Aggressive variants of prostate cancer: underlying mechanisms of neuroendocrine transdifferentiation

Abstract

Prostate cancer is a hormone-driven disease and its tumor cell growth highly relies on increased androgen receptor (AR) signaling. Therefore, targeted therapy directed against androgen synthesis or AR activation is broadly used and continually improved. However, a subset of patients eventually progresses to castration-resistant disease. To date, various mechanisms of resistance have been identified including the development of AR-independent aggressive variant prostate cancer based on neuroendocrine transdifferentiation (NED). Here, we review the highly complex processes contributing to NED. Genetic, epigenetic, transcriptional aberrations and posttranscriptional modifications are highlighted and the potential interplay of the different factors is discussed. Background Aggressive variant prostate cancer (AVPC) with traits of neuroendocrine differentiation emerges in a rising number of patients in recent years. Among others, advanced therapies targeting the androgen receptor axis have been considered causative for this development. Cell growth of AVPC often occurs completely independent of the androgen receptor signal transduction pathway and cells have mostly lost the typical cellular features of prostate adenocarcinoma. This complicates both diagnosis and treatment of this very aggressive disease. We believe that a deeper understanding of the complex molecular pathological mechanisms contributing to transdifferentiation will help to improve diagnostic procedures and develop effective treatment strategies. Indeed, in recent years, many scientists have made important contributions to unravel possible causes and mechanisms in the context of neuroendocrine transdifferentiation. However, the complexity of the diverse molecular pathways has not been captured completely, yet. This narrative review comprehensively highlights the individual steps of neuroendocrine transdifferentiation and makes an important contribution in bringing together the results found so far.

Keywords: Aggressive variant prostate cancer; Neuroendocrine prostate cancer; Neuroendocrine transdifferentiation; Small cell prostate cancer.

Fig. 1

Histologic staining of small-cell NEPC. Top Small cell neuroendocrine prostate cancer with typical features such as scant cytoplasm, granular chromatin and a high number of apoptoses and mitoses, magnification 10x (left), 20 x (right), Lower left Incomplete loss of AR expression, magnification 20x, Lower right expression of neuroendocrine marker synaptophysin, magnification 10x

Fig. 2

Origin of t-NEPC. Two opposing theories have been proposed to explain the origin of t-NEPC: Clonal expansion – the outgrowth of neuroendocrine or NE-differentiated basal cells – and transdifferentiation of adenocarcinoma cells

Fig. 3

Key mechanisms contributing to t-NEPC transdifferentiation. Genes and proteins discussed in this review are ordered based on the effects of their respective aberrations in t-NEPC

Fig. 4

Overview of epigenetic alterations in t-NEPC. Factors contributing to epigenetic deregulation are assigned to their respective mechanism of action; methylation of histone tails or DNA is indicated by green dots, histone acetylation is represented by orange triangles