Ligand-independent activation of c-Met by fibronectin and α(5)β(1)-integrin regulates ovarian cancer invasion and metastasis.
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.
Department of Obstetrics and Gynecology, Section of Gynecologic Oncology, Center for Integrative Science, University of Chicago, Chicago, IL 60637, USA.
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Mitra
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Sawada
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Tiwari
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Mui
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Gwin
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Lengyel
D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D005353:Fibronectins / Q000502:physiology*; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism; D006801:Humans; D039081:Integrin alpha5beta1 / Q000502:physiology*; D008024:Ligands; D051379:Mice; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic / Q000209:etiology; D010051:Ovarian Neoplasms / Q000098:blood supply / Q000473:pathology*; D010766:Phosphorylation; D019859:Proto-Oncogene Proteins c-met / Q000502:physiology*; D015398:Signal Transduction; D019061:src-Family Kinases / Q000378:metabolism
D005353:Fibronectins; D039081:Integrin alpha5beta1; D008024:Ligands; D019859:Proto-Oncogene Proteins c-met; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; D019061:src-Family Kinases