Prostate tumor neuroendocrine differentiation via EMT: The road less traveled

Abstract

The long-standing challenge in the treatment of prostate cancer is to overcome therapeutic resistance during progression to lethal disease. Aberrant transforming-growth factor-β (TGF-β) signaling accelerates prostate tumor progression in a transgenic mouse model via effects on epithelial-mesenchymal transition (EMT), and neuroendocrine differentiation driving tumor progression to castration-resistant prostate cancer (CRPC). Neuroendocrine prostate cancer (NEPC) is highly aggressive exhibiting reactivation of developmental programs associated with EMT induction and stem cell-like characteristics. The androgen receptor (AR) is a critical driver of tumor progression as well as therapeutic response in patients with metastatic CRPC. The signaling interactions between the TGF-β mechanistic network and AR axis impact the EMT phenotypic conversions, and perturbation of epithelial homeostasis via EMT renders a critical venue for epithelial derived tumors to become invasive, acquire the neuroendocrine phenotype, and rapidly metastasize. Combinations of microtubule targeting taxane chemotherapy and androgen/AR targeting therapies have survival benefits in CRPC patients, but therapeutic resistance invariability develops, leading to mortality. Compelling evidence from our group recently demonstrated that chemotherapy (cabazitaxel, second line taxane chemotherapy), or TGF-β receptor signaling targeted therapy, caused reversion of EMT to mesenchymal-epithelial transition and tumor re-differentiation, in in vitro and in vivo prostate cancer models. In this review, we discuss the functional contribution of EMT dynamic changes to the development of the neuroendocrine phenotype—the newly characterized pathological feature of prostate tumors in the context of the tumor microenvironment-navigated cell lineage changes and the role of this neuroendocrine phenotype in metastatic progression and therapeutic resistance.

The role of WNT10B in normal prostate gland development and prostate cancer

“…As such, the loss of the antiproliferative WNT10B effects in localized PCa may be, in part, mediated through downregulation of TGFβ1. However, TGFβ1 is also known to be a primary inducer of EMT which underscores its role as a driver of aggressive disease . In this context, reversion of the EMT phenotype and aggressive characteristics seen with knockdown of WNT10B could similarly be mediated through downregulation of TGFβ1.…”

“…However, TGFβ1 is also known to be a primary inducer of EMT 48 which underscores its role as a driver of aggressive disease. 49 In this context, reversion of the EMT phenotype and aggressive characteristics seen with knockdown of WNT10B could similarly be mediated through downregulation of TGFβ1. Obviously, this poses a conundrum with targeted therapy as stage of disease becomes critically important with the risk of TGFβ1 downregulation inhibiting metastatic disease progression while concomitantly leading to a loss of tumor suppression in a different subset of cells.…”

Cutaneous metastases from prostate cancer revealing neuroendocrine differentiation

“…On the other hand, NE differentiation may appear as a cellular response to androgen‐blockade therapies, which affect not only the neoplastic cells themselves but also the entire tumoral microenvironment. A secondary pathway to the NE phenotype is a direct differentiation from a cell with stem cell‐like properties …”

“…Therefore, androgen blockade is the base of the treatment of advanced and recurrent adenocarcinoma, although the tumor may evolve to a castration‐resistant phenotype. This resistance is mainly explained by the development of neuroendocrine (NE) differentiation …”

MicroRNA-194 promotes lineage plasticity in advanced prostate cancer

“…We propose that dysregulation of these networks by elevated miR-194 during PCa progression EMT (32) and transdifferentiation from an adenocarcinoma-like cell to an NE-like cell (this study). While this hypothesis remains to be proven, we note the EMT and emergence of NE features are manifestations of cell plasticity that share many fundamental characteristics; indeed, it appears as if the re-activation of a developmental EMT program is a crucial strategy by which PCa cells evolve towards a NE lineage (1,56).…”