文章：

细胞衰老和癌症

Cell senescence and cancer

原文发布日期：2001-12-01

DOI: 10.1038/35106045

类型: Review Article

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要点：

1. Recently, it has been demonstrated that cell senescence in culture is not only induced by an intrinsic cell division counter mechanism (replicative senescence), but can also be induced by extrinsic factors such as culture conditions (premature senescence). The only known cell division counter is telomere shortening.
2. It has been proposed that replicative senescence suppresses tumorigenesis in vivo, as >90% tumours express telomerase at high levels and maintain telomere lengths. This is essential for their continued proliferation.
3. The increased cancer phenotype of the telomerase knockout mouse has shown that the role of telomere shortening in human cancer is difficult to predict. Depending on genetic context, telomere shortening can either promote or protect against tumorigenesis in mice. It is difficult to extrapolate these results to humans due to differing telomerase expression patterns and different telomere lengths.
4. Telomerase expression in human cells appears to correlate with proliferative requirements. These expression patterns may reflect a balance between different aspects of telomerase function: maintenance of telomere length and thus proliferative capacity; maintenance of genetic integrity; and a possible direct proliferative role.
5. Premature senescence, for example induced by oncogenic RAS or by suboptimal conditions equivalent to 'culture shock', may also operate as a tumour-suppressive mechanism.
6. Telomere shortening and thus increased genetic instability may account for the increased incidence of cancer as we age. An accumulation of senescent cells may also create environments that are more sustainable for tumour growth.
7. Both premature and replicative senescence could contribute to the progressive decline in bodily function associated with ageing. An accumulation of senescent cells may hinder normal function, decrease regenerative capacity and increase genetic damage.
8. The elevated expression of telomerase in almost all tumours may provide a diagnostic and prognostic tool for cancer. Moreover, as tumour cells require telomerase expression for continued proliferation, inhibitors of telomerase activity may provide effective cancer therapies.

要点翻译：

1. 近期研究表明，细胞在培养中的衰老不仅由内在细胞分裂计数机制（复制性衰老）诱导，也可由外部因素如培养条件（早熟性衰老）引发。目前已知唯一的细胞分裂计数器是端粒缩短。
2. 有观点认为复制性衰老可抑制体内肿瘤发生，因为超过90%的肿瘤会高水平表达端粒酶并维持端粒长度，这对肿瘤持续增殖至关重要。
3. 端粒酶敲除小鼠表现出的增强癌症表型表明，端粒缩短在人类癌症中的作用难以预测。根据遗传背景差异，端粒缩短在小鼠体内可能促进或抑制肿瘤发生。由于端粒酶表达模式和端粒长度存在种间差异，这些结果难以直接外推至人类。
4. 人类细胞中端粒酶的表达似乎与增殖需求相关。这种表达模式可能反映了端粒酶功能不同方面的平衡：维持端粒长度从而保障增殖能力；保持基因组完整性；以及可能存在的直接促增殖作用。
5. 早熟性衰老（例如由致癌基因RAS或相当于"培养休克"的次优条件诱导）也可能作为一种肿瘤抑制机制发挥作用。
6. 端粒缩短导致的基因组不稳定性增加，可以解释为何癌症发病率随年龄增长而上升。衰老细胞的积累也可能创造更有利于肿瘤生长的微环境。
7. 早熟性衰老和复制性衰老共同促使机体功能随衰老进程逐渐衰退。衰老细胞的积累可能阻碍正常功能、降低再生能力并增加基因损伤。
8. 端粒酶在几乎所有肿瘤中的高表达为癌症诊断和预后评估提供了工具。此外，由于肿瘤细胞依赖端粒酶表达维持持续增殖，端粒酶活性抑制剂可能成为有效的癌症治疗手段。

英文摘要：

Historically, the senescent state has been associated with, and was named after, the cell-cycle arrest that occurs after cells have undergone an intrinsically defined number of divisions in vitro. More recently, however, it has been shown that extrinsic factors, including those encountered in normal tissue-culture environments, can prematurely induce an indistinguishable senescent phenotype. In this review, we discuss the pathways of cell senescence, the mechanisms involved and the role that these pathways have in regulating the initiation and progression of cancer.

摘要翻译： 

从历史上看，衰老状态与细胞在体外经历固有分裂次数后发生的细胞周期停滞相关，并因此得名。然而，近期研究表明，包括正常组织培养环境中存在的某些外在因子，可提前诱导出具有不可区分性的衰老表型。本文综述将探讨细胞衰老的途径、相关机制，以及这些通路在调控癌症发生和发展中的作用。

原文链接：

Cell senescence and cancer