Abstract
In normal prostate, neuroendocrine (NE) cells are rare and interspersed among the epithelium. These cells are believed to provide trophic signals to epithelial cell populations through the secretion of an abundance of neuropeptides that can diffuse to influence surrounding cells. In the setting of prostate cancer (PC), NE cells can also stimulate surrounding prostate adenocarcinoma cell growth, but in some cases adenocarcinoma cells themselves acquire NE characteristics. This epithelial plasticity is associated with decreased androgen receptor (AR) signaling and the accumulation of neuronal and stem cell characteristics. Transformation to an NE phenotype is one proposed mechanism of resistance to contemporary AR-targeted treatments, is associated with poor prognosis, and thought to represent up to 25% of lethal PCs. Importantly, the advent of high-throughput technologies has started to provide clues for understanding the complex molecular profiles of tumors exhibiting NE differentiation. Here, we discuss these recent advances, the multifaceted manner by which an NE-like state may arise during the different stages of disease progression, and the potential benefit of this knowledge for the management of patients with advanced PC.
Highlights
Prostate cancer (PC) is the most frequently diagnosed malignancy in men and is accompanied by a frequent source of morbidity and mortality [1]
Using nextgeneration sequencing as a tool to define the transcriptome of both NE- and adeno-PCs, we discovered that the vast majority of NEPC over-express the cell cycle kinase AURKA (Aurora kinase A) and MYCN compared to adenocarcinoma [50]
In collaboration with Dr Buttyan and his colleagues, we have shown that over-expression of PCDH–PC in human prostate adenocarcinoma cells promotes NE transdifferentiation and this is further supported by our survey of human specimens [36, 76]
Summary
Prostate cancer (PC) is the most frequently diagnosed malignancy in men and is accompanied by a frequent source of morbidity and mortality [1]. Like the normal prostatic glands that develop, regenerate, and function under the influence of androgens, prostatic adenocarcinoma (thereafter adeno-PC) relies on androgens working through the androgen receptor (AR) for its development and progression. This is the basis for the use of therapeutic intervention to block androgen synthesis (e.g., chemical and surgical castration), or inhibit AR function (e.g., AR antagonists), as standard therapies for patients with advanced and recurrent diseases [2, 3].
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