Desmosomes: a role in cancer?

Abstract

Much evidence now attests to the importance of desmosomes and their constituents in cancer. Alterations in the expression of desmosomal components could contribute to the progression of the disease by modifying intracellular signal transduction pathways and/or by causing reduced cell adhesion. The Wnt/beta-catenin pathway is a potential target because of the involvement of the cytoplasmic desmosomal protein plakoglobin. Loss of desmosomal adhesion is a prerequisite for the epithelial-mesenchymal transition, implicated in the conversion of early stage tumours to invasive cancers.

Figure 1

A model outlining how desmosomes could contribute to tumourigenesis. Unbroken arrows indicate that plakoglobin is released from desmosomes as a result of either loss or modulation of expression of desmosomal cadherins or desmoplakin and displaces β-catenin from adherens junctions. The latter translocates to the nucleus, stimulates transcription of β-catenin-responsive genes and ultimately results in cell proliferation. Broken arrows indicate that plakoglobin liberated from desmosomes translocates to the nucleus, stimulates transcription of genes, such as c-myc or Bcl-2, and promotes uncontrolled cell growth. Further possibilities (data not shown) are that loss of expression of plakoglobin itself could predispose to cancer by reducing its ability to antagonise β-catenin-mediated Wnt signalling or that plakophilins are involved (see text). Plakoglobin (yellow), β-catenin (blue), plakophilin (red). α-cat, α-catenin; DP, desmoplakin; E-cad, E-cadherin; IFs, intermediate filaments.

Figure 2

Epithelial–mesenchymal transition. Epithelial–mesenchymal transition in Madin–Darby canine kidney epithelial cells is characterised by a change in morphology, loss of expression of desmoplakin and gain in expression of vimentin. DP, desmoplakin.