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

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.

• Authors: Masako Nakanishi, Hiroshi Tazawa, Naoto Tsuchiya, Takashi Sugimura, Takuji Tanaka, Hitoshi Nakagama
• Journal: Cancer science (Cancer Sci) Vol. 98 Issue 8 Pg. 1157-63 (Aug 2007) ISSN: 1347-9032 [Print] England
• PMID: 17573895 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Carcinogens
• Imidazoles
• Dextran Sulfate
• 2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine

Topics

• Adenocarcinoma (chemically induced, etiology)
• Animals
• Carcinogenicity Tests
• Carcinogens (toxicity)
• Cocarcinogenesis
• Colitis (chemically induced)
• Colon (drug effects, immunology)
• Colonic Neoplasms (chemically induced, etiology)
• Dextran Sulfate (administration & dosage, toxicity)
• Disease Susceptibility
• Imidazoles (administration & dosage, toxicity)
• Intestinal Mucosa (drug effects, immunology)
• Mice
• Mice, Inbred BALB C
• Mice, Inbred Strains
• Species Specificity
• Time Factors