PMID- 14555767
OWN - NLM
STAT- MEDLINE
DCOM- 20040105
LR  - 20220310
IS  - 0027-8424 (Print)
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Linking)
VI  - 100
IP  - 22
DP  - 2003 Oct 28
TI  - Hepatocyte growth factor/scatter factor mediates angiogenesis through positive 
      VEGF and negative thrombospondin 1 regulation.
PG  - 12718-23
AB  - 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.
FAU - Zhang, Yu-Wen
AU  - Zhang YW
AD  - Laboratory of Molecular Oncology, Van Andel Research Institute, 333 Bostwick 
      Avenue NE, Grand Rapids, MI 49503, USA.
FAU - Su, Yanli
AU  - Su Y
FAU - Volpert, Olga V
AU  - Volpert OV
FAU - Vande Woude, George F
AU  - Vande Woude GF
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20031010
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (Angiogenesis Inhibitors)
RN  - 0 (Thrombospondin 1)
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - 67256-21-7 (Hepatocyte Growth Factor)
SB  - IM
MH  - Angiogenesis Inhibitors/*pharmacology
MH  - Breast Neoplasms
MH  - Female
MH  - Gene Expression Regulation, Neoplastic/*drug effects
MH  - Hepatocyte Growth Factor/*pharmacology
MH  - Humans
MH  - Kinetics
MH  - Leiomyosarcoma
MH  - Neovascularization, Pathologic/*pathology/*prevention & control
MH  - Thrombospondin 1/*genetics
MH  - Time Factors
MH  - Transfection
MH  - Tumor Cells, Cultured
MH  - Vascular Endothelial Growth Factor A/*genetics
PMC - PMC240684
EDAT- 2003/10/14 05:00
MHDA- 2004/01/06 05:00
PMCR- 2004/04/28
CRDT- 2003/10/14 05:00
PHST- 2003/10/14 05:00 [pubmed]
PHST- 2004/01/06 05:00 [medline]
PHST- 2003/10/14 05:00 [entrez]
PHST- 2004/04/28 00:00 [pmc-release]
AID - 2135113100 [pii]
AID - 10012718 [pii]
AID - 10.1073/pnas.2135113100 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2003 Oct 28;100(22):12718-23. doi: 
      10.1073/pnas.2135113100. Epub 2003 Oct 10.