文章：

有丝分裂染色体不稳定性和癌症：人类疾病的小鼠模型

Mitotic chromosomal instability and cancer: mouse modelling of the human disease

原文发布日期：2010-02-01

DOI: 10.1038/nrc2781

类型: Review Article

开放获取: 否

要点：

1. Chromosomal instability (CIN), the inability to correctly segregate sister chromatids during mitosis, provides the evolutionary fuel to initiate and propagate the transformed state of multiple forms of cancer.
2. The mitotic checkpoint is seldom lost or weakened in human tumours.
3. Mitotic checkpoint overactivation is a more frequent observation in human tumours and is sufficient to generate CIN in vivo and in vitro. Mitotic checkpoint overactivation results in a prolonged mitosis, abnormal stabilization of cyclin B1 and securin, and an increased incidence of merotelic attachments and lagging chromosomes.
4. Many of the key regulators of the mitotic checkpoint are downstream targets of the Rb tumour suppressor pathway and are therefore upregulated in most human tumours.
5. The consequences of CIN are manifold and context-dependent. Although CIN can initiate tumour formation in many mouse models, under some conditions it decreases cellular fitness, providing a potential tumour suppressor effect. This effect is nevertheless often overcome, giving rise to the karyotypic complexity observed in advanced tumours.
6. Mitotic checkpoint overactivation could prove effective as a novel therapeutic target as mitotic checkpoint loss is incompatible with cellular viability.

要点翻译：

1. 染色体不稳定性（CIN）作为细胞有丝分裂过程中姐妹染色单体正确分离能力的缺失，为多种癌症的转化态发生和演进提供了进化动力。
2. 人类肿瘤中罕见有丝分裂检查点功能丧失或减弱的情况。
3. 更常见的观察发现是，人类肿瘤中存在有丝分裂检查点过度激活现象，这种过度激活足以在体内和体外诱导CIN。有丝分裂检查点的过度激活会导致有丝分裂期延长、细胞周期蛋白B1和分离蛋白异常稳定化，并增加错位附着和染色体滞后现象的发生率。
4. 有丝分裂检查点的多个关键调控因子是Rb肿瘤抑制通路的下游靶标，因此在大多数人类肿瘤中呈现上调表达。
5. CIN的影响具有多重性且与背景环境相关。虽然在许多小鼠模型中CIN可启动肿瘤形成，但在某些条件下它会降低细胞适应性，从而产生潜在的肿瘤抑制效应。然而这种抑制效应常被突破，进而导致晚期肿瘤中观察到的核型复杂性。
6. 鉴于有丝分裂检查点功能缺失与细胞存活不相容，针对有丝分裂检查点过度激活的干预可能成为新型治疗策略的有效靶点。

英文摘要：

The stepwise progression from an early dysplastic lesion to full-blown metastatic malignancy is associated with increases in genomic instability. Mitotic chromosomal instability — the inability to faithfully segregate equal chromosome complements to two daughter cells during mitosis — is a widespread phenomenon in solid tumours that is thought to serve as the fuel for tumorigenic progression. How chromosome instability (CIN) arises in tumours and what consequences it has are still, however, hotly debated issues. Here we review the recent literature with an emphasis on models that recapitulate observations from human disease.

摘要翻译： 

从早期异型增生性病变逐步发展为全面转移性恶性肿瘤的过程中，伴随着基因组不稳定性的增加。有丝分裂中的染色体不稳定性——即在细胞分裂时无法将等量染色体准确分配给两个子细胞的现象——在实体瘤中十分普遍，被认为是推动肿瘤进展的“燃料”。然而，染色体不稳定性（CIN）在肿瘤中如何产生、又会带来哪些后果，仍是激烈争论的问题。本文综述近期文献，重点介绍能够重现人类疾病观察结果的模型。

原文链接：

Mitotic chromosomal instability and cancer: mouse modelling of the human disease