Hepatocyte growth factor / scatter factor (HGF / SF), acting through the Met
receptor, plays an important role in most human
solid tumors and inappropriate expression of this ligand-
receptor pair is often associated with
poor prognosis. The molecular basis for the malignant activity imparted by signaling of HGF / SF-Met in
cancer cells has been attributed to its mitogenic and invasive properties. However, HGF / SF also induces
angiogenesis, but the signaling mechanism has not been understood, nor has this activity been directly associated with HGF / SF-Met mediated tumorigenesis. HGF / SF induces expression
in vitro of VEGF, a key
agonist of
tumor angiogenesis. By contrast,
thrombospondin-1 (TSP-1) is a
negative regulator of
angiogenesis. This application discloses that, in the very same
tumor cells, in addition to inducing
VEGF expression, HGF / SF dramatically down regulates TSP-1 expression. TSP shut off plays an important, extrinsic role in HGF / SF-mediated tumor development, as
ectopic expression of TSP-1 markedly inhibited
tumor formation through the suppression of
angiogenesis. While VEGF induced expression is sensitive to inhibitors of several pathways, including MAP
kinase, PI3
kinase and Stat3, TSP-1 shut off by HGF / SF is prevented solely by inhibiting MAP
kinase activation. Thus HGF / SF is a “switch” for turning on angiogenesis. TSP-1 is a useful
antagonist to
tumor angiogenesis, and therefore TSP-1 and
agonist peptides and mimics, as well as inducers of TSP-1, have therapeutic value when used in conjunction with inhibitors of VEGF.