CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China.
Cancer Res. 2020 Aug 15;80(16):3383-3398. doi: 10.1158/0008-5472.CAN-20-0506. Epub 2020 May 4.
Cellular senescence is a potent tumor-suppressive program that prevents neoplastic events. Paradoxically, senescent cells develop an inflammatory secretome, termed the senescence-associated secretory phenotype, which is implicated in age-related pathologies including cancer. Here, we report that senescent cells actively synthesize and release small extracellular vesicles (sEV) with a distinctive size distribution. Mechanistically, SIRT1 loss supported accelerated sEV production despite enhanced proteome-wide ubiquitination, a process correlated with ATP6V1A downregulation and defective lysosomal acidification. Once released, senescent stromal sEVs significantly altered the expression profile of recipient cancer cells and enhanced their aggressiveness, specifically drug resistance mediated by expression of ATP-binding cassette subfamily B member 4 (ABCB4). Targeting SIRT1 with agonist SRT2104 prevented development of cancer resistance by restraining sEV production by senescent stromal cells. In clinical oncology, sEVs in peripheral blood of posttreatment cancer patients were readily detectable by routine biotechniques, presenting an exploitable biomarker to monitor therapeutic efficacy and predict long-term outcome. Together, this study identifies a distinct mechanism supporting pathologic activities of senescent cells and provides a potent avenue to circumvent advanced human malignancies by cotargeting cancer cells and their surrounding microenvironment, which contributes to drug resistance via secretion of sEVs from senescent stromal cells. SIGNIFICANCE: Senescent stromal cells produce a large number of sEVs to promote cancer resistance in therapeutic settings, a process driven by SIRT1 decline in stromal cells and ABCB4 augmentation in cancer cells. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/16/3383/F1.large.jpg.
细胞衰老（Cellular senescence）是一种强大的肿瘤抑制程序，可防止肿瘤发生。矛盾的是，衰老细胞会产生一种炎症性的分泌组，称为衰老相关分泌表型（senescence-associated secretory phenotype），这与包括癌症在内的与年龄相关的病理学有关。在这里，我们报告说衰老细胞主动合成并释放具有独特大小分布的小细胞外囊泡（small extracellular vesicles，sEV）。从机制上讲，尽管蛋白质组范围内的泛素化增强，但 SIRT1 的缺失支持了加速的 sEV 产生，这一过程与 ATP6V1A 的下调和溶酶体酸化缺陷相关。一旦释放，衰老的基质 sEV 会显著改变受体癌细胞的表达谱，并增强其侵袭性，特别是通过表达 ABCB4 介导的药物抗性。用激动剂 SRT2104 靶向 SIRT1 可通过抑制衰老基质细胞的 sEV 产生来阻止癌症耐药性的发展。在临床肿瘤学中，通过常规生物技术可在治疗后的癌症患者的外周血中轻松检测到 sEV，为监测治疗效果和预测长期预后提供了一种可利用的生物标志物。总的来说，这项研究确定了一种支持衰老细胞病理活性的独特机制，并提供了一种有效的途径，通过靶向癌细胞及其周围微环境，来规避晚期人类恶性肿瘤，这是通过衰老基质细胞分泌 sEV 促进药物抗性来实现的。
衰老的基质细胞产生大量的 sEV，以促进治疗环境中的癌症耐药性，这个过程是由基质细胞中 SIRT1 的下降和癌细胞中 ABCB4 的增加驱动的。
