Premium
Dextran sodium sulfate strongly promotes colorectal carcinogenesis in Apc Min/+ mice: Inflammatory stimuli by dextran sodium sulfate results in development of multiple colonic neoplasms
Author(s) -
Tanaka Takuji,
Kohno Hiroyuki,
Suzuki Rikako,
Hata Kazuya,
Sugie Shigeyuki,
Niho Naoko,
Sakano Katsuhisa,
Takahashi Mami,
Wakabayashi Keiji
Publication year - 2005
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.21282
Subject(s) - adenomatous polyposis coli , nitrotyrosine , nitric oxide synthase , familial adenomatous polyposis , azoxymethane , colitis , medicine , colorectal cancer , pathology , microbiology and biotechnology , biology , endocrinology , cancer research , nitric oxide , cancer
The mouse model for familial adenomatous polyposis, Apc Min /+ mouse, contains a truncating mutation in the Apc gene and spontaneously develops numerous adenomas in the small intestine but few in the large bowel. Our study investigated whether dextran sodium sulfate (DSS) treatment promotes the development of colonic neoplasms in Apc Min /+ mice. Apc Min /+ and Apc +/+ mice of both sexes were exposed to 2% dextran sodium sulfate in drinking water for 7 days, followed by no further treatment for 4 weeks. Immunohistochemistry for cyclooxygenase‐2, inducible nitric oxide synthase, β‐catenin, p53, and nitrotyrosine, and mutations of β‐ catenin and K‐ ras and loss of wild‐type allele of the Apc gene in the colonic lesions were examined. Sequential observation of female Apc Min /+ mice that received DSS was also performed up to week 5. At week 5, numerous colonic neoplasms developed in male and female Apc Min /+ mice but did not develop in Apc +/+ mice. Adenocarcinomas developed in Apc Min /+ mice that received DSS showed loss of heterozygosity of Apc and no mutations in the β‐ catenin and K‐ ras genes. The treatment also significantly increased the number of small intestinal polyps. Sequential observation revealed increase in the incidences of colonic neoplasms and dysplastic crypts in female Apc Min /+ mice given DSS. DSS treatment increased inflammation scores, associated with high intensity staining of β‐catenin, cyclooxygenase‐2, inducible nitric oxide synthase and nitrotyrosine. Interestingly, strong nuclear staining of p53 was specifically observed in colonic lesions of Apc Min /+ mice treated with DSS. Our results suggest a strong promotion effect of DSS in the intestinal carcinogenesis of Apc Min /+ mice. The findings also suggest that strong oxidative/nitrosative stress caused by DSS‐induced inflammation may contribute to the colonic neoplasms development. © 2005 Wiley‐Liss, Inc.