Department of Urologic Sciences, Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada.
Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
BJU Int. 2018 Oct;122(4):560-570. doi: 10.1111/bju.14207. Epub 2018 Apr 24.
Prostate cancer (PCa) is the most common form of cancer in men in the developed world and the second leading cause of cancer-related deaths. While advanced PCa is initially controlled with hormonal therapies targeting the androgen receptor (AR) pathway, recurrence occurs because of the emergence of lethal castration-resistant PCa (CRPC). Despite newer AR pathway inhibitors that prolong survival, resistance still emerges, most often with rising PSA levels indicative of AR-driven activity, but increasingly as non-AR-driven cancer. Treatment resistance mechanisms include AR-signalling pathway alterations, AR-signalling bypass mechanisms, and AR-independent clonal evolution. The latter mechanism can lead to the emergence of neuroendocrine prostate cancer (NEPC), an aggressive lethal subtype of PCa. The incidence of treatment-induced NEPC is rising because of the widespread use of more potent AR pathway inhibitors. This comprehensive review of major NEPC drivers and facilitators defines three coordinated processes contributing to NEPC progression. Specifically, castration-resistant adenocarcinoma cells gain lineage plasticity under selective pressures of potent AR suppression to transform into AR-independent tumour cells. In concert, neuroendocrine (NE)-specific transdifferentiation factors induce NE lineage of these PCa cells, which, with support of increased proliferation factors, contributes to clonal expansion and tumour repopulation into NEPC. We examine the roles of each of the major NEPC contributors during the disease progression and identify potential therapeutic opportunities for targeted therapies.
前列腺癌（PCa）是发达国家男性中最常见的癌症类型，也是癌症相关死亡的第二大主要原因。虽然针对雄激素受体（AR）途径的激素疗法可以控制晚期 PCa，但由于致命的去势抵抗性 PCa（CRPC）的出现，复发仍然会发生。尽管新型 AR 途径抑制剂可以延长生存时间，但耐药性仍然会出现，最常见的是 PSA 水平升高表明 AR 驱动的活性，但越来越多地表现为非 AR 驱动的癌症。治疗耐药机制包括 AR 信号通路改变、AR 信号旁路机制和 AR 独立的克隆进化。后一种机制可导致神经内分泌前列腺癌（NEPC）的出现，这是一种侵袭性致命的 PCa 亚型。由于更有效的 AR 途径抑制剂的广泛使用，治疗诱导的 NEPC 的发生率正在上升。本文全面综述了主要的 NEPC 驱动因素和促进因素，定义了三个协调的过程，有助于 NEPC 的进展。具体来说，在强效 AR 抑制的选择性压力下，去势抵抗性腺癌细胞获得谱系可塑性，转化为 AR 独立的肿瘤细胞。同时，神经内分泌（NE）特异性转分化因子诱导这些 PCa 细胞的 NE 谱系，在增殖因子增加的支持下，促进克隆扩展和肿瘤重新填充到 NEPC 中。我们检查了每个主要 NEPC 贡献者在疾病进展过程中的作用，并确定了针对这些贡献者的潜在治疗机会。
