Human ASH1 expression in prostate cancer with neuroendocrine differentiation

Abstract

Neuroendocrine differentiation in prostate cancer correlates with overall prognosis and disease progression after androgen-deprivation therapy, although its specific mechanisms are currently poorly understood. A role of Notch pathway has been reported in determining neuroendocrine phenotype of normal and neoplastic tissues. The aim of this study was to analyze whether this pathway might affect neuroendocrine differentiation in prostate cancer. Human achaete-scute homolog 1 (hASH1), a pivotal member of the Notch pathway, was investigated in 80 prostate cancers selected and grouped according to chromogranin A immunohistochemistry, as follows: prostate cancers without neuroendocrine differentiation, untreated (25 cases); prostate cancers with neuroendocrine differentiation, untreated (40 cases); prostate cancers with previous androgen-deprivation therapy, all having neuroendocrine differentiation (15 cases). Human ASH1 protein was analyzed by immunohistochemistry, whereas the presence of hASH1 mRNA transcripts was investigated on paraffin material by real-time PCR. By immunohistochemistry, hASH1 was colocalized with chromogranin A in neuroendocrine cells of normal prostatic gland. It was absent in all but one prostate cancers without neuroendocrine differentiation, whereas it was positive in 25% of prostate cancers with neuroendocrine differentiation/ untreated, with a significant correlation with the extent of neuroendocrine features (P ¼ 0.02). Moreover, comparing untreated and treated prostate cancers with neuroendocrine differentiation, a positive association with androgen-deprivation therapy was observed (P ¼ 0.01). In prostate cancers with neuroendocrine differentiation, RNA analysis confirmed the association of higher transcript levels in androgen deprivationtreated compared with untreated patients (P ¼ 0.01). In addition, hASH1 mRNA analysis in microdissected chromogranin A-positive and chromogranin A-negative areas within the same tumor demonstrated a two-to sevenfold increase of hASH1 mRNA expression in chromogranin A-positive tumor cell populations.

Increased neuroendocrine cells in resected metastases compared to primary colorectal adenocarcinomas

“…In this respect, the expression of transcription factors known to drive neuroendocrine differentiation in the embryonic life, such as human achaete-scute-homologue type 1 (hASH1) may be involved in the occurrence of neuroendocrine differentiation [16]. Unfortunately, in the present series, no hASH1 expression was observed (data not shown) suggesting that at least in the intestinal area, the development of neuroendocrine differentiated cells may follow alternative pathways, compared to other models such as the prostate [17].…”

A Prominent Couple

“…Absent AR expression and disproportional low PSA levels are hallmarks of NEPC [70,71]. NE foci exist within virtually all human prostate adenocarcinomas, reported incidence rates range from 25-90% [67,72,73]. It was suggested that the different morphologic manifestations of NEPC, i.e.…”

“…NE cells containing neurosecretory granules by electron microscopy, are immunohistochemically detected by positive staining for synaptophysin (SYP) (Figure 1.1A), chromogranins A and B (CHGA, CHGB), neuron-specific enolase (NSE/ENO2), or neuronal cell adhesion molecule (NCAM1/CD56) [67] [68]. NEPC is the most significant histological subtype of PCa compared to other rare categories such as ductal adenocarcinoma, mucinous carcinoma, and signet ring carcinoma [69].…”

“…Among patients with advanced disease, manifestation of a high-grade neuroendocrine PCa (NEPC) phenotype is detected, distinguished from prostatic acinar carcinoma by unique clinical and ultrastructural characteristics and immunohistochemical staining for various neuroendocrine elements and polypeptide hormones [67]. NE cells containing neurosecretory granules by electron microscopy, are immunohistochemically detected by positive staining for synaptophysin (SYP) (Figure 1.1A), chromogranins A and B (CHGA, CHGB), neuron-specific enolase (NSE/ENO2), or neuronal cell adhesion molecule (NCAM1/CD56) [67] [68].…”

“…In 2014, the highest incidence rates for PCa in the US were in the age group of [65][66][67][68][69][70][71][72][73][74] years, while between 1975-1995 the incidence rates were in the group of 75 years or older indicating that the diagnosis is currently made at younger age [7]. The incidence rates for PCa are highly variable between different geographical areas, with highest incidence in industrialized countries [6].…”