EGFR Signalling in EMT - Therapeutic Strategies in Cancer Biology and Pathology - page 54

are closely involved with EGFR signal mediation to generate phenotypic effects of
motility and proliferation.
The hyaluran receptor CD44 expression has been closely associated with EGFR
signalling and EMT. CD44, another marker of EMT, has been described as being
able to activate EGFR. Overexpression of CD44 correlated closely with EMT and
interestingly also with increased expression of EGFR together with the activation
of PI3K/Akt and enhanced GSK-3β expression. Also in parallel the expression of
E-cadherin was reduced but that of N-cadherin and vimentin increased (Cho et al.,
2012).
The ERM (Ezrin-Radixin-Moesin) proteins are a family of proteins that link the
plasma membrane with the actin cytoskeleton. The ERM binding protein EBP50
forms this link. EBP50 contains the PDZ (PSD-95 a synaptic signalling protein,
DLG Discs Large protein and the zonula occludens ZO-1 protein) domain and by
virtue of this it is able to recognise and interact with several target proteins involved
in biological processes including cell adhesion, motility and signal transduction.
With the ability to interact with E-cadherin, EBP50 has been attributed with a func-
tion in EMT. EBP50 interacts with and forms complexes with EGFR and FAK and
in this way promote focal adhesion and cell migration (Song et al., 2012b). This
interaction between EBP50 and EGFR is an essential requirement in the activation of
EMT by EGFR (Claperon et al., 2012).
CA125 (cancer antigen 125, MUC16) is a membrane glycoprotein involved in cell
adhesion, cell proliferation and apoptosis and linked with tumour progression. It is a
marker of malignancy in many tumours, prominently ovarian cancer. High serum lev-
els of the marker correlate with peritoneal dissemination of ovarian cancer and poor
prognosis (Emoto et al., 2012). Tumour tissues also express the antigen in a variable
pattern, but high tissue expression too correlates with poor prognosis (Strappel et al.,
2012). Ogmundsdottir et al. (1996) measured serum and tissue CA125 in breast cancers
and noted difference in the surface and cytoplasmic distribution between normal breast
tissue and carcinomas; in a majority of carcinomas CA125 was associated, albeit not
exclusively, with cytoplasmic granules. The expression of both may be relevant in pre-
dicting recurrence and prognosis. The possibility that the loss of membrane associated
CA125 might contribute to EMT has to be entertained. EMT is induced under certain
circumstances such as downregulation of CA125. It could be facilitating the formation
of peritoneal metastases by aiding the binding of the tumour cells to mesothelial cells.
At first sight these findings look intrinsically contradictory. However, CA125 which is
believed to interact with E-cadherin and β-catenin and it could be stabilising the mem-
brane location of E-cadherin. Downregulation of CA125 not only activates EMT but
also activates EGFR signalling via ERK and PI3K/Akt (Comamala et al., 2011).
An important aspect of EGFR activation is internalisation of the ligand-recep-
tor complex. Receptor dimerisation, activation of RTK and autophosphorylation of
the receptor are important requirements for the internalisation process. E-cadherin
interacts through its extracellular domain with EGFR and other receptor tyrosine
kinases and this leads to regulation of EGFR by decreasing receptor mobility and
affinity of ligand to the receptor (Qian et al., 2004). So it seems possible that the
interactions between E-cadherin and EGFR or between CA125 and EGFR might