Role for epithelial dysregulation in early-onset colitis-associated colon cancer in Gi2-alpha-/- mice.

Colorectal cancer (CRC) is a feared complication of chronic inflammatory bowel disease (IBD), a condition that affects nearly half a million patients in the U.S. Although IBD-associated CRC shares some of the same genetic alterations seen in sporadic CRCs, there are differences in the timing and nature of these changes, including earlier loss of heterozygosity at the p53 locus and a lower incidence of ras mutations (reviewed in Ref. 1). There are important clinical and histopathological differences between sporadic and IBD-associated CRC as well (reviewed in Ref. 2). In the latter there is a greater incidence of right-sided/proximal bowel cancers, particularly in Crohn’s disease (CD).3 The incidence of tumors with mucinous differentiation is also higher in IBD patients, as is the likelihood of multiple synchronous malignancies4 and the presence of areas of flat dysplasia. On these grounds, IBD-associated colon cancer appears to be a distinct entity from sporadic colon cancer. Of the mediators that have been shown to be important in the regulation of mucosal immunity as well as carcinogenesis, the arachidonic acid (AA)-COX-PGE2 axis is particularly well studied. The role of PGE2 is controversial in IBD; PGE2 levels are commonly upregulated in diseased colonic mucosa, yet COX inhibition (and thus PGE2 production) following nonsteroidal antiinflammatory (NSAID) use is strongly associated with relapse and worsening of symptoms.5 While there is a great deal of evidence that COX inhibitors inhibit polyp growth and decrease the relative risk of developing sporadic colon cancers,6 the data are considerably less clear in IBD-associated carcinogenesis. Some studies have shown a benefit in ulcerative colitis (UC) patients,7 while other studies show no preventative benefit of NSAID use by patients.8–10 We have previously shown that Gi2-alpha−/− mice develop cancer despite lower colonic mucosal PGE2 levels, even in the setting of inflammation.11 IBD-associated carcinogenesis therefore appears to be less dependent on the COX-PGE2 pathway. Although there is great interest in the mechanisms underlying IBD-associated colon cancer, efforts have been impeded by a relative lack of suitable animal models. Mice on a 129Sv/C57 background that lack the G-protein alpha subunit Gi2-alpha spontaneously develop colitis starting at 6–8 weeks of age. During the initial characterization of Gi2-alpha−/− mice,12 it was noted that a subset of animals (8/26, or 31%) developed adenocarcinomas of the colon. However, the natural history and histopathologic features of cancer in Gi2-alpha−/− mice have not been completely enumerated, and it is not clear whether loss of Gi2-alpha signaling has a direct or indirect effect on the epithelium that may contribute to carcinogenesis. We tested the hypothesis that the loss of Gi2-alpha signaling would directly affect the balance of growth and apoptosis in the colonic epithelium, independent of the influence of other cell types or mediators. In this study we evaluated the natural history of colitis and colon cancer and studied whether known defects in arachidonic acid metabolism in the absence of Gi2-alpha are conserved in colonic epithelia, and whether the lack of Gi2-alpha signaling directly affects the balance of growth and apoptosis in colon cancer cells.