Ligand-independent activation of c-Met by fibronectin and α(5)β(1)-integrin regulates ovarian cancer invasion and metastasis

Oncogene. 2011 Mar 31;30(13):1566-76. doi: 10.1038/onc.2010.532. Epub 2010 Nov 29.

Abstract

The role of the fibronectin receptor, α(5)β(1)-integrin, as an adhesion receptor and in angiogenesis is well established. However, its role in cancer cell invasion and metastasis is less clear. We describe a novel mechanism by which fibronectin regulates ovarian cancer cell signaling and promotes metastasis. Fibronectin binding to α(5)β(1)-integrin led to a direct association of α(5)-integrin with the receptor tyrosine kinase, c-Met, activating it in a hepatocyte growth factor/scatter factor (HGF/SF) independent manner. Subsequently, c-Met associated with Src, and activated Src and focal adhesion kinase (FAK). Inhibition of α(5)β(1)-integrin decreased the phosphorylation of c-Met, FAK and Src, both in vitro and in vivo. Independent activation of c-Met by its native ligand, HGF/SF, or overexpression of a constitutively active FAK in HeyA8 cells could overcome the effect of α(5)β(1)-integrin inhibition on tumor cell invasion, indicating that α(5)β(1)-integrin is upstream of c-Met, Src and FAK. Inhibition of α(5)β(1)-integrin on cancer cells in two xenograft models of ovarian cancer metastasis resulted in a significant decrease of tumor burden, which was independent of the effect of α(5)β(1)-integrin on angiogenesis. These data suggest that fibronectin promotes ovarian cancer invasion and metastasis through an α(5)β(1)-integrin/c-Met/FAK/Src-dependent signaling pathway, transducing signals through c-Met in an HGF/SF-independent manner.

Publication types

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

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Female
  • Fibronectins / physiology*
  • Focal Adhesion Kinase 1 / metabolism
  • Humans
  • Integrin alpha5beta1 / physiology*
  • Ligands
  • Mice
  • Neoplasm Invasiveness
  • Neoplasm Metastasis
  • Neovascularization, Pathologic / etiology
  • Ovarian Neoplasms / blood supply
  • Ovarian Neoplasms / pathology*
  • Phosphorylation
  • Proto-Oncogene Proteins c-met / physiology*
  • Signal Transduction
  • src-Family Kinases / metabolism

Substances

  • Fibronectins
  • Integrin alpha5beta1
  • Ligands
  • Proto-Oncogene Proteins c-met
  • Focal Adhesion Kinase 1
  • PTK2 protein, human
  • src-Family Kinases