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. 2021 Apr 6;13(7):1736.
doi: 10.3390/cancers13071736.

Epithelial and Mesenchymal Markers in Adrenocortical Tissues: How Mesenchymal Are Adrenocortical Tissues?

Iuliu Sbiera  1 , Stefan Kircher  2 , Barbara Altieri  1 , Martin Fassnacht  1   3   4 , Matthias Kroiss  1   4   5 , Silviu Sbiera  1
Affiliations

Epithelial and Mesenchymal Markers in Adrenocortical Tissues: How Mesenchymal Are Adrenocortical Tissues?

Iuliu Sbiera et al. Cancers (Basel). .

Abstract

A clinically relevant proportion of adrenocortical carcinoma (ACC) cases shows a tendency to metastatic spread. The objective was to determine whether the epithelial to mesenchymal transition (EMT), a mechanism associated with metastasizing in several epithelial cancers, might play a crucial role in ACC. 138 ACC, 29 adrenocortical adenomas (ACA), three normal adrenal glands (NAG), and control tissue samples were assessed for the expression of epithelial (E-cadherin and EpCAM) and mesenchymal (N-cadherin, SLUG and SNAIL) markers by immunohistochemistry. Using real-time RT-PCR we quantified the alternative isoform splicing of FGFR 2 and 3, another known indicator of EMT. We also assessed the impact of these markers on clinical outcome. Results show that both normal and neoplastic adrenocortical tissues lacked expression of epithelial markers but strongly expressed mesenchymal markers N-cadherin and SLUG. FGFR isoform splicing confirmed higher similarity of adrenocortical tissues to mesenchymal compared to epithelial tissues. In ACC, higher SLUG expression was associated with clinical markers indicating aggressiveness, while N-cadherin expression inversely associated with these markers. In conclusion, we could not find any indication of EMT as all adrenocortical tissues lacked expression of epithelial markers and exhibited closer similarity to mesenchymal tissues. However, while N-cadherin might play a positive role in tissue structure upkeep, SLUG seems to be associated with a more aggressive phenotype.

Keywords: EMT; adrenocortical tissues; epithelial markers; mesenchymal markers; recurrence-free survival.

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Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Figures

Figure 1
Figure 1
Classical EMT in cancer cells. Upper panel: EMT (Epithelial to Mesenchymal Transition) and MET (Mesenchymal to Epithelial Transition) processes in metastatic spread. Lower panel: Canonical markers of epithelial (left) and mesenchymal (right) cells.
Figure 2
Figure 2
Expression of canonical immunohistochemical epithelial markers in adrenocortical tissues. Staining of epithelial markers E-cadherin (A–E) and Epithelial Cell Adhesion Molecule (EpCAM) (F–J) protein in classical epithelial tissues (A,F) vs. normal adrenal glands (NAG, n = 3; B,G) vs. adrenocortical adenomas (ACA, n = 29; C,H) vs. adrenocortical carcinomas (ACC, n = 138; D,I). Scale bar = 200 µm. Quantitative evaluation in (E,J), respectively.
Figure 3
Figure 3
Expression of canonical immunohistochemical mesenchymal markers in adrenocortical tissues. Staining of mesenchymal markers N-cadherin (A–E), Zinc finger protein SNAI1 (SNAIL) (F–J) and Zinc finger protein SNAI2 (SLUG) (K–O) in classical mesenchymal cancers (A,F,K) vs. normal adrenal glands (NAG, n = 3; B,G,L) vs. adrenocortical adenomas (ACA, n = 29; C,H,M) and vs. adrenocortical carcinomas (ACC, n = 138; D,I,N). Scale bar = 200 µm. Quantitative evaluation in (E,J,O), respectively.
Figure 4
Figure 4
Differential expression of FGFR splice variants mRNA in adrenocortical tissues. Analysis of the ratios between the “mesenchymal” (IIIC) and “epithelial” (IIIB) splice variants for FGFR-2 (A) and 3 (B), in normal adrenal glands (NAG), adrenocortical adenomas (ACA) and carcinomas (ACC) as compared to mesenchymal sarcomas and canonical epithelial tissues; for better visualization of the isoform switch, results are represented in log10 base.
Figure 5
Figure 5
Comparison between relevant clinicopathological data and expression levels of mesenchymal markers SLUG and N-Cadherin. (A,B) venous tumor infiltration, (C,D) lymph node tumor infiltration, (E,F) Weiss score distribution and (G,H) proliferation marker Ki67. "n" numbers represent the absolute number of cases in each subgroup. χ2 analyses have been performed between proportions (%) in each staining intensity group. * p < 0.05, ** p < 0.01, *** p < 0.001.
Figure 6
Figure 6
Correlation of patient survival with expression of mesenchymal markers SLUG and N-Cadherin. (A,B) overall survival (C,D) recurrence-free survival.
See this image and copyright information in PMC

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