The
cadherin-mediated cell-cell adhesion system plays a critical role in normal development and morphogenesis. Inactivation of this system is thought to be responsible for
cancer invasion and
metastasis. A human
hepatocellular carcinoma (HCC) cell line, KYN-2, was observed to have great potential for intrahepatic
metastasis when orthotopically implanted into the liver of SCID mice. In vitro cultures of KYN-2 cells showed that they formed trabecular structures in
suspension but lost tight cell-cell adhesion and became scattered when attached to a substratum such as
collagen or
fibronectin. In response to adhesion to the substratum, subcellular colocalization of
E-cadherin and actin filaments were shown to be reduced, and a significant amount of
alpha-catenin was dissociated from the
E-cadherin-
catenin complex in KYN-2 cells. These changes of cell-cell adhesion were blocked by inhibitory
monoclonal antibodies against beta1 and beta5
integrins. We found that c-Src was coimmunoprecipitated with
E-cadherin-
catenin complex and was
tyrosine-dephosphorylated and activated in the adherent cells. The
tyrosine dephosphorylation of c-Src was induced by cell adhesion to the substratum and inhibited by addition of inhibitory
monoclonal antibodies against beta1 and beta5
integrins. These findings indicate that
integrin-mediated cell-substratum adhesion inhibits
cadherin-mediated cell-cell adhesion, possibly through c-Src activation, and suggest that this cross-talk mediates transient inactivation of the
cadherin system and plays an important role in intrahepatic
metastasis of human HCC. Modulation of this interaction might provide a new approach to prevent
metastasis and recurrence of HCC.