Department of Urology, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Int J Mol Sci. 2021 Feb 20;22(4):2100. doi: 10.3390/ijms22042100.
Prostate cancer (PCa) mortality remains a significant public health problem, as advanced disease has poor survivability due to the development of resistance in response to both standard and novel therapeutic interventions. Therapeutic resistance is a multifaceted problem involving the interplay of a number of biological mechanisms including genetic, signaling, and phenotypic alterations, compounded by the contributions of a tumor microenvironment that supports tumor growth, invasiveness, and metastasis. The androgen receptor (AR) is a primary regulator of prostate cell growth, response and maintenance, and the target of most standard PCa therapies designed to inhibit AR from interacting with androgens, its native ligands. As such, AR remains the main driver of therapeutic response in patients with metastatic castration-resistant prostate cancer (mCRPC). While androgen deprivation therapy (ADT), in combination with microtubule-targeting taxane chemotherapy, offers survival benefits in patients with mCRPC, therapeutic resistance invariably develops, leading to lethal disease. Understanding the mechanisms underlying resistance is critical to improving therapeutic outcomes and also to the development of biomarker signatures of predictive value. The interconversions between epithelial-to-mesenchymal transition (EMT) and mesenchymal-to-epithelial transition (MET) navigate the prostate tumor therapeutic response, and provide a novel targeting platform in overcoming therapeutic resistance. Both microRNA (miRNA)- and long non-coding RNA (lncRNA)-mediated mechanisms have been associated with epigenetic changes in prostate cancer. This review discusses the current evidence-based knowledge of the role of the phenotypic transitions and novel molecular determinants (non-coding RNAs) as contributors to the emergence of therapeutic resistance and metastasis and their integrated predictive value in prostate cancer progression to advanced disease.
前列腺癌 (PCa) 死亡率仍然是一个重大的公共卫生问题，因为晚期疾病的生存能力很差，这是由于对标准和新型治疗干预的反应产生了耐药性。治疗耐药性是一个多方面的问题，涉及许多生物学机制的相互作用，包括遗传、信号和表型改变，并受到支持肿瘤生长、侵袭和转移的肿瘤微环境的影响。雄激素受体 (AR) 是前列腺细胞生长、反应和维持的主要调节剂，也是大多数旨在抑制 AR 与雄激素及其天然配体相互作用的标准 PCa 治疗的靶点。因此，AR 仍然是转移性去势抵抗性前列腺癌 (mCRPC) 患者治疗反应的主要驱动因素。虽然雄激素剥夺疗法 (ADT) 联合微管靶向紫杉烷化疗可使 mCRPC 患者获益，但耐药性不可避免地会发展，导致致命疾病。了解耐药性的机制对于改善治疗效果以及开发具有预测价值的生物标志物特征至关重要。上皮-间充质转化 (EMT) 和间充质-上皮转化 (MET) 之间的转换导航前列腺肿瘤治疗反应，并为克服治疗耐药性提供了一个新的靶向平台。microRNA (miRNA) 和长非编码 RNA (lncRNA) 介导的机制与前列腺癌中的表观遗传变化有关。这篇综述讨论了目前关于表型转换和新型分子决定因素 (非编码 RNA) 作为治疗耐药性和转移出现的贡献以及它们在前列腺癌进展为晚期疾病中的综合预测价值的循证知识。
