Neuroendocrine-like prostate cancer cells: neuroendocrine transdifferentiation of prostate adenocarcinoma cells

Abstract

Neuroendocrine (NE) cells represent a minor cell population in the epithelial compartment of normal prostate glands and may play a role in regulating the growth and differentiation of normal prostate epithelia. In prostate tumor lesions, the population of NE-like cells, i.e., cells exhibiting NE phenotypes and expressing NE markers, is increased that correlates with tumor progression, poor prognosis, and the androgen-independent state. However, the origin of those NE-like cells in prostate cancer (PCa) lesions and the underlying molecular mechanism of enrichment remain an enigma. In this review, we focus on discussing the distinction between NE-like PCa and normal NE cells, the potential origin of NE-like PCa cells, and in vitro and in vivo studies related to the molecular mechanism of NE transdifferentiation of PCa cells. The data together suggest that PCa cells undergo a transdifferentiation process to become NE-like cells, which acquire the NE phenotype and express NE markers. Thus, we propose that those NE-like cells in PCa lesions were originated from cancerous epithelial cells, but not from normal NE cells, and should be defined as 'NE-like PCa cells'. We further describe the biochemical properties of newly established, stable NE-like lymph node carcinoma of the prostate (LNCaP) cell lines, transdifferentiated from androgen-sensitive LNCaP cells under androgen-deprived conditions. Knowledge of understanding NE-like PCa cells will help us to explore new therapeutic strategies for treating PCa.

Upregulation of manganese superoxide dismutase (SOD2) is a common pathway for neuroendocrine differentiation in prostate cancer cells

“…In the latter, the increased number of NE cells in advanced prostate tumors are frequently observed in HRPC after long-term androgen deprivation therapy. 46 It has been reported that several factors secreted from NE cells induce cell proliferation and the expression of oncogenes but cell culture studies have shown no effect or even an inhibitory effect on cell growth and a lack of aggressiveness in normal epithelial cells. This has led to some investigators to suggest that these NE cells observed in PCa may have a different origin and should be considered as NE-like PCa cells and not NE cells.…”

Molecular genetics of prostate cancer: new prospects for old challenges

“…Perhaps the most significant histological variant is neuroendocrine prostate cancer, which is generally classified as either small cell carcinoma or a carcinoid tumor, and represents <2% of prostate cancer cases (Grignon 2004). However, focal regions of neuroendocrine differentiation are more commonly observed in prostate adenocarcinoma, particularly following recurrence after prostatectomy and androgen deprivation therapy (Yuan et al 2007;Komiya et al 2009), and expression of the neuroendocrine marker chromogranin A is associated with the development of castration-resistant tumors and shortened time to disease recurrence (Kokubo et al 2005;Berruti et al 2007). This prevalence of neuroendocrine differentiation after recurrence may be due to the lack of AR expression by neuroendocrine cells, which are inherently castration-resistant.…”

PSMA Ligands for PET Imaging of Prostate Cancer

“…PSMA ligand PET/CT has an evolving role in PSMA-targeting treatments (e.g., radioligand therapy), evaluating target expression and therefore potentially predicting response (62)(63)(64). A rare but potential limitation is absent or low PSMA expression (e.g., in visceral metastases) in advanced disease, which may be related to therapy-induced specific biologic subtypes (e.g., neuroendocrine differentiated PC) (65,66). Further information on the use of PSMA ligands for diagnosis has been published elsewhere (67,68).…”