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Related Experiment Videos

Cell adhesion system and human cancer morphogenesis.

Setsuo Hirohashi1, Yae Kanai

  • 1Pathology Division, National Cancer Center Research Institute, Chuo-ku, Tokyo 104-0045, Japan. shirohas@gan2.ncc.go.jp

Cancer Science
|July 5, 2003
PubMed
Summary

Reduced cell-cell adhesion, particularly E-cadherin system inactivation, drives cancer progression, invasion, and metastasis through genetic and epigenetic changes.

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Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Cell Biology

Background:

  • Cell-cell adhesion is crucial for tissue structure and cell polarity.
  • Reduced cell adhesion is a hallmark of human cancers, enabling invasion and metastasis.
  • E-cadherin and catenins form a critical cell adhesion system in epithelial cells.

Purpose of the Study:

  • To investigate the role of the E-cadherin cell adhesion system in human carcinogenesis.
  • To elucidate the mechanisms of E-cadherin system inactivation in various cancers.
  • To understand the implications of E-cadherin dysfunction in tumor progression and metastasis.

Main Methods:

  • Analysis of E-cadherin gene silencing via DNA hypermethylation.
  • Identification of mutations in E-cadherin and catenin genes in diffuse infiltrating cancers.
  • Investigation of E-cadherin system inactivation through tyrosine phosphorylation of beta-catenin.
  • Exploration of the association between c-erbB-2 oncoprotein and beta-catenin.
  • Examination of the cross-talk between the E-cadherin system and the Wingless/Wnt signaling pathway.
  • Study of dysadherin's role in down-regulating E-cadherin and promoting metastasis.

Main Results:

  • E-cadherin gene silencing by promoter hypermethylation is frequent, even in precancerous lesions.
  • Mutations in E-cadherin, alpha-catenin, and beta-catenin genes are observed in diffuse infiltrating cancers.
  • Tyrosine phosphorylation of beta-catenin inactivates the E-cadherin system at the invasive front.
  • c-erbB-2 protein directly associates with beta-catenin.
  • The E-cadherin system interacts with the Wingless/Wnt pathway, potentially regulating cancer-related genes.
  • Dysadherin down-regulates E-cadherin, enhancing cancer metastasis.

Conclusions:

  • Inactivation of the E-cadherin cell adhesion system is a significant factor in multistage human carcinogenesis.
  • Both genetic alterations and epigenetic modifications contribute to E-cadherin system dysfunction.
  • E-cadherin inactivation promotes cancer cell de-differentiation, invasion, and metastasis.

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