文章：

通往癌症的道路：非整倍体和有丝分裂检查点

On the road to cancer: aneuploidy and the mitotic checkpoint

原文发布日期：2005-10-01

DOI: 10.1038/nrc1714

类型: Review Article

开放获取: 否

要点：

1. Aneuploidy, or abnormal chromosome content, is the most common characteristic of human solid tumours. Aneuploidy might contribute to tumour formation and is associated with acquired resistance to some chemotherapeutics.
2. Tumour cells become aneuploid as a result of aberrant mitotic divisions. These aberrant divisions are caused by divisions with a multipolar spindle as a result of previous defects in cytokinesis or centrosome amplification, by defects in chromosome cohesion, by spindle attachment defects, or by impairment of the mitotic checkpoint response.
3. The mitotic checkpoint is a signalling cascade that arrests the cell cycle in mitosis when even a single chromosome is not properly attached to the mitotic spindle. This arrest is achieved by inhibiting the anaphase-promoting complex/cyclosome (APC/C), an E3 ubiquitin ligase that is essential for mitotic progression.
4. Many tumour cells have a diminished, but not absent, mitotic checkpoint response. Mouse models in which mitotic checkpoint signalling is decreased show an increase in spontaneous or carcinogen-induced tumour formation.
5. Mutations in mitotic checkpoint genes themselves are not a common mechanism of checkpoint impairment in human tumour cells.
6. Mitotic checkpoint impairment and aneuploidy in human tumour cells are often associated with changes in the protein levels of mitotic checkpoint proteins. In some tumour cells, these changes occur through altered transcriptional regulation by tumour suppressors or oncogene products.
7. Complete inactivation of mitotic checkpoint signalling causes cell-autonomous lethality. Drugs that specifically and efficiently interfere with mitotic checkpoint signalling could therefore be useful as anticancer agents.

要点翻译：

1. 非整倍体，即染色体含量异常，是人类实体肿瘤最常见的特征。非整倍体可能促进肿瘤形成，并与对某些化疗药物的获得性耐药相关。
2. 肿瘤细胞因异常有丝分裂而成为非整倍体。这些异常分裂由以下原因引起：由于先前胞质分裂缺陷或中心体扩增导致的多极纺锤体分裂、染色体黏连缺陷、纺锤体附着缺陷，或纺锤体组装检查点反应受损。
3. 纺锤体组装检查点是一种信号级联反应，当哪怕仅有一条染色体未正确附着于纺锤体时，即可将细胞周期阻滞在有丝分裂期。该阻滞通过抑制后期促进复合物/周期体（APC/C）实现——这是一种对有丝分裂进程至关重要的E3泛素连接酶。
4. 许多肿瘤细胞的纺锤体组装检查点反应减弱但并未完全缺失。纺锤体组装检查点信号减弱的小鼠模型显示自发或致癌物诱导的肿瘤形成增加。
5. 纺锤体组装检查点基因本身的突变并非人类肿瘤细胞检查点受损的常见机制。
6. 人类肿瘤细胞中的纺锤体组装检查点损伤和非整倍体常与纺锤体检查点蛋白的蛋白水平变化相关。在某些肿瘤细胞中，这些变化通过肿瘤抑制因子或癌基因产物的转录调控改变而发生。
7. 纺锤体组装检查点信号的完全失活会导致细胞自主性死亡。因此，能特异性且有效干扰纺锤体组装检查点信号的药物或可作为有效的抗癌剂。

英文摘要：

Abnormal chromosome content — also known as aneuploidy — is the most common characteristic of human solid tumours. It has therefore been proposed that aneuploidy contributes to, or even drives, tumour development. The mitotic checkpoint guards against chromosome mis-segregation by delaying cell-cycle progression through mitosis until all chromosomes have successfully made spindle-microtubule attachments. Defects in the mitotic checkpoint generate aneuploidy and might facilitate tumorigenesis, but more severe disabling of checkpoint signalling is a possible anticancer strategy.

摘要翻译： 

异常染色体含量——也称为非整倍性——是人类实体瘤最常见的特征。因此有人提出，非整倍性促进甚至驱动肿瘤的发生发展。有丝分裂检查点通过延迟细胞周期进程，直到所有染色体都成功与纺锤体微管连接，从而防止染色体错分。有丝分裂检查点缺陷会导致非整倍性，并可能促进肿瘤发生，但更严重的检查点信号失活则是一种潜在的抗癌策略。

原文链接：

On the road to cancer: aneuploidy and the mitotic checkpoint