Senescence surveillance of pre- malignant hepatocytes limits liver cancer development

摘要

致癌基因诱导的衰老曾被发现起一个内在肿瘤rn抑制机制的作用.现在,Lars Zerlder及其同事rn提出了"衰老监测"的概念:他们发现,恶变rn前的衰老肝细胞能通过一个由肿瘤抗原引导的rn免疫反应被清除.这个过程需要CD4+T细胞的rn参与,并且在小鼠模型中抑制肝癌的发展.本rn文作者们还提供了这样的证据.衰老肝细胞会rn在免疫系统被抑制的患者肝脏中积累,说明衰rn老监测对人类也可能行得通.设计用来利用对rn恶变前的衰老细胞进行抗原特异性免疫监测的rn策略在癌症预防和治疗中可能会有潜力,而这rn种类型的抗原特异性免疫反应在疫苗生产中也rn可能会有用.%Upon the aberrant activation of oncogenes, normal cells can enter the cellular senescence program, a state of stable cell-cycle arrest, which represents an important barrier against tumour development in vivo1. Senescent cells communicate with their environment by secreting various cytokines and growth factors, and it was reported that this 'secretory phenotype' can have pro- as well as anti-tumorigenic effects2 5. Here we show that oncogene-induced senescence occurs in otherwise normal murine hepatocytes in vivo. Pre-malignant senescent hepatocytes secrete chemo- and cytokines and are subject to immune-mediated clearance (designated as 'senescence surveillance'), which depends on an intact CD4~+ T-cell-mediated adaptive immune response. Impaired immune surveillance of pre-malignant senescent hepatocytes results in the development of murine hepatocellular carcinomas (HCCs), thus showing that senescence surveillance is important for tumour suppression in vivo. In accordance with these observations, ras-specific Thl lymphocytes could be detected in mice, in which oncogene-induced senescence had been triggered by hepatic expression of Nras~(G12V). We also found that CD4~+ T cells require monocytes/ macrophages to execute the clearance of senescent hepatocytes. Our study indicates that senescence surveillance represents an important extrinsic component of the senescence anti-tumour barrier, and illustrates how the cellular senescence program is involved in tumour immune surveillance by mounting specific immune responses against antigens expressed in pre-malignant senescent cells.