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

• Sasaki, Soichiro

• Baba, Tomohisa

• Shinagawa, Kei

• Matsushima, Kouji

• Mukaida, Naofumi

抄録

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. © 2014 UICC.

収録刊行物

• International Journal of Cancer

  International Journal of Cancer 135 (6), 1297-1306, 2014-09-15

  Wiley-Liss

キーワード

• CCL3
• CCR5
• colorectal cancer
• fibroblast
• HB-EGF

詳細情報

• CRID: 1050001335984123904
• NII論文ID: 120005463351
• NII書誌ID: AA11621537
• ISSN: 10970215
• Web Site: http://hdl.handle.net/2297/39054
• 本文言語コード: en
• 資料種別: journal article
• データソース種別:
  • IRDB
  • CiNii Articles