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Inactivation of the E-cadherin-mediated cell adhesion system in human cancers
1Pathology Division, National Cancer Center Research Institute, Tokyo, Japan. shirohas@ncc.go.jp
Abstract:
It has long been known that cell-cell adhesiveness is generally reduced in 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 cell adhesion system appear to exist. This paper focuses on the cadherin system, which mediates Ca2+-dependent homophilic cell-cell adhesion. The E (epithelial)-cadherin-mediated cell adhesion system in cancer cells is inactivated by multiple mechanisms corresponding to the pathological features described above. Mutations have been found in the genes for E-cadherin and its undercoat proteins, alpha- and beta-catenins, which connect cadherins to actin filaments and establish firm cell-cell adhesion. Transcriptional inactivation of E-cadherin expression was shown to occur frequently in tumor progression. E-cadherin expression in human cancer cells is regulated by CpG methylation around the promoter region. The cadherin system interacts directly with products of oncogenes, eg, cerbB-2 protein and the epidermal growth factor receptor, and of the tumor suppressor gene, adenomatous polyposis coli (APC) protein, through beta-catenin, which may be important in signal transduction pathways contributing to the determination of the biological properties of human cancers. In conclusion, inactivation of the E-cadherin system by multiple mechanisms, including both genetic and epigenetic events, plays a significant role in multistage carcinogenesis.
Insights
Reduced cell-cell adhesion in human cancers involves E-cadherin inactivation. Genetic mutations and epigenetic changes like CpG methylation disrupt this system, promoting tumor progression and multistage carcinogenesis.
Area of Science:
- Cell Biology
- Oncology
- Molecular Biology
Background:
- Cell-cell adhesiveness is reduced in human cancers.
- Tumor cell dissociation varies with cancer type and metastatic potential.
- Mechanisms for inactivating cell adhesion systems can be irreversible or reversible.
Purpose of the Study:
- Focus on the cadherin system, specifically E-cadherin, in cancer.
- Investigate mechanisms of E-cadherin inactivation in human cancers.
- Explore the role of E-cadherin system inactivation in multistage carcinogenesis.
Main Methods:
- Analysis of mutations in E-cadherin and catenin genes.
- Assessment of transcriptional inactivation of E-cadherin expression.
- Investigation of E-cadherin regulation by CpG methylation.
- Examination of interactions between the cadherin system and oncogenes/tumor suppressors.
Main Results:
- Mutations in E-cadherin, alpha-catenin, and beta-catenin genes are found.
- Transcriptional inactivation of E-cadherin is frequent during tumor progression.
- CpG methylation regulates E-cadherin expression in cancer cells.
- Cadherin system interacts with oncogenes (e.g., c-erbB-2, EGFR) and APC protein via beta-catenin.
Conclusions:
- Inactivation of the E-cadherin system is a significant factor in human cancers.
- Multiple mechanisms, including genetic and epigenetic events, contribute to E-cadherin inactivation.
- E-cadherin system alterations impact signal transduction pathways crucial for cancer biology.