Activation of the Met receptor by cell attachment induces and sustains hepatocellular carcinomas in transgenic mice.
Overexpression is the most common abnormality of receptor tyrosine kinases (RTKs) in human tumors. It is presumed that overexpression leads to constitutive activation of RTKs, but the mechanism of that activation has been uncertain. Here we show that overexpression of the Met RTK allows activation of the receptor by cell attachment and that this form of activation can be tumorigenic. Transgenic mice that overexpressed Met in hepatocytes developed hepatocellular carcinoma (HCC), one of the human tumors in which Met has been implicated previously. The tumorigenic Met was activated by cell attachment rather than by ligand. Inactivation of the transgene led to regression of even highly advanced tumors, apparently mediated by apoptosis and cessation of cellular proliferation. These results reveal a previously unappreciated mechanism by which the tumorigenic action of RTKs can be mediated, provide evidence that Met may play a role in both the genesis and maintenance of HCC, and suggest that Met may be a beneficial therapeutic target in tumors that overexpress the receptor.
Wang
R
R
G.W. Hooper Foundation and Department of Microbiology and Immunology, University of California at San Francisco, San Francisco, CA 94143, USA. rwang@cgl.ucsf.edu
Ferrell
L D
LD
Faouzi
S
S
Maher
J J
JJ
Bishop
J M
JM
D000818:Animals; D017209:Apoptosis; D006528:Carcinoma, Hepatocellular / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D002448:Cell Adhesion; D002455:Cell Division; D002470:Cell Survival; D002478:Cells, Cultured; D004318:Doxycycline / Q000494:pharmacology; D004789:Enzyme Activation; D006367:HeLa Cells; D017228:Hepatocyte Growth Factor / Q000494:pharmacology; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008024:Ligands; D051379:Mice; D008822:Mice, Transgenic; D010766:Phosphorylation; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D019076:Transgenes / Q000235:genetics; D014407:Tumor Cells, Cultured
D008024:Ligands; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met; D004318:Doxycycline