PMID- 12019177
OWN - NLM
STAT- MEDLINE
DCOM- 20020710
LR  - 20091119
IS  - 0008-5472 (Print)
IS  - 0008-5472 (Linking)
VI  - 62
IP  - 10
DP  - 2002 May 15
TI  - Constitutive c-Met signaling through a nonautocrine mechanism promotes metastasis 
      in a transgenic transplantation model.
PG  - 2951-6
AB  - Normal cells are dependent on exogenous, receptor-mediated growth stimulation for 
      cell cycle entry and progression, providing a critical homeostatic mechanism 
      regulating cellular proliferation. In contrast, tumor cells acquire some degree 
      of growth signal autonomy, often through their ability to produce growth factors 
      as well as their receptors (autocrine signaling). Recently, data have begun to 
      emerge implicating heterotypic signaling between diverse cell types within a 
      tumor in the genesis and progression of cancer; however, current experimental 
      approaches in vivo have not adequately addressed this critical relationship. Here 
      we used transgenic mice overexpressing hepatocyte growth factor/scatter factor 
      (HGF/SF), or its growth antagonist NK2, as genetically modified hosts for 
      transplantation of tumor cells expressing their receptor, c-Met, to directly 
      assess the contribution of heterotypic signaling to metastatic colonization. We 
      demonstrate that metastatic potential under nonautocrine signaling conditions 
      (i.e., where tumor cells expressing c-Met are transplanted into transgenic hosts 
      producing HGF/SF) rivaled that observed under conditions of autocrine signaling 
      (i.e., where tumor cells expressing both HGF/SF and c-Met are transplanted into 
      wild-type hosts). HGF/SF and NK2 were not functionally equivalent in vivo. 
      Attenuation of NK2-associated growth inhibition by the presence of an HGF/SF-Met 
      autocrine loop uncovered a shift in metastatic site preference from lung to liver 
      only in NK2-transgenic hosts, a qualitative behavioral alteration likely 
      detectable only through the genetic approach used here. Our data demonstrate that 
      growth factors not intrinsic to malignant cells can have profound effects on 
      metastatic efficiency in vivo and provide experimental support of a role for 
      heterotypic signaling in tumor progression.
FAU - Yu, Yanlin
AU  - Yu Y
AD  - Molecular Genetics Section, Laboratory of Molecular Biology, National Cancer 
      Institute/NIH, Bethesda, MD 20892-4264, USA.
FAU - Merlino, Glenn
AU  - Merlino G
LA  - eng
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 67256-21-7 (Hepatocyte Growth Factor)
RN  - EC 2.7.10.1 (Proto-Oncogene Proteins c-met)
SB  - IM
MH  - Animals
MH  - Hepatocyte Growth Factor/antagonists & inhibitors/genetics/physiology
MH  - Liver Neoplasms, Experimental/secondary
MH  - Lung Neoplasms/secondary
MH  - Male
MH  - Melanoma, Experimental/genetics/pathology/*secondary
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Nude
MH  - Mice, Transgenic
MH  - Neoplasm Transplantation
MH  - Proto-Oncogene Proteins c-met/genetics/*physiology
MH  - Signal Transduction/physiology
MH  - Transfection
EDAT- 2002/05/23 10:00
MHDA- 2002/07/12 10:01
CRDT- 2002/05/23 10:00
PHST- 2002/05/23 10:00 [pubmed]
PHST- 2002/07/12 10:01 [medline]
PHST- 2002/05/23 10:00 [entrez]
PST - ppublish
SO  - Cancer Res. 2002 May 15;62(10):2951-6.