Hepatocyte growth factor/scatter factor mediates angiogenesis through positive VEGF and negative thrombospondin 1 regulation

Proc Natl Acad Sci U S A. 2003 Oct 28;100(22):12718-23. doi: 10.1073/pnas.2135113100. Epub 2003 Oct 10.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiogenesis Inhibitors / pharmacology*
  • Breast Neoplasms
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Hepatocyte Growth Factor / pharmacology*
  • Humans
  • Kinetics
  • Leiomyosarcoma
  • Neovascularization, Pathologic / pathology*
  • Neovascularization, Pathologic / prevention & control*
  • Thrombospondin 1 / genetics*
  • Time Factors
  • Transfection
  • Tumor Cells, Cultured
  • Vascular Endothelial Growth Factor A / genetics*


  • Angiogenesis Inhibitors
  • Thrombospondin 1
  • Vascular Endothelial Growth Factor A
  • Hepatocyte Growth Factor