1. ¹Pathology Division, National Cancer Center Research Institute, Tokyo, Japan
2. ²The Third Department of Internal Medicine, Faculty of Medicine, Niigata University, Niigata, Japan

Correspondence: Dr. S. Hirohashi, Pathology Division, National Cancer Center Research Institute, 5–1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan. Fax: 81 3 3248 2737. E-mail: shirohas@gan2.res.ncc.go.jp

Received 8 November 1999.

Abstract

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 -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 1 and 5 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 1 and 5 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.