N-cadherin as a therapeutic target in cancer

Abstract

During tumor progression, cancer cells undergo dramatic changes in the expression profile of adhesion molecules resulting in detachment from original tissue and acquisition of a highly motile and invasive phenotype. A hallmark of this change, also referred to as the epithelial–mesenchymal transition, is the loss of E- (epithelial) cadherin and the de novo expression of N- (neural) cadherin adhesion molecules. N-cadherin promotes tumor cell survival, migration and invasion, and a high level of its expression is often associated with poor prognosis. N-cadherin is also expressed in endothelial cells and plays an essential role in the maturation and stabilization of normal vessels and tumor-associated angiogenic vessels. Increasing experimental evidence suggests that N-cadherin is a potential therapeutic target in cancer. A peptidic N-cadherin antagonist (ADH-1) has been developed and has entered clinical testing. In this review, the authors discuss the biochemical and functional features of N-cadherin, its potential role in cancer and angiogenesis, and summarize the preclinical and clinical results achieved with ADH-1.

Keywords::

• adhesion
• angiogenesis
• E-cadherin
• histidine–alanine–valine
• invasion
• N-cadherin

Acknowledgements

The authors thank FJ Lejeune for continuous support; and W Peters, R Norris and RK Malik (Adherex Technologies, Inc.) for sharing preclinical data on ADH-1. The authors apologize to those colleagues whose work could not be cited due to space limitations.

Work in the authors’ laboratories is supported by grants from the Swiss National Science Foundation, National Center for Competence in Research Molecular Oncology (a research instrument of the FNS), Oncosuisse, the Medic Foundation, the Fondazione San Salvatore, Roche Research Foundation, Novartis Foundation and the Southern European New Drugs Organization Foundation.

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