Neuroendocrine Differentiation in the Progression of Prostate Cancer: An Update on Recent Developments

Abstract

Neuroendocrine (NE) differentiation, either benign or malignant, is the hallmark of prostate cancer (PCa). Clusters of malignant NE cells are found in most prostate cancer cases. NE differentiation is among the non-mutually exclusive theories proposed to explain the progression to androgen independence of PCa. NE differentiation is usually associated with an increased aggressivity and invasiveness of prostate tumors and a poor prognosis. This review aims to present an overview of current knowledge on neuroendocrine differentiation in PCa to improve our understanding of tumour progression and androgen independence. The NE component represents an important therapeutic axis. Development of new generation of drugs that selectively target NE-like cells may lead to the development of new therapeutic modalities for advanced and hormone-refractory PCa.

Neuroendocrine Transdifferentiation in Human Prostate Cancer Cells: An Integrated Approach

“…In normal prostatic parenchyma, neuroendocrine cells are part of a diffuse system that contributes to the homeostasis of the surrounding epithelial population (6). The neuroendocrine system acts through its secreted products such as calcitonin, parathyroid hormone-related protein (PTHrP), chromogranins (CgA, CgB), neuron-specific enolase (NSE), neurotensin, serotonin, bombesin, and somatostatin (7). These peptide hormones and biogenic amines can either be released into the bloodstream or act locally by paracrine or autocrine signaling in an androgen-independent way (7).…”

“…The neuroendocrine system acts through its secreted products such as calcitonin, parathyroid hormone-related protein (PTHrP), chromogranins (CgA, CgB), neuron-specific enolase (NSE), neurotensin, serotonin, bombesin, and somatostatin (7). These peptide hormones and biogenic amines can either be released into the bloodstream or act locally by paracrine or autocrine signaling in an androgen-independent way (7). Neuroendocrine cells and the associated neuropeptides play also a crucial role in sustaining both growth and progression of many, if not all, conventional prostate adenocarcinomas (8,9) with a wide preclinical and clinical evidence of a poor prognosis correlation (10).…”

Differentiation of Neonatal Human-Induced Pluripotent Stem Cells to Prostate Epithelial Cells: A Model to Study Prostate Cancer Development

“…In addition, in prostate cancer, cancerous luminal secretory cells may directly transdifferentiate into NE cells suggesting existence of alternative mechanism for generating this unique population. A higher proportion of NE cells in prostatic tumors is associated with more aggressive behavior and worse prognosis [64]. NE cells are characterized by expression of several neuronal as well as secretory markers, but the most prominent are the neuron specific enolase (NSE) and chromogranin A (CgA) [65].…”

“…NE cells do not express androgen receptor making them refractory to anti-androgen therapy [66][67][68]. Intriguingly, androgen deprivation can itself drive transdifferentiation of PCSC into NE cells [64]. In addition, NE cells can support the survival of other prostatic cells in their vicinity by allowing them to survive in the absence of androgens via secretion of trophic paracrine factors [68,69].…”

“…Hence, NE transdifferentiation of prostate cancer stem cells could contribute to the failure of both hormonal as well as cytotoxic therapy in this disease [66][67][68][69][70][71][72]. While several approaches are under investigation to interfere with function of NE cells in prostate cancer [64], there are no treatments in the pipeline that could prevent transdifferentiation of PCSC into NE cells.…”