HGF/SF in angiogenesis

Abstract

Hepatocyte growth factor/scatter factor (HGF/SF) is a mesenchyme-derived cytokine that stimulates motility and invasiveness of epithelial and cancer cells. These responses are transduced through the c-met proto-oncogene product, a transmembrane tyrosine kinase that functions as the HGF/SF receptor. We have shown that HGF/SF is a potent angiogenic molecule and that its angiogenic activity is mediated primarily through direct actions on vascular endothelial cells. These include stimulation of cell migration, proliferation, protease production, invasion, and organization into capillary-like tubes. We further showed that HGF/SF is overexpressed in invasive human cancers, including breast cancer, relative to non-invasive cancers and benign conditions. In invasive breast cancers, the content of HGF/SF is strongly correlated with that of von Willebrand's factor, a marker of vascular endothelial cells. Furthermore, transfection of breast cancer and glioma cell lines with HGF/SF cDNA greatly enhanced the ability of these cells to grow as tumours in orthotopic sites in syngeneic or immunocompromized host animals. The increased growth rate of the HGF/SF-transfected cells was attributable, in part, to increased tumour angiogenesis. These findings suggest that HGF/SF may function as a tumour progression factor, in part by stimulating tumour cell invasiveness and in part by stimulating angiogenesis.