title: Crucial involvement of the CCL3-CCR5 axis-mediated fibroblast accumulation in colitis-associated carcinogenesis in mice.
abstract: 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.
authors: Division of Molecular Bioregulation, Cancer Research Institute, Kanazawa University, Kanazawa, Japan; Japan Science and Technology Agency, Core Research for Evolutionary Science and Technology, Tokyo, Japan.
authors: Soichiro
authors: S
authors: Sasaki
authors: Tomohisa
authors: T
authors: Baba
authors: Kei
authors: K
authors: Shinagawa
authors: Kouji
authors: K
authors: Matsushima
authors: Naofumi
authors: N
authors: Mukaida
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology; D000818:Animals; D063646:Carcinogenesis / Q000378:metabolism* / Q000473:pathology; D054405:Chemokine CCL3 / Q000378:metabolism*; D003092:Colitis / Q000378:metabolism* / Q000473:pathology; D003110:Colonic Neoplasms / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D019713:Receptors, CCR5 / Q000378:metabolism*
chemical_list: C496534:Ccl3 protein, mouse; D054405:Chemokine CCL3; D019713:Receptors, CCR5
keywords: CCL3; CCR5; HB-EGF; colorectal cancer; fibroblast