Senescence surveillance of pre-malignant hepatocytes limits liver cancer development
Senescence surveillance of pre-malignant hepatocytes limits liver cancer development
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DOI：
10.1038/nature10599
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发表时间：
2011-11-24
期刊：
影响因子：
64.8
通讯作者：
Zender, Lars
中科院分区：
文献类型：
--
作者：
Kang, Tae-Won;Yevsa, Tetyana;Zender, Lars
一旦癌基因异常激活，正常细胞就可以进入细胞衰老程序，这是一种稳定的细胞周期停滞状态，这是体内对抗肿瘤发展的重要屏障(1)。衰老细胞通过分泌各种细胞因子和生长因子与环境进行交流，据报道，这种“分泌表型”既有促肿瘤作用，也有抗肿瘤作用(2-5)。在这里，我们证明了癌基因诱导的衰老发生在活体内正常的小鼠肝细胞中。癌前衰老的肝细胞分泌化学和细胞因子，并接受免疫介导的清除(称为衰老监测)，这依赖于完整的CD4(+)T细胞介导的适应性免疫反应。癌前衰老肝细胞的免疫监视功能受损导致小鼠肝细胞癌的发生，从而表明衰老监视对体内肿瘤抑制具有重要意义。根据这些观察，可以在小鼠中检测到ras特异性的Th1淋巴细胞，其中癌基因诱导的衰老是由肝脏NRAS(G12V)的表达引发的。我们还发现，CD4(+)T细胞需要单核/巨噬细胞来执行衰老肝细胞的清除。我们的研究表明，衰老监测是衰老抗肿瘤屏障的重要外在组成部分，并阐明了细胞衰老程序如何通过启动针对癌前衰老细胞中表达的抗原的特异性免疫反应而参与肿瘤免疫监测。
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(1). 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(2-5). 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 Th1 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.