FSP1+ fibroblasts promote skin carcinogenesis by maintaining MCP-1-mediated macrophage infiltration and chronic inflammation

Am J Pathol. 2011 Jan;178(1):382-90. doi: 10.1016/j.ajpath.2010.11.017. Epub 2010 Dec 23.

Abstract

Cancer development is often associated with increased fibroblast proliferation and extensive fibrosis; however, the role of fibroblasts during carcinogenesis remains largely unknown. Using the 7,12-dimethylbenz-(a)anthracene and 12-O-tetradecanoylphorbol-13-acetate-induced two-stage skin carcinogenesis model, we demonstrated here that there was a massive accumulation and proliferation of fibroblasts in the skin shortly after application of carcinogen. Selective abatement of these cells during the promotion stage drastically decreased incidence and progression of papillomas. This correlated well with reduced macrophage infiltration and impaired cytokine storm in the affected skin. 12-O-tetradecanoylphorbol-13-acetate stimulated skin fibroblasts, secreting high levels of monocyte chemotactic protein-1, and neutralization of this chemokine eliminated almost completely the fibroblast-induced chemotaxis of macrophages. These results strongly suggest that fibroblasts promote skin tumor development by producing monocyte chemotactic protein-1 and maintaining chronic inflammation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 9,10-Dimethyl-1,2-benzanthracene / toxicity
  • Animals
  • Cell Proliferation
  • Cell Transformation, Neoplastic / chemically induced
  • Cell Transformation, Neoplastic / metabolism
  • Cell Transformation, Neoplastic / pathology*
  • Chemokine CCL2 / metabolism*
  • Chronic Disease
  • Fibroblasts / metabolism*
  • Humans
  • Inflammation / chemically induced
  • Inflammation / pathology*
  • Macrophages / physiology*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Transgenic
  • Skin Neoplasms / chemically induced
  • Skin Neoplasms / pathology*
  • Tetradecanoylphorbol Acetate / toxicity

Substances

  • Chemokine CCL2
  • 9,10-Dimethyl-1,2-benzanthracene
  • Tetradecanoylphorbol Acetate