11月24日，nature杂志在线发表了德国研究人员的最新研究成果，揭示了肝细胞癌变前的衰老监测可以限制肝癌的发展。致癌基因诱导的衰老曾被发现起一个内在肿瘤抑制机制的作用。Lars Zender及其同事提出了“衰老监测”的概念：他们发现，恶变前的衰老肝细胞能通过一个由肿瘤抗原引导的免疫反应被清除。这个过程需要CD4+ T细胞的参与，并且在小鼠模型中抑制肝癌的发展。本文作者们还提供了这样的证据：衰老肝细胞会在免疫系统被抑制的患者肝脏中积累，说明衰老监测对人类也可能行得通。设计用来利用对恶变前的衰老细胞进行抗原特异性免疫监测的策略在癌症预防和治疗中可能会有潜力，而这种类型的抗原特异性免疫反应在疫苗生产中也可能会有用。（生物谷Bioon.com）
doi:10.1038/nature10599
PMC:
PMID:
Senescence surveillance of pre-malignant hepatocytes limits liver cancer development
Tae-Won Kang, Tetyana Yevsa, Norman Woller, Lisa Hoenicke, Torsten Wuestefeld, Daniel Dauch, Anja Hohmeyer, Marcus Gereke, Ramona Rudalska, Anna Potapova, Marcus Iken, Mihael Vucur, Siegfried Weiss, Mathias Heikenwalder, Sadaf Khan, Jesus Gil, Dunja Bruder, Michael Manns, Peter Schirmacher, Frank Tacke, Michael Ott, Tom Luedde, Thomas Longerich, Stefan Kubicka & Lars Zender
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 vivo. 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 effects. 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 Th1 lymphocytes could be detected in mice, in which oncogene-induced senescence had been triggered by hepatic expression of NrasG12V. 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.
