Tumor necrosis factor receptors play a role in the development of colitis‐mediated colon cancer

Abstract

Individuals with inflammatory bowel disease (IBD) are at greater risk of developing colon cancer. Tumor-necrosis factor (TNF), elevated in IBD, can induce apoptosis in intestinal epithelial cells, therefore we hypothesized mice deficient in TNF receptors, TNFR1 or TNFR2, would be more susceptible to colitis-mediated colon cancer compared to wildtype (WT). Mice (WT, TNFR1−/− and TNFR2−/−) were treated with azoxymethane (AOM), followed by 4 cycles of dextran sulphate sodium (DSS 3% w/v 5 days + 14 days of water) to induce colitis. All mice experienced weight loss and loose stools after DSS. Disease severity did not differ significantly between strains. Control mice treated with DSS or AOM alone did not develop tumors. In WT mice, 6/9 developed tumors. Fewer TNFR1−/− mice (3/9) developed tumors compared to WT while all (7/7) TNFR2−/− mice developed tumors. TNFR1−/− mice had a fewer tumors than WT and TNFR2−/− mice, although tumor size did not differ between groups. Disease severity did not correlate with tumor number nor did inflammation scores differ between mice with or without dysplasia, indicating that the difference in the number of tumors was due to the genotype and not the degree of inflammation. Therefore, the absence of TNFR2, but not TNFR1, increases the susceptibility to tumor development in mice after inflammation. Funded by Dalhousie Cancer Research Program, Nova Scotia Health Research Foundation