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

Abstract

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.

Endothelin-3 is epigenetically silenced in endometrioid endometrial cancer

“…Endothelin signaling is involved in a number of processes related to tumor growth and its progression, including cell survival, invasion, and metastasis (Bagnato et al 2008 ). Papanikolaou et al ( 2017 ) demonstrated EDN1 and EDNRA overexpression in prostate cancer which correlated with SNAIL activity, indicating possible EMT induction via the endothelin pathway. Similar conclusions were also drawn in the case of endometrial cancer (Czerwiński et al 2021 ), where EDN1 and EDNRA levels were elevated, which is consistent with our observations.…”

Endothelin-1 induces changes in the expression levels of steroidogenic enzymes and increases androgen receptor and testosterone production in the PC3 prostate cancer cell line

“…The results demonstrated that low GS samples exhibited higher ET A R expression compared with intermediate GS samples, indicating that in primary tumors from patients without treatment, the expression levels of ET A R were decreased and may be associated with the progression of PCa. Upregulation of ET A R and ET-1 expression has been demonstrated in the early stages of PCa ( 16 ) and higher expression levels of ET A R and ET-1 are associated with advanced tumor stage ( 25 ). Furthermore, androgen-sensitive cells (LNCaP) cultured in androgen-deprived medium for 5 months have been indicated to exhibit increased levels of ET A R and ET-1 mRNA, suggesting that this axis may serve an important role in the progression of PCa to CRPC ( 26 ).…”

YAP and endothelin-1 signaling: an emerging alliance in cancer

“…Here, we aim to define how the signaling transduced by ET-1/ET-1R axis stands at the centerpiece of a signaling hub shared by tumor and stromal cells, expanding aspects that are critical for tumor growth and metastatic progression. Such feature may be attributable to the ET-1 axis ability to intercept other signaling pathways, realizing an intricate network that modulates multiple steps related to cancer metastatization [ 5 , 51 – 53 ]. Downstream of ET-1R, β-arr1 has now become a reference node able to engage multiple signal transducers from different cell compartments and with various functions, in turn, directing the integration of ET-1R signaling with other pathways.…”

“…Downstream of ET-1R, β-arr1 has now become a reference node able to engage multiple signal transducers from different cell compartments and with various functions, in turn, directing the integration of ET-1R signaling with other pathways. Among the ET-1R/β-arr1-directed functions rank the cell attitude to switch from an epithelial to a mesenchymal phenotype (EMT), that fuels tumor cell migration, invasion and therapy resistance [ 33 , 34 , 45 , 51 – 53 ]. In the array of the ET-1R/β-arr1-integrated signaling, the RTK-activated signaling pathways have been well characterized.…”