The Immunohistochemical Pattern of Epithelial-Mesenchymal Transition Markers In Endometrial Carcinoma

Abstract

The majority of endometrial carcinoma are diagnosed at an early stage and exhibit a favorable prognosis. However, 10% to 15% of ECs recur and the majority are type II tumors which are high-grade carcinomas. The epithelial-mesenchymal transition (EMT) has been considered as a fundamental step for the development of the invasive phenotype of cancer cells. During EMT, many of epithelial surface markers, primarily E-cadherin disappear, and mesenchymal markers including N-cadherin gain. This feature resides predominantly at the invasive front (IF) of the tumor. Therefore, we examined the immunohistochemical expression of E-cadherin and N-cadherin at the IF, in central areas of the tumor and lymphovascular space, in type I and type II endometrial carcinoma. The association of each protein with the clinicopathologic features was also evaluated. Our results confirmed a stronger E-cadherin immunostaining in type I tumors indicating that the loss of E-cadherin may be responsible for a more aggressive behavior of type II ECs. In both types, E-cadherin was strongly expressed in central areas and the reactivity decreased toward the IF. On contrary, N-cadherin was overexpressed at the IF confirming an inverse relationship between these markers. In addition, a decrease in E-cadherin expression was observed in cells within the lymphovascular space. Downregulation of E-cadherin was associated only with high-grade tumors while no correlations between both markers and other clinicopathologic features were found. Our results confirm that EMT occurs at the IF that represents a critical interface between the tumor and the host.

The association of Wnt-signalling and EMT markers with clinical characteristics in women with endometrial cancer

“…However, none of our results were statistically significant. Other authors have reported correlation between low expression of E-cadherin and higher expression of other cadherins, most importantly N-cadherin, marker of mesothelial differentiation and thus indicator of EMT (6,38,57). Our study, on the contrary, showed a positive correlation between expression of both cadherins, a phenomenon that has not yet been recognized.…”

“…In comparison to most other studies, we studied the average overall expression of cadherins in tumour tissue. We did not compare or distinguish between only membranous or cytoplasmic staining to take into an account a possible different intracellular location of the marker, also we did not compare the IHC reaction in centre of the tumour-to-tumour front, where differences have been most observed ( 6 , 38 ). Our N-cadherin staining has been very strong overall, having a very high mean H-score, regardless of tumour type, stage, or grade.…”

“…Currently, four molecular subtypes of EC have been proposed based on genetic characteristics of tumors: (i) POLE (DNA Polymerase Epsilon) ultra-mutated tumors, (ii) mismatch repairdeficient (MMRd) tumors, (iii) p53-mutant tumors (p53abn), and (iv) tumors of no specific molecular profile (NSMP) (5). Molecular classification of EC has offered new insight in the process of carcinogenesis and progression of EC and it has provided new potential targets for treatment and different prognostic subgroups of patients (6)(7)(8).…”

“…Another important mechanism of carcinogenesis and progression of EC is epithelial-to-mesenchymal transition (EMT). EMT leads to the loss of intracellular junctions and of apical-basal polarity in tumor cells as well as the reorganization of the cytoskeleton, increased motility of individual cells, and degradation of the extracellular matrix proteins (6). One of the hallmarks of EMT is the loss of epithelial surface markers, most notably E-cadherin and subsequently the expression of mesenchymal markers, such as N-cadherin and vimentin (28)(29)(30).…”

“…One of the hallmarks of EMT is the loss of epithelial surface markers, most notably E-cadherin and subsequently the expression of mesenchymal markers, such as N-cadherin and vimentin (28)(29)(30). The phenomenon of balanced downregulation of E-cadherin expression and N-cadherin overexpression is described as "cadherin switch" and is regarded as a marker of EMT (6,30). Wnt signaling is needed for both, the initiation and the maintenance of the mesenchymal phenotype of tumor cells which is mainly achieved by activating the transcription of target genes, contributing to EMT process (31,32) and is also connected to loss of E-cadherin expression, enabling translocation of b-catenin to participate in Wnt cascade (33).…”