Cancer-associated fibroblasts lead tumor invasion through integrin-β3-dependent fibronectin assembly

J Cell Biol. 2017 Nov 6;216(11):3509-3520. doi: 10.1083/jcb.201702033. Epub 2017 Sep 20.

Abstract

Cancer-associated fibroblasts (CAFs) are the most abundant cells of the tumor stroma. Their capacity to contract the matrix and induce invasion of cancer cells has been well documented. However, it is not clear whether CAFs remodel the matrix by other means, such as degradation, matrix deposition, or stiffening. We now show that CAFs assemble fibronectin (FN) and trigger invasion mainly via integrin-αvβ3. In the absence of FN, contractility of the matrix by CAFs is preserved, but their ability to induce invasion is abrogated. When degradation is impaired, CAFs retain the capacity to induce invasion in an FN-dependent manner. The level of expression of integrins αv and β3 and the amount of assembled FN are directly proportional to the invasion induced by fibroblast populations. Our results highlight FN assembly and integrin-αvβ3 expression as new hallmarks of CAFs that promote tumor invasion.

Publication types

  • Video-Audio Media
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cancer-Associated Fibroblasts / metabolism*
  • Cancer-Associated Fibroblasts / pathology
  • Cell Communication*
  • Cell Line, Tumor
  • Cell Movement*
  • Coculture Techniques
  • Colonic Neoplasms / metabolism*
  • Colonic Neoplasms / pathology
  • Extracellular Matrix / metabolism*
  • Fibronectins / metabolism*
  • Integrin alphaV / genetics
  • Integrin alphaV / metabolism
  • Integrin alphaVbeta3 / genetics
  • Integrin alphaVbeta3 / metabolism
  • Integrin beta3 / metabolism*
  • Mice
  • Neoplasm Invasiveness
  • Proteolysis
  • RNA Interference
  • Signal Transduction
  • Transfection
  • Tumor Cells, Cultured

Substances

  • Fibronectins
  • ITGB3 protein, human
  • Integrin alphaV
  • Integrin alphaVbeta3
  • Integrin beta3