Dextran sodium sulfate strongly promotes colorectal carcinogenesis in ApcMin/+ mice: Inflammatory stimuli by dextran sodium sulfate results in development of multiple colonic neoplasms

✍ Scribed by Takuji Tanaka; Hiroyuki Kohno; Rikako Suzuki; Kazuya Hata; Shigeyuki Sugie; Naoko Niho; Katsuhisa Sakano; Mami Takahashi; Keiji Wakabayashi

• Publisher: John Wiley and Sons
• Year: 2005
• Tongue: French
• Weight: 623 KB
• Volume: 118
• Category: Article
• ISSN: 0020-7136
• DOI: 10.1002/ijc.21282

✦ Synopsis

Abstract

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.