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Crucial involvement of the CCL3‐CCR5 axis‐mediated fibroblast accumulation in colitis‐associated carcinogenesis in mice
Author(s) -
Sasaki Soichiro,
Baba Tomohisa,
Shinagawa Kei,
Matsushima Kouji,
Mukaida Naofumi
Publication year - 2014
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.28779
Subject(s) - azoxymethane , ccl3 , colitis , cancer research , fibroblast , chemokine , colorectal cancer , carcinogenesis , fibroblast growth factor , chemistry , immunology , biology , medicine , inflammation , receptor , cancer , in vitro , ccl2 , biochemistry
Patients with inflammatory bowel diseases often develop colon carcinoma. Combined treatment of azoxymethane (AOM) and dextran sulfate sodium (DSS) recapitulates colitis‐associated cancer in mice. AOM/DSS‐induced tumor formation was reduced in CCL3 ‐ or its specific receptor, CCR5 ‐deficient mice despite the presence of a massive infiltration of inflammatory cells. However, AOM/DSS‐induced type I collagen‐positive fibroblast accumulation in the colon was reduced in CCL3‐ or CCR5 ‐deficient mice. This was associated with depressed expression of heparin‐binding epidermal growth factor‐like growth factor (HB‐EGF), which is expressed mainly by fibroblasts. Moreover in vitro, CCL3 induced fibroblasts to proliferate and to enhance HB‐EGF expression. Furthermore, CCR5 blockade reduced tumor formation together with reduced fibroblast accumulation and HB‐EGF expression, even when administered after the development of multiple colon tumors. Thus, CCL3‐CCR5‐mediated fibroblast accumulation may be required, in addition to leukocyte infiltration, to induce full‐blown colitis‐associated carcinogenesis. Our studies shed light on a therapeutic potential of CCR5 antagonist for patients with colitis‐associated cancer.