Regulation of angiogenesis by scatter factor

Abstract

Scatter factor (SF, hepatocyte growth factor) is a cytokine that stimulates motility, proliferation, and morphogenesis of epithelia. These responses are transduced through a tyrosine kinase receptor that is encoded by a proto-oncogene (c-met). SF is a potent angiogenic molecule, and its angiogenic activity is mediated, in part, through direct actions on endothelial cells. These include stimulation of cell motility, proliferation, protease production, invasion, and organization into capillary-like tubes. SF also stimulates the proliferation of smooth muscle cells and pericytes, cell types that also participate in the formation of capillaries and other microvessels. SF is chronically overexpressed in tumors, and it is postulated SF may function as a tumor angiogenesis factor. SF production in tumors may be due, in part, to an abnormal tumor: stroma interaction in which tumor cells secrete soluble proteins (SF-inducing factors) that stimulate stromal cell SF production and in part to autocrine production by the tumor cells themselves. Recent studies suggest a linkage between tumor suppressors (anti-oncogenes) and inhibition of angiogenesis. We hypothesize that tumor suppressor gene mutations may contribute to activation of an SF-->c-met signalling pathway, leading to an invasive and angiogenic tumor phenotype. Modulation of this pathway may provide clinically useful methods of enhancing or inhibiting angiogenesis.