Mouse strain differences in inflammatory responses of colonic mucosa induced by dextran sulfate sodium cause differential susceptibility to PhIP-induced large bowel carcinogenesis.
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.
Nakanishi
Masako
M
Biochemistry Division, National Cancer Center Research Institute, 5-1-1 Tsukiji, Tokyo 104-0045, Japan.
Tazawa
Hiroshi
H
Tsuchiya
Naoto
N
Sugimura
Takashi
T
Tanaka
Takuji
T
Nakagama
Hitoshi
H
D000230:Adenocarcinoma / Q000139:chemically induced* / Q000209:etiology; D000818:Animals; D015197:Carcinogenicity Tests; D002273:Carcinogens / Q000633:toxicity; D003043:Cocarcinogenesis; D003092:Colitis / Q000139:chemically induced*; D003106:Colon / Q000187:drug effects / Q000276:immunology; D003110:Colonic Neoplasms / Q000139:chemically induced* / Q000209:etiology; D016264:Dextran Sulfate / Q000008:administration & dosage / Q000633:toxicity*; D004198:Disease Susceptibility; D007093:Imidazoles / Q000008:administration & dosage / Q000633:toxicity*; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008815:Mice, Inbred Strains; D013045:Species Specificity; D013997:Time Factors
D002273:Carcinogens; D007093:Imidazoles; D016264:Dextran Sulfate; C049584:2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine