Prostate Cancer and Neuroendocrine Differentiation: More Neuronal, Less Endocrine?

Abstract

Neuroendocrine differentiation (NED) marks a structural and functional feature of certain cancers, including prostate cancer (PCa), whereby the malignant tissue contains a significant proportion of cells displaying neuronal, endocrine, or mixed features. NED cells produce, and can secrete, a cocktail of mediators commonly encountered in the nervous system, which may stimulate and coordinate cancer growth. In PCa, NED appears during advanced stages, subsequent to treatment, and accompanies treatment resistance and poor prognosis. However, the term “neuroendocrine” in this context is intrinsically vague. This article seeks to provide a framework on which a unified view of NED might emerge. First, we review the mutually beneficial interplay between PCa and neural structures, mainly supported by cell biology experiments and neurological conditions. Next, we address the correlations between PCa and neural functions, as described in the literature. Based upon the integration of clinical and basic observations, we suggest that it is legitimate to seek for true neural differentiation, or neuromimicry, in cancer progression, most notably in PCa cells exhibiting what is commonly described as NED.

Germline BRCA2 mutations drive prostate cancers with distinct evolutionary trajectories

“…MED12L/MED12 are components of the mediator complex and important regulators of the WNT pathway, which has been implicated in cell proliferation and neuroendocrine differentiation in PCa22232425. The MED12L / MED12 axis is implicated in metastatic sporadic PCa, with MED12 nuclear overexpression common in mCRPC and localized recurrent PCa but not in localized primary PCa or benign prostate tissue26.…”

Triiodothyronine Attenuates Prostate Cancer Progression Mediated by β-Adrenergic Stimulation

“…In low invasive LNCaP cells, β-adrenergic stimulation induces the acquisition of a highly malignant neuroendocrine (NE) phenotype. NE prostate tumors exhibit neurite-like (NE-like) projections; they synthesize and secrete amines and peptides, are androgenreceptor negative and apoptosis resistant (8,9,13,14). In humans, β2-adrenergic receptors (ADR-β 2) are highly expressed in androgen-refractory metastatic tumors and are strongly associated with for 3-5 years with adrenergic antagonists (2)(3)(4)(5)(6)(7).…”

A Prominent Couple

“…NE cancer cells have been considered as non-proliferative, postmitotic cells located adjacent to proliferative Bcl-2-positive cells [13,85]. NED areas exhibited the highest proliferation index across tumor tissue and the extent of NED correlated with a higher proliferation index of the whole tumor [86,87]. It was further shown that NE cancer cells secrete growth stimulating peptides (e.g.…”

“…There is a growing body of evidence that the extent of neuroendocrine differentiation (NED) correlates with exposure to ADT and represents an adaptive clinical phenotype, which is of special significance regarding the advent of novel highly potent AR-targeted therapies [75,[77][78][79][80][81][82][83][84][85][86]. Androgen-deprived culture conditions were shown to induce a neuronal morphology and expression of NSE and CHGA in LNCaP cells [87]. Intriguing molecular mechanisms of ADT-induced NED in PCa have recently been elucidated (Table 1.1).…”