Insights into the Role of Cell–Cell Junctions in Physiology and Disease - International Review of Cell and Molecular Biology - page 201

options for cancer treatment. Moreover, targeting critical players at the
convergence of several EMT pathways, such as NF- k B, AKT/mTOR axis,
TGF- b , hedgehog, MAPK, Wnt/ b -catenin, PKC, and AP-1/SMAD
factors provide a realistic strategy to control tumor progression. Several
selective inhibitors and blocking antibodies targeting these signaling path-
ways are already being tested in preclinical and clinical oncology ( Sabbah
et al., 2008 ). While these clinical approaches may not directly target the
cadherins, they were inspired by cadherin-mediated processes and may
involve modulating cadherin functions.
4.3.2 Desmosomes in cancer
Alterations in desmosomal proteins may lead to reduced intercellular adhe-
sion and aberrant signaling pathways. Though definitive evidence that links
desmosomes to causing cancer is lacking, a substantial amount of evidence
support their involvement in cancer progression. Of particular interest
(especially as a potential clinical target) is plakoglobin's role in the Wnt/
b -catenin pathway, which was first discovered in screens for oncogenes
( Brown et al., 1986; Fung et al., 1985 ). There is considerable evidence
suggesting that plakoglobin has a tumor suppressor role. For example, the
plakoglobin gene is subjected to loss of heterozygosity in breast and ovarian
cancers ( Aberle et al., 1995 ). Reduced plakoglobin expression promotes
decreased cell-cell contact and increases the invasive behavior of lung
cancer, breast cancer, and prostate cancer cells. Plakoglobin's role in
Wnt/ b -catenin signaling and Src signaling-dependent gene transcription
may be relevant for such processes ( Franzen et al., 2012; Holen et al.,
2012; Winn et al., 2002 ). Similarly, upregulated plakoglobin expression
has displayed antineoplastic activity in both bladder and lung cancer cell
( Canes et al., 2005; Rieger-Christ et al., 2005; Winn et al., 2002 ). Overall,
the evidence clearly supports a role for plakoglobin in cancer. Whether
desmosomes could serve as a junctional “sink” to sequester plakoglobin
and thus regulate Wnt/ b -catenin signaling in the same way that adherens
junctions and E-cadherin do remains unclear ( Gottardi et al., 2001;
Kuphal and Behrens, 2006 ). Moreover, there is emerging evidence
suggesting that desmosomes may also play a role in cancer through EMT
and its reversal process (MET) ( Katafiasz et al., 2011; Kuner et al., 2009;
Tselepis et al., 1998; Vandewalle et al., 2005 ).
Besides plakoglobin, recent studies showed alterations in expression of
different desmosomal proteins are reported in a variety of cancers ( Aigner
et al., 2007; Biedermann et al., 2005; Chen et al., 2002; Furukawa et al.,