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

Oncogene volume 30, pages 1566–1576 (2011)Cite this article

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Abstract

The role of the fibronectin receptor, α5β1-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 α5β1-integrin led to a direct association of α5-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 α5β1-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 α5β1-integrin inhibition on tumor cell invasion, indicating that α5β1-integrin is upstream of c-Met, Src and FAK. Inhibition of α5β1-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 α5β1-integrin on angiogenesis. These data suggest that fibronectin promotes ovarian cancer invasion and metastasis through an α5β1-integrin/c-Met/FAK/Src-dependent signaling pathway, transducing signals through c-Met in an HGF/SF-independent manner.

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Acknowledgements

We thank Dr Alan Horwitz, Department of Cell Biology, University of Virginia School of Medicine for providing us with the FAK constructs. We thank Gail Isenberg for critically reviewing the manuscript. We appreciate the inputs of Dr Vinay Bhaskar and Dr Vanitha Ramakrishnan during the initial part of the project. Funding: Ernst Lengyel holds a Clinical Scientist Award in Translational Research from the Burroughs Wellcome Fund and is supported by grants from the Ovarian Cancer Research Fund (Liz Tilberis Scholars Program), and the NCI (RO1 CA111882).

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  1. Department of Obstetrics and Gynecology, Section of Gynecologic Oncology, Center for Integrative Science, University of Chicago, Chicago, IL, USA

    A K Mitra, K Sawada, P Tiwari, K Mui & E Lengyel

  2. Pathology, University of Chicago, Chicago, IL, USA

    K Gwin

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  1. A K Mitra
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Correspondence to E Lengyel.

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Facet Biotech Corp. provided funding and antibodies for the animal experiments (Figure 1).

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Mitra, A., Sawada, K., Tiwari, P. et al. Ligand-independent activation of c-Met by fibronectin and α5β1-integrin regulates ovarian cancer invasion and metastasis. Oncogene 30, 1566–1576 (2011). https://doi.org/10.1038/onc.2010.532

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