Molecular aspects of adhesion-epigenetic mechanisms for inactivation of the E-Cadherin-mediated cell adhesion system in cancers.

E-Cadherin and its undercoat proteins, alpha- and beta-Catenins, which connect cadherins to actin filaments and establish firm cell-cell adhesion, act as an invasion suppressor system. It was demonstrated that transcriptional inactivation of E-Cadherin expression occurred frequently in tumor progression, and that E-Cadherin expression in human cancer cells was regulated by CpG methylation around the promoter region. In diffusely infiltrating cancers, mutations were found in the genes for E-Cadherin and alpha- and beta-Catenins. The E-Cadherin-mediated cell-adhesion system is inactivated by tyrosine phosphorylation of beta-Catenin at the invading front of cancers with high metastatic ability. An attempt was made to identify the kinases that participate in the aberrant tyrosine phosphorylation, and c-erbB-2 protein was found to be directly associated with beta-Catenin. Transfection of N-terminally deleted beta-Catenin, which binds to c-erbB-2 but not to cadherin, markedly reduced peritoneal dissemination and hematogenous metastasis of gastrointestinal cancer cells in mouse inoculation models. Regulation of the E-Cadherin-mediated cell adhesion system by tyrosine phosphorylation of beta-Catenin is important in determining the biological properties of human cancers. Tumor cells are dissociated throughout the entire tumor masses of diffuse-type cancers, whereas those of solid tumors with high metastatic potentials are often focally dissociated or dedifferentiated at the invading fronts. Thus, both irreversible and reversible mechanisms for inactivating the E-Cadherin-mediated cell adhesion system well correspond to the pathological features of human cancers.