Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, VA, USA.
Department of Internal Medicine, Division of Hematology, Oncology & Palliative Care, VCU Health, Richmond, VA, USA.
Biochim Biophys Acta Rev Cancer. 2020 Dec;1874(2):188424. doi: 10.1016/j.bbcan.2020.188424. Epub 2020 Sep 18.
The development of Castration-Resistant Prostate Cancer (CRPC) remains a major challenge in the treatment of this disease. While Androgen Deprivation Therapy (ADT) can result in tumor shrinkage, a primary response of Prostate Cancer (PCa) cells to ADT is a senescent growth arrest. As a response to cancer therapies, senescence has often been considered as a beneficial outcome due to its association with stable growth abrogation, as well as the potential for immune system activation via the Senescence-Associated Secretory Phenotype (SASP). However, there is increasing evidence that not only can senescent cells regain proliferative capacity, but that senescence contributes to deleterious effects of cancer chemotherapy, including disease recurrence. Notably, the preponderance of work investigating the consequences of therapy-induced senescence on tumor progression has been performed in non-PCa models. Here, we summarize the evidence that ADT promotes a senescent response in PCa and postulate mechanisms by which senescence may contribute to the development of castration-resistance. Primarily, we suggest that ADT-induced senescence may support CRPC development via escape from senescence, by cell autonomous-reprogramming, and by the formation of a pro-tumorigenic SASP. However, due to the scarcity of direct evidence from PCa models, the consequences of ADT-induced senescence outlined here remain speculative until the relationship between senescence and CRPC can be experimentally defined.
去势抵抗性前列腺癌（CRPC）的发展仍然是治疗这种疾病的主要挑战。虽然雄激素剥夺疗法（ADT）可以导致肿瘤缩小，但前列腺癌（PCa）细胞对 ADT 的主要反应是衰老的生长停滞。作为对癌症治疗的反应，衰老通常被认为是有益的，因为它与稳定的生长抑制有关，并且通过衰老相关分泌表型（SASP）有激活免疫系统的潜力。然而，越来越多的证据表明，衰老细胞不仅可以恢复增殖能力，而且衰老会导致癌症化疗的有害影响，包括疾病复发。值得注意的是，研究治疗诱导的衰老对肿瘤进展的影响的大部分工作都是在非 PCa 模型中进行的。在这里，我们总结了 ADT 促进 PCa 衰老反应的证据，并推测衰老可能导致去势抵抗的机制。主要地，我们认为 ADT 诱导的衰老可能通过逃避衰老、细胞自主重编程以及形成促肿瘤 SASP 来支持 CRPC 的发展。然而，由于缺乏来自 PCa 模型的直接证据，此处概述的 ADT 诱导的衰老的后果仍然是推测性的，直到衰老与 CRPC 之间的关系可以通过实验来定义。
