文章：

衰老、细胞凋亡和治疗——切断癌症的生命线

Senescence, apoptosis and therapy — cutting the lifelines of cancer

原文发布日期：2003-04-01

DOI: 10.1038/nrc1044

类型: Review Article

开放获取: 否

要点：

1. Oncogene-driven hyperproliferation and failsafe defects are the key cellular insults that enable malignant growth.
2. Mitogenic oncogenes preferentially provoke either apoptosis or premature senescence as cellular counteraction, leading to malignancies that harbour failsafe defects as 'oncogenic signatures'.
3. The 'lifelines' of cancer reflect defects in cellular growth control that are essential for tumorigenesis, such as disrupted apoptosis or senescence.By contrast, not all the mutations that are acquired during tumour progression are required to maintain neoplastic growth.
4. DNA-damaging anticancer drugs recruit the cell's failsafe machinery to execute apoptosis or cellular senescence.Defects in stress-response programmes that are acquired during tumour formation can co-select for drug resistance — even prior to drug exposure.
5. Identifying therapeutic approaches to 'cut the lifelines of cancer' is an appealing concept.By contrast, utilization or restoration of drug effector programmes that are not targeted during tumour formation could be a more efficient alternative.
6. Large-scale genetic screens and physiological test systems that allow high-throughput functional genomics are needed to identify key defects in failsafe pathways and to validate their implication for drug responses and novel therapeutic interventions.

要点翻译：

1. 致癌基因驱动的过度增殖与安全机制缺陷是促成恶性生长的关键细胞损伤。
2. 促癌基因优先引发细胞凋亡或早衰作为细胞对抗反应，导致携带安全机制缺陷的恶性肿瘤成为"致癌特征"。
3. 癌症的"生命线"反映了细胞生长调控缺陷（如凋亡或衰老机制破坏）对肿瘤发生至关重要。相比之下，并非所有肿瘤进展过程中获得的突变都是维持肿瘤生长所必需的。
4. DNA损伤性抗癌药物通过调动细胞安全机制来执行凋亡或细胞衰老。肿瘤形成过程中获得的应激反应程序缺陷可能共同选择耐药性——甚至在药物暴露前就已发生。
5. 开发"切断癌症生命线"的治疗策略是个诱人的概念。相比之下，利用或恢复肿瘤形成过程中未靶向的药物效应程序可能是更有效的替代方案。
6. 需要建立允许高通量功能基因组学的大规模遗传筛选和生理测试系统，以识别安全通路的关键缺陷并验证其对药物反应及新型治疗干预的意义。

英文摘要：

Apoptosis and senescence are cellular failsafe programmes that counteract excessive mitogenic signalling from activated oncogenes. Cancellation of apoptosis or senescence is therefore a prerequisite for tumour formation, and the ability of the cancer cell to disrupt these processes can be considered its 'lifeline'. Ironically, the efficacy of anticancer agents also depends on the activation of apoptosis or an acutely inducible form of cellular senescence. Understanding how the 'lifelines' of the cancer cell interfere with treatment sensitivity is of crucial importance for developing safer and more effective treatment strategies.

摘要翻译： 

细胞凋亡与衰老是细胞固有的安全程序，可对抗激活癌基因产生的过度有丝分裂信号。因此，取消凋亡或衰老是肿瘤形成的先决条件，而癌细胞破坏这些过程的能力可视为其“生命线”。讽刺的是，抗癌药物的疗效也依赖于细胞凋亡或急性可诱导的细胞衰老的激活。理解癌细胞的“生命线”如何干扰治疗敏感性，对开发更安全、更有效的治疗策略至关重要。

原文链接：

Senescence, apoptosis and therapy — cutting the lifelines of cancer