Clinicopathological and prognostic significance of epithelial mesenchymal transition-related protein expression in intrahepatic cholangiocarcinoma

Abstract

BackgroundThe aim of this study was to examine the patterns of expression of epithelial-mesenchymal transition (EMT)-related proteins in intrahepatic cholangiocarcinoma. The clinicopathological and prognostic value of these markers was also evaluated.MethodsWe detected the expression status of three EMT-related proteins, ie, E-cadherin, vimentin, and N-cadherin, by immunohistochemistry in consecutive intrahepatic cholangiocarcinoma specimens from 96 patients.ResultsThe frequency of loss of the epithelial marker E-cadherin, and acquisition of mesenchymal markers, vimentin and N-cadherin, in intrahepatic cholangiocarcinoma was 43.8%, 37.5% and 57.3%, respectively. Altered expression of EMT markers was associated with aggressive tumor behavior, including lymph node metastasis, undifferentiated-type histology, advanced tumor stage, venous invasion, and shorter overall survival. Moreover, loss of E-cadherin was retained as an independent prognostic factor for patients with intrahepatic cholangiocarcinoma in multivariate analysis.ConclusionOur results suggest that the EMT process is associated with tumor progression and a poor outcome in patients with intrahepatic cholangiocarcinoma, and inhibition of EMT might offer novel promising molecular targets for the treatment of affected patients.

Epithelial-mesenchymal transition in cholangiocarcinoma: From clinical evidence to regulatory networks

“…This switch operates in both types of CCA in which an up-regulation of N-cadherin expression has been observed [18,25,34,40,41]. Increasing N-cadherin expression has been associated with lower OS in both CCA subclasses [25,40] and is an independent unfavorable prognostic factor in eCCA [40].…”

“…Several studies confirmed an aberrant staining of vimentin in CCA tumor cells while there was no staining in benign cholangiocytes [24,25,32,35,40,[48][49][50]. Vimentin expression was associated with lymph node metastasis, portal vein invasion, tumor size, pTNM stage and poorer OS and DFS [25,31,32,35,50]. In addition, vimentin was mostly detected in poorly differentiated tumor foci and a multivariate analysis demonstrated that aberrant vimentin expression is an independent adverse prognostic factor in iCCA [50].…”

“…While E-cadherin is localized at the plasma membrane in healthy biliary epithelium, its down-regulation and/or ectopic localization, i.e. cytoplasmic internalization, have been reported in malignant cholangiocytes [18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37]. Genetic mutations and epigenetic silencing through promoter hypermethylation of the E-cadherin gene (CDH1) are among the mechanisms that account for the down-regulation of E-cadherin [30,33,38].…”

“…Although, down-regulation of E-cadherin in iCCA has been correlated with poor tumor differentiation, tumor size, advanced pTNM stage, intrahepatic metastasis and lymph node metastasis [25,26,29,31,32,36], its prognostic value is still controversial. Ryu et al, did not find any impact of E-cadherin expression on overall survival (OS) or disease free survival (DFS) [24] whereas other groups demonstrated that E-cadherin loss was significantly associated with these parameters and was an independent prognostic factor [25,32,36]. In eCCA, patients with weak E-cadherin expression displayed lower survival rate than patients with high E-cadherin expression [18] and was also an independent prognostic factor [40].…”

“…CK19 down-regulation has been observed in tumor cells of CCA, and this down-regulation was significantly associated with neural invasion, intrahepatic metastasis, undifferentiated tumor grade and shortened DFS and OS [24]. Several studies confirmed an aberrant staining of vimentin in CCA tumor cells while there was no staining in benign cholangiocytes [24,25,32,35,40,[48][49][50]. Vimentin expression was associated with lymph node metastasis, portal vein invasion, tumor size, pTNM stage and poorer OS and DFS [25,31,32,35,50].…”