Mouse strain differences in inflammatory responses of colonic mucosa induced by dextran sulfate sodium cause differential susceptibility to PhIP-induced large bowel carcinogenesis

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Abstract

In mice, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) induces a high incidence of malignant lymphoma and leukemia, but exhibits little, if any, carcinogenic activity in the large intestine after long-term exposure. However, recent studies have revealed that colonic adenocarcinomas can be efficiently and rapidly induced by combined treatment with PhIP and dextran sulfate sodium (DSS), a potent inducer of colitis. In the present study, the authors investigated the effects of inflammation on PhIP-induced carcinogenesis using two mouse strains, C57BL/6J and MSM/Ms, showing distinct temporal profiles of inflammatory responses to DSS. A long-term carcinogenesis experiment conducted with a single i.g. administration of PhIP (200 mg/kg body weight), followed by DSS treatment in drinking water for 4-6 days, revealed an increase in tumor incidence in C57BL/6J mice in accordance with the DSS intake. In contrast, neoplastic lesions were rarely observed in the MSM/Ms strain. From the short-term exposure to DSS for 4 days, C57BL/6J mice demonstrated severe chronic colitis, accompanied by hyperplastic cryptal epithelium and extensive cellular infiltration. Splenomegaly and swelling of mesenteric lymph nodes were also evident for over 1 month as chronic symptoms of systemic immunological disturbance. However, no inflammatory lesions were detected in MSM/Ms mice. The present results provide strong evidence that prolonged chronic inflammatory responses induced by DSS are directly responsible for the observed enhancement of PhIP-induced large bowel carcinogenicity. © 2007 Japanese Cancer Association.

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Nakanishi, M., Tazawa, H., Tsuchiya, N., Sugimura, T., Tanaka, T., & Nakagama, H. (2007). Mouse strain differences in inflammatory responses of colonic mucosa induced by dextran sulfate sodium cause differential susceptibility to PhIP-induced large bowel carcinogenesis. Cancer Science, 98(8), 1157–1163. https://doi.org/10.1111/j.1349-7006.2007.00528.x

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