Cadherins and epithelialmesenchymal transition EMT

Cadherins play an essential role in maintaining the integrity of the epithelial layer. Cadherins mediate tight cell-cell junctions and are integral components of adherens junctions and desmosomes.150 The large extracellular domain forms a calcium-dependent homophilic interaction with cadherin molecules on neighboring cells while the cytoplasmic domain associates with alpha-, beta-, and gamma-catenins. These molecules interact, in turn, with the actin cytoskeleton and intracellular signaling components. As described above, free beta-catenin can translocate to the nucleus, associate with the TCF/LEF transcription factor complex, and drive expression of proproliferative genes, such as c-Myc and cyclin D1. Disruption of cadherin complexes would therefore affect cell-cell interaction and regulation of the actin cytoskeleton, and potentially increase the levels of available beta-catenin. In fact, accumulating evidence suggests that alterations in cadherin expression, or 'cadherin switching', is a critical event during tumor progression. Loss of E-cadherin, predominantly expressed in epithelial cells, has been associated with more aggressive, invasive, and poorly differentiated tumors.151 Various mechanisms of E-cadherin downregulation have been characterized in tumors including loss-of-function mutations, upregulation of transcriptional repressors such as TWIST and members of the SLUG/SNAIL family, aberrant promoter methylation, proteolytic degradation as well as phosphorylation by both receptor (RTK) and Src family tyrosine kinases (SFK).152 Tyrosine phosphorylation and recruitment of Hakai, a Cbl-like E3-ubiquitin ligase, leads to internalization of E-cadherin by endocytosis. In agreement with a seminal role in tumor invasion, forced overexpression of E-cadherin impairs invasiveness in an experimental tumor model while its downregulation, via targeted proteolytic degradation, leads to the development of breast carcinoma.153

Changes in expression of other cadherins accompanies downregulation of E-cadherin, in a situation reminiscent of the epithelial-mesenchymal transition that occurs during embryonic development. This transition is characterized by a loss of epithelial cell polarity and cell-cell contact, gain of mesenchymal markers such as N-cadherin, and an increased migratory phenotype.154 Increased levels of N-cadherin, normally expressed in neuronal cells and fibroblasts in adults, are observed in breast and prostate cancer and invasive melanoma.155 N-cadherin is thought to mediate a less stable and more dynamic form of cell-cell adhesion, and its overexpression enhances invasion and formation of metastasis. These changes occurred despite the presence of E-cadherin, suggesting that N-cadherin may play a dominant role. N-cadherin invasive activity occurs, at least partly, via association with the fibroblast growth factor receptor-1 (FGFR-1). Interaction results in stabilization of FGFR-1 leading to sustained downstream signaling and upregulation of proteolytic activity.156 Other cadherins have also been implicated in tumor progression. Aberrant methylation of the H-cadherin promoter results in its in silencing in breast, colorectal, and lung cancers.157 Loss of H-cadherin, normally expressed in the ductal epithelium, was observed in breast carcinomas before invasion was apparent.158 Furthermore, expression of H-cadherin, but not E-cadherin, was sufficient to suppress the invasiveness and tumorigenicity of an aggressive breast cancer cell line, MDA-MB-435.159 Therefore alterations in H-cadherin may represent a necessary earlier event in a cancer's progression to a more invasive phenotype.

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