Ligand-independent activation of c-Met by fibronectin and α5β1-integrin regulates ovarian cancer invasion and metastasis

AK Mitra, K Sawada, P Tiwari, K Mui, K Gwin… - Oncogene, 2011 - nature.com
AK Mitra, K Sawada, P Tiwari, K Mui, K Gwin, E Lengyel
Oncogene, 2011nature.com
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 …
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.
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