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Review
. 2015 Feb 5;370(1661):20140042.
doi: 10.1098/rstb.2014.0042.

Cell adhesion and urothelial bladder cancer: the role of cadherin switching and related phenomena

Richard T Bryan  1
Affiliations
Review

Cell adhesion and urothelial bladder cancer: the role of cadherin switching and related phenomena

Richard T Bryan. Philos Trans R Soc Lond B Biol Sci. .

Abstract

Cadherins are mediators of cell-cell adhesion in epithelial tissues. E-cadherin is a known tumour suppressor and plays a central role in suppressing the invasive phenotype of cancer cells. However, the abnormal expression of N- and P-cadherin ('cadherin switching', CS) has been shown to promote a more invasive and m̀alignant phenotype of cancer, with P-cadherin possibly acting as a key mediator of invasion and metastasis in bladder cancer. Cadherins are also implicated in numerous signalling events related to embryonic development, tissue morphogenesis and homeostasis. It is these wide ranging effects and the serious implications of CS that make the cadherin cell adhesion molecules and their related pathways strong candidate targets for the inhibition of cancer progression, including bladder cancer. This review focuses on CS in the context of bladder cancer and in particular the switch to P-cadherin expression, and discusses other related molecules and phenomena, including EpCAM and the development of the cancer stem cell phenotype.

Keywords: EpCAM; bladder cancer; cadherin; catenin; cell adhesion; stem cells.

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Figures

Figure 1.
Figure 1.
Cell–cell adhesion in epithelial tissues (taken from reference [22] with permission). (a) Overview of cell–cell adhesion complexes; (b) pictorial representation of cell–cell interactions on neighbouring cells; (c) molecular structure of the adherens junction, showing the relationship between E-cadherin molecules on neighbouring cells, and between E-cadherin, the catenins (α, β, γ, p120) and the cell cytoskeleton. Traditionally, cadherins on neighbouring cells adhere via EC1 domains, although more recent research suggests that all five EC domains are required for optimal adhesion [64].
Figure 2.
Figure 2.
Cadherin switching in bladder UCs (taken from reference [22] with permission). (a) E-cadherin is strongly expressed at the cell membrane throughout the normal urothelium. Reduced expression is observed in a proportion of NMIBCs, and the majority of MIBCs demonstrate either reduced expression or a complete absence of E-cadherin; (b) P-cadherin is expressed in the basal one to two layers of normal urothelium, and this pattern is preserved in the majority of NMIBCs. The majority of MIBCs demonstrate strong P-cadherin expression throughout the tumour mass; (c) N-cadherin is not expressed in normal urothelium or the majority of NMIBCs. However, the majority of muscle-invasive UCs express N-cadherin throughout the tumour mass.
Figure 3.
Figure 3.
Proposed pathways for the development of a bladder cancer stem cell phenotype and the relationship with EpCAM (adapted from [23]). Cancer stem cells (CSCs) result in the development of treatment-resistant disease in some cancer settings, and this diagram proposes potential pathways for their development in UBC. There is likely considerable plasticity in these pathways [110], with cells reverting to a less aggressive state by mesenchymal-to-epithelial transition (MET) or by the reversal of the CSC phenotype, and most likely influenced by the tumour microenvironment [23]. We also propose a model whereby EpCAM modulates the development of EMT and/or CSCs (see text).
Figure 4.
Figure 4.
EpCAM's relationship with E-cadherin (adapted from [117,119]). The dual role of EpCAM in epithelial tissues is demonstrated. EpCAM can either disrupt the adherens junction, resulting in the release of β-catenin (a), or stabilize the adherens junction to maintain E-cadherin's anchorage to the cell cytoskeleton (b). In (a), released β-catenin subsequently forms a complex with EpICD and the transcriptional cofactor FHL2 [120], either at the cell membrane or in the cell nucleus. The EpICD/FHL2/β-catenin complex then interacts with the Lef-1 transcription factor in the cell nucleus to activate the transcription of various target genes, including known oncogenes. In UBC, we demonstrated that the extracellular domain of EpCAM is released by cleavage immediately adjacent to the cell membrane [51]. The exact location of cleavage was not described by Maetzel et al. [117], but the protease involved (TACE or ADAM 17) usually cleaves membrane proteins 10–15 residues away from the membrane surface [121], suggesting atypical cleavage or an alternative mechanism of extracellular domain release in UBC (α, α-catenin; β, β-catenin).
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