Cancer-Associated Fibroblasts Are Activated in Incipient Neoplasia to Orchestrate Tumor-Promoting Inflammation in an NF-kappaB-Dependent Manner

Cancer Cell. 2010 Feb 17;17(2):135-47. doi: 10.1016/j.ccr.2009.12.041. Epub 2010 Feb 4.

Abstract

Cancer-associated fibroblasts (CAFs) support tumorigenesis by stimulating angiogenesis, cancer cell proliferation, and invasion. We demonstrate that CAFs also mediate tumor-enhancing inflammation. Using a mouse model of squamous skin carcinogenesis, we found a proinflammatory gene signature in CAFs isolated from dysplastic skin. This signature was maintained in CAFs from subsequent skin carcinomas and was evident in mammary and pancreatic tumors in mice and in cognate human cancers. The inflammatory signature was already activated in CAFs isolated from the initial hyperplastic stage in multistep skin tumorigenesis. CAFs from this pathway promoted macrophage recruitment, neovascularization, and tumor growth, activities that are abolished when NF-kappaB signaling was inhibited. Additionally, we show that normal dermal fibroblasts can be "educated" by carcinoma cells to express proinflammatory genes.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinoma, Pancreatic Ductal / blood supply
  • Carcinoma, Pancreatic Ductal / genetics
  • Carcinoma, Pancreatic Ductal / immunology
  • Carcinoma, Pancreatic Ductal / pathology
  • Carcinoma, Squamous Cell / blood supply
  • Carcinoma, Squamous Cell / genetics
  • Carcinoma, Squamous Cell / immunology
  • Carcinoma, Squamous Cell / pathology
  • Female
  • Fibroblasts / pathology
  • Fibroblasts / physiology*
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Inflammation Mediators / metabolism*
  • Mammary Neoplasms, Experimental / blood supply
  • Mammary Neoplasms, Experimental / genetics
  • Mammary Neoplasms, Experimental / immunology
  • Mammary Neoplasms, Experimental / pathology
  • Mice
  • Mice, Transgenic
  • NF-kappa B / physiology*
  • Neoplasms / blood supply
  • Neoplasms / genetics*
  • Neoplasms / immunology
  • Neoplasms / pathology
  • Neovascularization, Pathologic
  • Skin Neoplasms / blood supply
  • Skin Neoplasms / genetics
  • Skin Neoplasms / immunology
  • Skin Neoplasms / pathology
  • Uterine Cervical Neoplasms / blood supply
  • Uterine Cervical Neoplasms / genetics
  • Uterine Cervical Neoplasms / immunology
  • Uterine Cervical Neoplasms / pathology

Substances

  • Inflammation Mediators
  • NF-kappa B

Associated data

  • GEO/GSE17817