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

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 a HGF/SF independent manner.

A Highly Potent and Specific MET Therapeutic Protein Antagonist with Both Ligand-Dependent and Ligand-Independent Activity

“…Mitra and colleagues showed that activation of MET by fibronectin and a5b1-integrin regulates ovarian cancer invasion and metastasis (16). They postulate that ligand-independent signaling potentially forms an important first step in ovarian cancer metastasis (16). Dulak and colleagues also describe ligand-independent activation of MET via cooperation with EGFR in non-small cell lung carcinoma, suggesting that lateral communication with MET is required to maximize the tumorigenic impact of EGFR signaling (15).…”

“…Although HGF is a key initiator of MET signaling, recent preclinical data have shown the importance of HGF-independent activation of MET. Mitra and colleagues showed that activation of MET by fibronectin and a5b1-integrin regulates ovarian cancer invasion and metastasis (16). They postulate that ligand-independent signaling potentially forms an important first step in ovarian cancer metastasis (16).…”

“…Dulak and colleagues also describe ligand-independent activation of MET via cooperation with EGFR in non-small cell lung carcinoma, suggesting that lateral communication with MET is required to maximize the tumorigenic impact of EGFR signaling (15). The complexity of ligand-independent MET activation is highlighted by its ability to behave as a promiscuous receptor that can potentially cooperate with many cell surface proteins including Erb3, EGFR, a6b4 integrin, the semaphorin receptors of the plexin B family, and CD44v6 to induce cell signaling or tumorogenesis (15,16,44,45). Optimal therapeutic inhibition of the MET pathway should therefore target both ligand-dependent and ligand-independent mechanisms of MET activation.…”

“…A link between MET pathway dysregulation and poor patient prognosis has been reported for several cancers (8)(9)(10)(11)(12)(13)(14). Apart from ligand-dependent signaling of MET, the pathway can be induced in cancers through MET gene amplification/mutation; receptor overexpression or through cooperation with other membrane bound proteins or receptors to drive HGF-independent tumorigenesis (15,16). Thus, optimal targeting of the pathway benefiting the broadest patient population requires a drug with both ligand-dependent and ligand-independent efficacy.…”

Integrin α5β1 and p53 convergent pathways in the control of anti-apoptotic proteins PEA-15 and survivin in high-grade glioma

“…4 In tumor cells, integrins impact on proliferation/survival, therapy resistances and tumor recurrence. α5β1 integrin has emerged recently and has been shown to participate in aggressiveness of solid tumors [5][6][7][8][9] as reviewed in Schaffner et al 10 High expression of α5 integrin is associated with a decrease in patient overall survival, making α5β1 integrin an important factor in resistance to therapies. Numerous preclinical data support the ability of integrin antagonists to disrupt integrin signaling pathways leading to inhibition of angiogenesis and/or tumor growth but also to sensitization toward therapies.…”