Hepatocyte growth factor/scatter factor mediates angiogenesis through positive VEGF and negative thrombospondin 1 regulation.
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 potential of the HGF/SF-Met signal in cancer cells has mostly been attributed to its mitogenic and invasive properties. However, HGF/SF also induces angiogenesis, but the signaling mechanism has not been fully explained, nor has this activity been directly associated with HGF/SF-Met-mediated tumorigenesis. It is known that HGF/SF induces in vitro expression of vascular endothelial growth factor (VEGF), a key agonist of tumor angiogenesis; by contrast, thrombospondin 1 (TSP-1) is a negative regulator of angiogenesis. Here, we show that, in the very same tumor cells, in addition to inducing VEGF expression, HGF/SF dramatically down-regulates TSP-1 expression. We show that TSP-1 shut-off plays an important, extrinsic role in HGF/SF-mediated tumor development, because ectopic expression of TSP-1 markedly inhibits tumor formation through the suppression of angiogenesis. Interestingly, although VEGF-induced expression is sensitive to inhibitors of several pathways, including mitogen-activated protein kinase, phosphoinositide 3-kinase, and signal transducer and activator of transcription 3, TSP-1 shut-off by HGF/SF is prevented solely by inhibiting mitogen-activated protein kinase activation. These studies identify HGF/SF as a key switch for turning on angiogenesis. They suggest that TSP-1 is a useful antagonist to tumor angiogenesis and that it may have therapeutic value when used in conjunction with inhibitors of VEGF.
Zhang
Yu-Wen
YW
Laboratory of Molecular Oncology, Van Andel Research Institute, 333 Bostwick Avenue NE, Grand Rapids, MI 49503, USA.
Su
Yanli
Y
Volpert
Olga V
OV
Vande Woude
George F
GF
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D001943:Breast Neoplasms; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D017228:Hepatocyte Growth Factor / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D007890:Leiomyosarcoma; D009389:Neovascularization, Pathologic / Q000473:pathology* / Q000517:prevention & control*; D019700:Thrombospondin 1 / Q000235:genetics*; D013997:Time Factors; D014162:Transfection; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics*
D020533:Angiogenesis Inhibitors; D019700:Thrombospondin 1; D042461:Vascular Endothelial Growth Factor A; D017228:Hepatocyte Growth Factor