Ulcerative colitis is associated with an increased risk of colonic dysplasia and progression to invasive colorectal cancer (CRC). Although the molecular events required for tumor 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 colitis-associated CRC as is evident from the presence of p53 mutations in the non-tumor inflamed colon tissue. In addition, 70-80% of colitis-associated CRCs have p53 mutations, but only 27% of them have APC mutations. However, there are no mouse models that recapitulate the genetic and histopathological changes that accompany human colitis-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 colitis and subsequent dysplasia similar to ulcerative colitis in humans. Induction of colitis in p53 mice with DSS should lead to the establishment of an excellent model with which to examine the hypothesis that inflammation-related p53 mutation is an initiating event in CRC associated with colitis. Colitis will be induced in heterozygous p53 mice (p53) by administration 4 cycles of DSS (4 days of 4% DSS followed by 17 days of plain water). The gatekeeper function of the p53 and APC genes in colitis-associated CRC will be determined by mutational analysis of these genes in microdissected inflamed noncancerous colonic epithelial cells. Microarray-based techniques will be utilized to identity early changes in the expression of genes within the inflamed noncancerous colonic epithelium that may serve as molecular targets for chemopreventivc intervention. The effect of a p53 deficiency on both the formation of colitis-associated colorectal dysplasias/cancers and the pathological characteristics of these lesions will be assessed in this mouse model by allowing animals to live for an extended period of time following DSS exposure. Establishment of the first clinically relevant model for ulcerative colitis-associated CRC is anticipated to facilitate the elucidation of the molecular mechanisms of colitis-associated colon tumor formation and the identification of cellular targets for early chemopreventive intervention.
| Clapper, Margie Lee; Cooper, Harry Stanley; Chang, Wen-Chi Lee (2007) Dextran sulfate sodium-induced colitis-associated neoplasia: a promising model for the development of chemopreventive interventions. Acta Pharmacol Sin 28:1450-9 |
| Chang, Wen-Chi L; Coudry, Renata A; Clapper, Margie L et al. (2007) Loss of p53 enhances the induction of colitis-associated neoplasia by dextran sulfate sodium. Carcinogenesis 28:2375-81 |
