Neuroendocrine cells of prostate cancer: biologic functions and molecular mechanisms.

Prostate cancer (PCa) is a major health risk for older men worldwide. Existing systemic therapies mostly target androgen receptor (AR). Although treatments are initially effective, the disease always recurs. A potential mechanism for the treatment failure is that PCa contains, in addition to the AR-positive luminal type tumor cells, a small component of neuroendocrine (NE) cells. The function of NE cells in PCa remains poorly understood, and one important characteristic of these cells is their lack of expression of AR and resistance to hormonal therapy. In addition, many patients develop the more aggressive small-cell neuroendocrine carcinoma (SCNC) after hormonal therapy. Although this clinical phenomenon of disease transformation from adenocarcinoma to SCNC is well established, the cell of origin for SCNC remains unclear. Recently, loss of function of Rb and TP53 and amplification and overexpression of MYCN and Aurora A kinase have been identified as important biomarkers and potential disease drivers. In this article, we systematically review the histology of normal prostate and prostate cancer including the main histologic types: adenocarcinoma and SCNC. We also review the findings from many studies using cellular and animal models as well as human specimens that attempt to understand the molecular mechanisms of treatment failure, disease progression, and tumor transformation from adenocarcinoma to SCNC.

Potential therapeutic effect of epigenetic therapy on treatment-induced neuroendocrine prostate cancer.

Although adenocarcinomas of the prostate are relatively indolent, some patients with advanced adenocarcinomas show recurrence of treatment-induced neuroendocrine prostate cancer, which is highly aggressive and lethal. Detailed biological features of treatment-induced neuroendocrine prostate cancer have not been characterized owing to limited biopsies/resections and the lack of a cellular model. In this study, we used a unique cellular model (LNCaP/NE1.8) to investigate the potential role of cancer stem cells in treatment-induced neuroendocrine prostate cancer with acquired resistance to hormonal therapy and chemotherapy. We also studied the role of cancer stem cells in enhancing invasion in treatment-induced neuroendocrine prostate cancer cells that recurred after long-term androgen-ablation treatment. Using an in vitro system mimicking clinical androgen-ablation, our results showed that the neuroendocrine-like subclone NE1.8 cells were enriched with cancer stem cells. Compared to parental prostate adenocarcinoma LNCaP cells, NE1.8 cells are more resistant to androgen deprivation therapy and chemotherapeutic agents and show increased cancer cell invasiveness. Results from this study also suggest a potential epigenetic therapeutic strategy using suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, as a chemotherapeutic agent for therapy-resistant treatment-induced neuroendocrine prostate cancer cells to minimize the risk of prostate cancer recurrence and metastasis.

Histone methyltransferase SETDB1 is required for prostate cancer cell proliferation, migration and invasion.

SETDB1 has been established as an oncogene in a number of human carcinomas. The present study was to evaluate the expression of SETDB1 in prostate cancer (PCa) tissues and cells and to preliminarily investigate the role of SETDB1 in prostate tumorigenesis in vitro. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) and immunohistochemistry (IHC) were used to detect the expression of SETDB1 in PCa tissues, adjacent normal tissues, benign prostatic hyperplasia (BPH) tissues, PCa cell lines and normal prostate epithelial cells. The results suggested that SETDB1 was upregulated in human PCa tissues compared with normal tissues at the mRNA and protein levels. The role of SETDB1 in proliferation was analyzed with cell counting kit-8, colony-forming efficiency and flow cytometry assays. The results indicated that downregulation of SETDB1 by siRNA inhibited PCa cell growth, and induced G0/G1 cell cycle arrest. The PCa cell migration and invasion decreased by silcencing SETDB1 which were assessed by using in vitro scratch and transwell invasion assay respectively. Our data suggested that SETDB1 is overexpressed in human PCa. Silencing SETDB1 inhibited PCa cell proliferation, migration and invasion.