Crucial involvement of the CCL3‐CCR5 axis‐mediated fibroblast accumulation in colitis‐associated carcinogenesis in mice

• Published in: International journal of cancer Vol. 135; no. 6; pp. 1297 - 1306
• Main Authors: Sasaki, Soichiro, Baba, Tomohisa, Shinagawa, Kei, Matsushima, Kouji, Mukaida, Naofumi
• Format: Journal Article
• Language: English
• Published: Hoboken, NJ Wiley-Blackwell 15.09.2014; Wiley Subscription Services, Inc
• Subjects: Adenocarcinoma - metabolism; Adenocarcinoma - pathology; Animals; Antagonist drugs; Azoxymethane; Biological and medical sciences; Cancer; Carcinogenesis; Carcinogenesis - metabolism; Carcinogenesis - pathology; CC chemokine receptors; CCL3; CCR5; Chemokine CCL3 - metabolism; Colitis; Colitis - metabolism; Colitis - pathology; Collagen (type I); Colon; Colonic Neoplasms - metabolism; Colonic Neoplasms - pathology; Colorectal cancer; Dextran; Dextran sulfate; Epidermal growth factor; Female; fibroblast; Fibroblasts; Fibroblasts - metabolism; Fibroblasts - pathology; Gastroenterology. Liver. Pancreas. Abdomen; HB‐EGF; Heparin; Infiltration; Inflammatory bowel disease; Inflammatory bowel diseases; Laboratory animals; Medical research; Medical sciences; Metastases; Mice; Mice, Inbred BALB C; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Receptors, CCR5 - metabolism; Rodents; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Studies; Tumors; Rectal disease; HB-EGF; Rodentia; Colorectal cancer; Macrophage inflammatory protein 1alpha; Chemokine receptor; Malignant tumor; CC chemokine; Carcinogenesis; Colonic disease; CCR5 chemokine receptor; Vertebrata; Mammalia; Cancerology; Heparin-binding epidermal growth factor-like growth factor; Mouse; Animal; CCL3; Digestive diseases; Intestinal disease; Colitis; CCR5; Fibroblast; Cancer; colorectal cancer; fibroblast
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.28779

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. What's new? Inflammation of the bowel can lead to cancer, in some cases. By learning how one leads to the other, researchers hope to find a way to stave off this progression. Previously, it's been observed that these cancers have a lot of chemokine CCL3 hanging around. In this paper, the authors replicated these colitis‐induced cancers in mice and investigated what CCL3 was doing. They learned that CCL3 and its receptor, CCR5, gather up cancer‐associated fibroblasts, which promote transformation and tumor growth. Leukocyte infiltration wasn't enough, they found; without CCL3 and CCL5 bringing in fibroblasts, the tumor development slowed.