The role of the endothelin axis in promoting epithelial to mesenchymal transition and lymph node metastasis in prostate adenocarcinoma.

Introduction: Aberrant activation of endothelin (ET) axis has been identified as a key player in tumor growth and metastasis in several tumor types. However, little is known about the possible interaction of the ET with epithelial to mesenchymal transition (EMT), a process that transforms tumor cells in a motile, resistant to apoptosis phenotype prone to invasion and metastasis. The aim of this study was to investigate the activation of the ET axis in prostate adenocarcinoma and examine possible associations with EMT markers, lymph node (LN) metastasis, and other clinicopathological parameters.

Materials and Methods: We immunohistochemically evaluated the expression of ET-1 and its receptors A and B (ET-A, ET-B) in 64 N0 and 23 N1 prostate adenocarcinoma cases. EMT markers E-cadherin, N-cadherin, and β-catenin and the transcriptional factor SNAIL were evaluated. We examined possible correlations of ET pathway members with EMT markers, LN status, Gleason grade, and T stage.

Results: Our results revealed increased expression of ET-1 and ET-A (but not ET-B) in prostate carcinoma; both ET-1 and ET-A were associated with lymph metastasis and T stage but not with Gleason grade. We observed E-cadherin and β-catenin decrease/relocalization and increased N-cadherin expression. SNAIL also showed increased expression in tumor tissue and was associated with LN metastasis (Mann-Whitney test, P = 0.0032). Expression of ET-1 and ET-A correlated well with SNAIL expression (Spearman r, P = 0.0002 and P = 0.0176, respectively).

Conclusions: These findings indicate that activation of the ET pathway may induce EMT through SNAIL activation and correlates with increased metastatic potential.