Clinical significance of epithelial-mesenchymal transition markers in prostate cancer

The process of epithelial-to-mesenchymal transition (EMT) contributes to cancer progression, with activation of transcription factors leading to loss of epithelial characteristics and acquirement of mesenchymal properties. We analyzed in human prostate cancer (PCa) the expression of EMT markers at the different stages of PCa natural history, and evaluated its clinical significance. The expression of the key EMT transcription factor Zeb1, together with E-cadherin, vimentin, and N-cadherin, was evaluated by immunohistochemistry on tissue microarrays containing samples of normal prostate (n = 58), clinically localized cancer (CLC) (n = 242), castration-resistant PCa (CRPC) (n = 48), and metastases (n = 43). Zeb 1 expression was not found in normal tissues, and significantly increased with disease progression from pT2 (20% of cases) to pT3 tumors (34%), and then from CLC to metastases and CRPC (62% and 92%). The expression of EMT target genes was more fluctuant according to disease stages, although in CLC N-cadherin was closely associated with Zeb1 staining. In CLC, after adjusting for classical prognostic markers, only vimentin expression was significantly predictive of shorter recurrence-free survival. In CRPC, preserved E-cadherin staining was associated with longer overall survival, and Zeb1 expression in metastases was predictive of decreased survival. Although Zeb1 expression increased according to the different steps of PCa progression, the expression of its target genes does not seem to follow the same kinetics. However, the potential clinical interest of these EMT markers at several stages of the disease is strongly suggested by their predictive value on both recurrence-free and overall survival.