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 constitu tive activation of RTKs, but the mechanism of that activation has been unce rtain. 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 tu morigenic. Transgenic mice that overexpressed Met in hepatocytes developed hepatocellular carcinoma (HCC), one of the human tumors in which Met has be en implicated previously. The tumorigenic Met was activated by cell attachm ent rather than by ligand. Inactivation of the transgene led to regression of even highly advanced tumors, apparently mediated by apoptosis and cessat ion of cellular proliferation. These results reveal a previously unapprecia ted mechanism by which the tumorigenic action of RTKs can be mediated, prov ide evidence that Met may play a role in both the genesis and maintenance o f HCC, and suggest that Met may be a beneficial therapeutic target in tumor s that overexpress the receptor.