PMID- 9823327
OWN - NLM
STAT- MEDLINE
DCOM- 19981207
LR  - 20091119
IS  - 0008-5472 (Print)
IS  - 0008-5472 (Linking)
VI  - 58
IP  - 22
DP  - 1998 Nov 15
TI  - c-Met autocrine activation induces development of malignant melanoma and 
      acquisition of the metastatic phenotype.
PG  - 5157-67
AB  - The molecular and genetic events that contribute to the genesis and progression 
      of cutaneous malignant melanoma, a complex and aggressive disease with a high 
      propensity for metastasis, are poorly understood due in large part to the dearth 
      of relevant experimental animal models. Here we used transgenic mice ectopically 
      expressing hepatocyte growth factor/scatter factor (HGF/SF) to show that the Met 
      signaling pathway is an important in vivo regulator of melanocyte function, whose 
      subversion induces malignant melanoma. Tumorigenesis occurred in stages, 
      beginning with the abnormal accumulation of melanocytes in the epidermis and 
      dermis and culminating in the development of metastatic melanoma. Oncogenesis in 
      this model was driven by creation of HGF/SF-Met autocrine loops through forced 
      expression of the transgenic ligand and apparent selection of melanocytes 
      overexpressing endogenous receptor, rather than paracrine stimulation or 
      mutational activation of c-met. Preference for liver as a metastatic target 
      correlated with high HGF/SF-Met autocrine activity, consistent with the notion 
      that such activity may influence colonization. Although basic fibroblast growth 
      factor and its receptor were both weakly expressed in the majority of melanomas 
      examined, high levels were found only in those rare neoplasms with low or 
      undetectable HGF/SF and Met expression, suggesting that these two tyrosine kinase 
      receptor autocrine loops serve a critical overlapping function in melanocytic 
      tumorigenesis. Our data support a causal role for HGF/SF-Met signaling in the 
      development of melanoma and acquisition of the metastatic phenotype. Moreover, 
      this transgenic mouse should serve as a highly useful model, facilitating our 
      understanding of mechanisms by which human melanoma progresses to malignancy and 
      expediting the development of efficacious therapeutic modalities designed to 
      constrain metastasis.
FAU - Otsuka, T
AU  - Otsuka T
AD  - Laboratory of Molecular Biology, National Cancer Institute, Bethesda, Maryland 
      20892-4255, USA.
FAU - Takayama, H
AU  - Takayama H
FAU - Sharp, R
AU  - Sharp R
FAU - Celli, G
AU  - Celli G
FAU - LaRochelle, W J
AU  - LaRochelle WJ
FAU - Bottaro, D P
AU  - Bottaro DP
FAU - Ellmore, N
AU  - Ellmore N
FAU - Vieira, W
AU  - Vieira W
FAU - Owens, J W
AU  - Owens JW
FAU - Anver, M
AU  - Anver M
FAU - Merlino, G
AU  - Merlino G
LA  - eng
GR  - N01-CO-56000/CO/NCI NIH HHS/United States
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  - 0 (Neoplasm Proteins)
RN  - 67256-21-7 (Hepatocyte Growth Factor)
RN  - EC 2.7.10.1 (Proto-Oncogene Proteins c-met)
SB  - IM
MH  - Animals
MH  - Female
MH  - Hepatocyte Growth Factor/*metabolism
MH  - Humans
MH  - Male
MH  - Melanocytes/*metabolism
MH  - Melanoma, Amelanotic/*etiology/*secondary
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Mice, Transgenic
MH  - Neoplasm Proteins/*metabolism
MH  - Proto-Oncogene Proteins c-met/metabolism
MH  - *Signal Transduction
MH  - Skin Neoplasms/*etiology/*pathology
EDAT- 1998/11/21 00:00
MHDA- 1998/11/21 00:01
CRDT- 1998/11/21 00:00
PHST- 1998/11/21 00:00 [pubmed]
PHST- 1998/11/21 00:01 [medline]
PHST- 1998/11/21 00:00 [entrez]
PST - ppublish
SO  - Cancer Res. 1998 Nov 15;58(22):5157-67.