Activation of the Met Receptor by Cell Attachment Induces and Sustains Hepatocellular Carcinomas in Transgenic Mice

Abstract

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.

Tetraspanin KAI1/CD82 suppresses invasion by inhibiting integrin-dependent crosstalk with c-Met receptor and Src kinases

“…However, expression of CD82 failed to inhibit this signaling pathway, suggesting the possibility that this may be a non-CD82-regulated invasion pathway. Our data support recent evidence for the existence of crosstalk between integrins and c-Met (Wang et al, 1996(Wang et al, , 2001Trusolino et al, 2001). Our data further suggest that CD82 may be regulating this crosstalk.…”

“…Thus our data indicate that in highly invasive cells that adhere, migrate, and invade well on laminin, CD82 expression does not change integrin expression, but rather acts downstream of integrin engagement. c-Met, the receptor for HGF/SF, is known to regulate migration and invasion and has been implicated in promoting metastasis in many different kinds of cancers (Pisters et al, 1995;Birchmeier et al, 1997Birchmeier et al, , 2003Wang et al, 2001), including prostate cancer (Humphrey et al, 1995;Nishimura et al, 1998;Knudsen et al, 2002;van Leenders et al, 2002;Nakashiro et al, 2003;Knudsen and Edlund, 2004). Previous studies in a mammary tumor cell line demonstrated that CD82 expression attenuated EGF-mediated EGFR signaling and reduced migration (Odintsova et al, 2000).…”

“…Both integrins and receptor tyrosine kinases are involved in cell migration and metastasis. Furthermore, integrins have been shown to activate several receptor tyrosine kinases in a ligandindependent manner, including EGFR, c-Met, PDGFR, and Ron (Sundberg and Rubin, 1996;Wang et al, 1996Wang et al, , 2001Moro et al, 1998Moro et al, , 2002Danilkovitch-Miagkova et al, 2000;Bill et al, 2004). Both integrins and receptor tyrosine kinases can interact with CD82 (Hemler, 1998;Odintsova et al, 2000).…”

hgf/c‐met expression and functional analysis during zebrafish embryogenesis

“…c-MET was initially identified as an oncogene expressed by a transformed human osteogenic sarcoma cell line (Cooper et al, 1984). Since then, strong evidence of a role for MET signaling in human cancer has come from work in cell culture models (Maulik et al, 2002), mice (Takayama et al, 1997;Wang et al, 2001), and humans with sporadic and hereditary forms of renal carcinoma, where germline and somatic missense mutations were identified in MET's kinase domain (Schmidt et al, 1997(Schmidt et al, , 1998. In addition to tumorigenesis, MET activity plays a significant role in promoting tumor cell invasion and metastasis (Rong et al, 1994;Ma et al, 2003).…”

Hydrogen ion dynamics and the Na+/H+ exchanger in cancer angiogenesis and antiangiogenesis

“…The trans-activation of growth factor receptors by integrins is an emerging field. Recently, an interesting study showed that cell adhesion, presumably through integrins, activates the human HGF receptor, c-Met, while overexpression of c-Met in hepatocytes resulted in hepatocellular carcinoma in mice (Wang et al, 2001). Most significantly, this effect of c-Met is independent of binding of HGF, suggesting that integrin-dependent trans-activation could be responsible for tumourigenesis.…”