The paper by Setsuo Hirohashi reviews the inactivation of the E-cadherin-mediated cell adhesion system in human cancers. It highlights that cell-cell adhesion is generally reduced in human cancers, leading to tumor cell dissociation and loss of polarity. The E-cadherin-mediated system, which mediates Ca2+-dependent homophilic cell-cell adhesion, is inactivated through multiple mechanisms, including genetic and epigenetic alterations. Genetic alterations involve mutations in E-cadherin and its undercoat proteins, α- and β-catenins, which disrupt the interaction between cadherins and actin filaments. Epigenetic alterations include CpG methylation around the promoter region of E-cadherin, which silences its expression. Additionally, reduced expression of E-cadherin can be regulated by transcription factors and is associated with poor clinical outcomes. The paper also discusses the role of β-catenin in the Wingless-Wnt signaling pathway, where its aberrant tyrosine phosphorylation by oncogene products like c-erbB-2 can transiently inactivate the E-cadherin system, promoting invasion and metastasis. Overall, the inactivation of the E-cadherin system plays a significant role in both early and late stages of carcinogenesis.The paper by Setsuo Hirohashi reviews the inactivation of the E-cadherin-mediated cell adhesion system in human cancers. It highlights that cell-cell adhesion is generally reduced in human cancers, leading to tumor cell dissociation and loss of polarity. The E-cadherin-mediated system, which mediates Ca2+-dependent homophilic cell-cell adhesion, is inactivated through multiple mechanisms, including genetic and epigenetic alterations. Genetic alterations involve mutations in E-cadherin and its undercoat proteins, α- and β-catenins, which disrupt the interaction between cadherins and actin filaments. Epigenetic alterations include CpG methylation around the promoter region of E-cadherin, which silences its expression. Additionally, reduced expression of E-cadherin can be regulated by transcription factors and is associated with poor clinical outcomes. The paper also discusses the role of β-catenin in the Wingless-Wnt signaling pathway, where its aberrant tyrosine phosphorylation by oncogene products like c-erbB-2 can transiently inactivate the E-cadherin system, promoting invasion and metastasis. Overall, the inactivation of the E-cadherin system plays a significant role in both early and late stages of carcinogenesis.