Neuroendocrine Differentiation of Prostate Cancer-An Intriguing Example of Tumor Evolution at Play

Abstract

Our understanding of neuroendocrine prostate cancer (NEPC) has assumed a new perspective in light of the recent advances in research. Although classical NEPC is rarely seen in the clinic, focal neuroendocrine trans-differentiation of prostate adenocarcinoma occurs in about 30% of advanced prostate cancer (PCa) cases, and represents a therapeutic challenge. Even though our knowledge of the mechanisms that mediate neuroendocrine differentiation (NED) is still evolving, the role of androgen deprivation therapy (ADT) as a key driver of this phenomenon is increasingly becoming evident. In this review, we discuss the molecular, cellular, and therapeutic mediators of NED, and emphasize the role of the tumor microenvironment (TME) in orchestrating the phenotype. Understanding the role of the TME in mediating NED could provide us with valuable insights into the plasticity associated with the phenotype, and reveal potential therapeutic targets against this aggressive form of PCa.

Keywords: Androgen deprivation therapy (ADT); castration resistant prostate cancer (CRPC); cellular plasticity; metastasis; neuroendocrine differentiation (NED); radiation therapy; therapy-induced neuroendocrine prostate cancer (t-NEPC); tumor microenvironment (TME).

Figure 1

A generalized overview of prostate cancer (PCa) progression, metastasis, drug resistance and neuroendocrine differentiation (NED). The illustration describes PCa development from normal epithelial cells (Basal, Luminal and NE cells) to prostatic intraepithelial neoplasia (PIN) to localized- and invasive adenocarcinoma. The cartoon depicts several therapeutic regimens used for the treatment of PCa including surgical resection, radiotherapy and androgen deprivation therapy (ADT). After the initial response to ADT, the majority of the patients relapse with resistance to ADT leading to castration resistant prostate cancer (CRPC) with or without metastasis. These patients are further treated with the next-generation ADTs, enzalutamide or abiraterone. During the course of CRPC treatment, about 30% of PCa patients develop a more aggressive and fatal form of the disease called t-NEPC that has very limited therapeutic responses.

Figure 2

The diverse factors (cellular, molecular and therapeutic) involved in mediating neuroendocrine differentiation (NED) in PCa. Various factors that affect PCa cells include androgen deprivation-, radio- and chemo-therapy. In addition, the cells of tumor microenvironment (TME) including mast cells, cancer associated fibroblasts (CAFs), macrophages and bone marrow stromal cells (BMSCs) have been shown to promote the NED. Furthermore, calcium ion channels and alteration in calcium ion homeostasis play crucial roles in drug resistance and NED. In addition, Exosomes secreted from PCa cells have also been associated with NED. A few examples of molecular pathways are represented.