The many faces of neuroendocrine differentiation in prostate cancer progression

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.

Keywords: NRSF/REST; androgen receptor; aurora kinase A; cancer biology; neuroendocrine differentiation; prostate cancer; protocadherin; small-cell carcinoma.

Figure 1

Schematic model for the emergence of NE phenotype in tumor progression in prostate cancer. An NE-like or NE phenotype may be driven by a conjunction of molecular events and environmental changes, combined with natural selection. Owing to treatment intervention and/or certain environmental changes associated with tumor development, some adenocarcinoma cells having accumulated genetic alterations are able to transdifferentiate from epithelial-like to neuroendocrine-like tumor cells that have superior anti-apoptotic and therapeutic-resistant properties. In addition, neuropeptides and growth factors released by the NE-transdifferentiated cells may act either as autocrine or paracrine signals to promote survival and tumor progression of both NE and adenocarcinoma components. Accumulation of new genetic alterations such as RB loss, AURKA, and MYCN amplifications under evolutionary pressures, or through natural selection of preexisting NE-like tumor subpopulations, may promote rapid cell expansion and subsequent emergence of a predominant NE component in the form of small-cell carcinoma characterized by rapid proliferative activity. Alternatively, small-cell carcinoma could arise by direct transformation of adenocarcinoma. Adenocarcinoma and small-cell carcinoma components may also originate from a common tumor clone with stem-like properties, or a cancer stem cell, converted into more differentiated tumor cells that accumulated molecular alterations driving epithelial or NE phenotypes. To date, very limited amounts of data are supportive of normal prostatic NE cell as a cell of origin for NE tumors (not shown here).