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4.3.1 Adherens junctions in cancer
During oncogenesis, cell junctions are affected by a variety of genetic and
epigenetic factors. Many human cancers arise as carcinomas from epithelial
tissues, with the result that E-cadherin is an attractive target for investigation
( Berx et al., 1998a; Birchmeier and Behrens, 1994; Thiery, 2002 ). In fact,
the importance of E-cadherin in tumor progression has been accepted for
sometime ( Takeichi, 1991 ). More recently, the participation of other
cadherins and cadherin-related proteins has been discovered, and an increas-
ing number are implicated as tumor suppressors or as proto-oncogenic pro-
teins, with different mechanisms.
The most extensive data for cadherin involvement in cancers are for
E-cadherin. Both somatic and germline E-cadherin mutations have been
identified in a number of cancers ( Berx et al., 1996, 1998a,b; Corso
et al., 2012; Guilford et al., 1998; Richards et al., 1999; Stone et al.,
1999 ). In vivo and in vitro studies reveal an inverse relationship between
E-cadherin function and tumor progression ( Derksen et al., 2006; Perl
et al., 1998; Vleminckx et al., 1991 ). Pathologic studies demonstrate a cor-
relation between tumor progression with loss of E-cadherin expression and/
or junctional localization. Though the underlying mechanisms relating
E-cadherin dysfunction to tumor progression are still poorly characterized,
one promising postulated mechanism involves canonical Wnt/ b -catenin
signaling. Aberrant activation of the canonical Wnt signaling is a key early
event in sporadic and familial colorectal cancers, as well as skin, breast, and
other tumors ( Fodde and Brabletz, 2007 ). Cadherins may serve as a “sink” to
sequester Wnt/ b -catenin signals, and thus the loss of the cadherin “sink”
results in altered signaling activation ( Brown et al., 1986; Fung et al.,
1985; Jeanes et al., 2008 ).
Besides mutations in the cadherin coding sequence, accumulating evi-
dence points to the involvement of EMT in tumor progression. The essen-
tial features of EMT of interest here are the disruption of cell-cell contacts
and enhancement of cell motility. However, the vital process of regulating
E-cadherin expression during development may instead play a less desirable
role in tumor progression, in supporting invasion and metastasis. Indeed, the
mechanisms involved in the EMT are also applicable to oncogenic pathways
( Sabbah et al., 2008 ). Thus, cadherin-based EMT may provide a new basis
for understanding tumor progression. A number of interconnected signaling
pathways and molecules have been examined ( Thiery, 2002 ). For example,
upstream EMT signaling pathways induced by receptor and nonreceptor
tyrosine kinases (e.g., EGF-R, IGF-R, VEGF-R, PDGF, HGF,
integrins/FAK, Src) and G-protein-coupled receptors provide practical
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