Mini-reviewCadherins and the tumour progression: is it all in a switch?
Introduction
The majority of human cancers originates from epithelial cells. Normal epithelia is organized by a number of specific intercellular junctions, including tight junctions, adherens-type junctions and desmosomes, which are intimately interconnected with the actin and intermediate filament cytoskeleton. Among the many types of cell-cell adhesion molecules, cadherins play a critical role in establishing adherens-type junctions by mediating Ca2+-dependent cell-cell adhesion [1], [2], [3]. Cadherin-based cell-cell adhesion is critically involved in early embryonic morphogenesis, as exemplified by the early embryonic lethality of mice lacking E-cadherin, a prototype classical cadherin [4], [5]. Cadherin-mediated cell-cell adhesion is accomplished by homophilic protein-protein interactions of extracellular cadherin domains in a zipper-like fashion. The intracellular domain of classical cadherins interacts with various proteins, collectively termed catenins, which assemble the cytoplasmic cell adhesion complex (CCC) that is critical for the formation of extracellular cell-cell adhesion. β-catenin and γ-catenin (also called plakoglobin) bind to the same conserved site at E-cadherin's C-terminus in a mutually exclusive way [6], [7], [8], whereas p120ctn interacts with multiple sites in E-cadherin's cytoplasmic tail, including its juxtamembrane region [9], [10]. β-catenin and γ-catenin bind directly to α-catenin, which links the CCC to the actin cytoskeleton. While the dual role of β-catenin and γ-catenin in cell adhesion and Wnt-signaling has been extensively studied (see below), the functions of p120ctn are poorly understood. p120ctn has been implicated both in cell-cell adhesion and in cell migration [11], and recent studies suggest that p120ctn promotes cell migration by recruiting and activating Rho-family GTPases [12].
Section snippets
E-cadherin and cancer
It has long been known that cell-cell adhesion is dramatically changed during the development of malignant cancer. In particular, in most if not all cancers of epithelial origin, E-cadherin-mediated cell-cell adhesion is lost concomitant with progression towards malignancy, and it has been proposed that the loss of E-cadherin-mediated cell-cell adhesion is a prerequisite for tumour cell invasion and metastasis formation [13]. Multiple mechanisms are found to underlie the loss of E-cadherin
The cadherin switch
Recent studies have shown that mesenchymal cadherins, in particular N-cadherin, enhance tumour cell motility and migration [30], [31], [32], [33], thus showing an opposite effect as compared to E-cadherin. N-cadherin-induced tumour cell invasion can even overcome E-cadherin-mediated cell-cell adhesion [30], [34]. The most intriguing findings in this context come from ex vivo studies documenting de novo expression of the mesenchymal cadherins N-cadherin and cadherin-11 in human tumours which
Conclusions
The cadherin switch and its functional implication in tumour malignancy is an exciting research area in tumour biology, and it is expected to give some insights into how tumours acquire an invasive and metastatic phenotype. However, several issues need to be addressed before considering the cadherin switch as a crucial step in tumour progression. Thus far, the cadherin switch in vivo has only been described during the development of malignant melanoma and prostate carcinoma [36], [44], [45].
Acknowledgements
We apologize to those colleagues whose work we could not cite due to space restrictions. Research in the laboratory of the authors is supported by Boehringer Ingelheim, the Austrian Industrial Research Promotion Fund (FFF) and by the Austrian Science Foundation (FWF).
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Institute of Biochemistry, University of Basel, Vesalgasse 1, CH-4051 Basel, Switzerland.