Loss of cell-cell contact is induced by integrin-mediated cell-substratum adhesion in highly-motile and highly-metastatic hepatocellular carcinoma cells.
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.
Genda
T
T
Pathology Division, National Cancer Center Research Institute, Tokyo, Japan.
Sakamoto
M
M
Ichida
T
T
Asakura
H
H
Hirohashi
S
S
D000081247:CSK Tyrosine-Protein Kinase; D015820:Cadherins / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000201:enzymology / Q000473:pathology*; D002448:Cell Adhesion / Q000502:physiology*; D002450:Cell Communication / Q000502:physiology*; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004789:Enzyme Activation; D006801:Humans; D016023:Integrins / Q000502:physiology*; D008113:Liver Neoplasms / Q000201:enzymology / Q000473:pathology*; D009362:Neoplasm Metastasis; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D015534:Trans-Activators; D014407:Tumor Cells, Cultured; D051176:beta Catenin; D019061:src-Family Kinases
C495270:CTNNB1 protein, human; D015820:Cadherins; D003598:Cytoskeletal Proteins; D016023:Integrins; D015534:Trans-Activators; D051176:beta Catenin; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human