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.
Hirohashi
S
S
National Cancer Center Research Institute, 1-1, Tsukiji 5-chome, Chuo-ku, Tokyo 104-0045, Japan.
D015820:Cadherins / Q000235:genetics / Q000502:physiology*; D002448:Cell Adhesion; D003598:Cytoskeletal Proteins / Q000235:genetics; D005770:Gastrointestinal Neoplasms / Q000235:genetics / Q000473:pathology; D006801:Humans; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology*; D011401:Promoter Regions, Genetic; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D015534:Trans-Activators; D051178:alpha Catenin; D051176:beta Catenin
D015820:Cadherins; D003598:Cytoskeletal Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D015534:Trans-Activators; D051178:alpha Catenin; D051176:beta Catenin; C495273:CTNNA1 protein, human; C495270:CTNNB1 protein, human