) is associated with an increased risk of colorectal cancer (CRC), which evolves from dysplasia. Although the molecular events required for UC associated CRC formation remain to be established, recent data suggest that this pathway differs from that of sporadic CRC. In particular, mutation of the p53 gene appears to be an early event in UC associated CRC as is evident from the presence of mutant p53 in non-neoplastic inflamed colonic mucosa. In addition, 70-80% of UC associated CRCs possess mutant p53 while only 27% have APC mutations. However, there are no mouse models that recapitulate the genetic and histopathological changes seen in human UC associated CRC. The dextran sulfate sodium (DSS) model of induced colitis provides a unique opportunity to evaluate the spectrum of histological changes that lead to the development of UC and subsequent dysplasia and CRC similar to UC in humans. To determine the function of p53 in UC associated dysplasia/cancers, p53 wild-type and deficient (p53+/− and p53-/-) mice were treated with 3 cycles of DSS, with each cycle consisting of 4% DSS in the drinking water for 4 days followed by 17 days of untreated water. Animals were allowed to live an additional 120 days on untreated water. At the end of the experiment, tissues were evaluated histopathologically and colon tumor incidence was determined. The tumor incidence in DSS-treated p53-/-, p53+/− and p53+/+ mice was 62%, 19% and 19%, respectively. Tumors were classified pathologically as dysplasia (flat or polypoid, low or high grade) or cancer (defined as invasion of cancer cells into the submucosa or beyond, flat or polypoid). Several important pathological features were observed in these mice. First, colon cancers were found in DSS-treated p53+/− and p53-/- mice, but not in p53+/+ mice. Second, DSS-treated p53+/− mice exhibited predominantly polypoid colonic dysplasia/cancers (polypoid vs. flat, 91% vs. 9%, respectively). In contrast, DSS-treated p53-/- mice exhibited predominantly flat dysplasia/cancers (flat vs. polypoid, 77% vs. 23%, respectively). Third, 29% of the colon cancers identified in p53+/− and p53-/- mice displayed mucinous differentiation, a common characteristic of human UC associated CRC. Fourth, in DSS-treated p53+/− and p53-/- mice, non-neoplastic epithelium and pools of mucin were found in the deeper layers of the bowel wall, similar to human colitis cystica profunda. Although the use of DSS-treated p53 deficient mice as a model for human UC associated CRC has been reported previously by Fujii et al. (2004), we report a much higher incidence of invasive CRC and additional relevant unique features that were not observed in their model. These data indicate that treatment of p53 deficient mice with DSS produces UC associated colorectal dysplasia/cancers with features similar to those of human UC associated CRC. (Supported by NIH R03 CA099122 and an ACS Institutional Research Grant).