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Exploiting aneuploidy-imposed stresses and coping mechanisms to battle cancer.
Open Biology ( IF 5.8 ) Pub Date : 2020-09-02 , DOI: 10.1098/rsob.200148
Lin Zhou 1 , Laura J Jilderda 1 , Floris Foijer 1
Affiliation  

Aneuploidy, an irregular number of chromosomes in cells, is a hallmark feature of cancer. Aneuploidy results from chromosomal instability (CIN) and occurs in almost 90% of all tumours. While many cancers display an ongoing CIN phenotype, cells can also be aneuploid without displaying CIN. CIN drives tumour evolution as ongoing chromosomal missegregation will yield a progeny of cells with variable aneuploid karyotypes. The resulting aneuploidy is initially toxic to cells because it leads to proteotoxic and metabolic stress, cell cycle arrest, cell death, immune cell activation and further genomic instability. In order to overcome these aneuploidy-imposed stresses and adopt a malignant fate, aneuploid cancer cells must develop aneuploidy-tolerating mechanisms to cope with CIN. Aneuploidy-coping mechanisms can thus be considered as promising therapeutic targets. However, before such therapies can make it into the clinic, we first need to better understand the molecular mechanisms that are activated upon aneuploidization and the coping mechanisms that are selected for in aneuploid cancer cells. In this review, we discuss the key biological responses to aneuploidization, some of the recently uncovered aneuploidy-coping mechanisms and some strategies to exploit these in cancer therapy.



中文翻译:

利用非整倍体施加的压力和应对机制来对抗癌症。

非整倍性是细胞中染色体数量不规则的现象,是癌症的一个标志特征。非整倍性是由染色体不稳定 (CIN) 引起的,几乎 90% 的肿瘤都会出现非整倍性。虽然许多癌症表现出持续的 CIN 表型,但细胞也可以是非整倍体而不表现出 CIN。CIN 驱动肿瘤进化,因为持续的染色体错误分离将产生具有可变非整倍体核型的细胞后代。由此产生的非整倍性最初对细胞具有毒性,因为它会导致蛋白质毒性和代谢应激、细胞周期停滞、细胞死亡、免疫细胞激活和进一步的基因组不稳定。为了克服这些非整倍体施加的压力并采取恶性命运,非整倍体癌细胞必须发展出非整倍体耐受机制来应对 CIN。因此,非整倍体应对机制可以被认为是有希望的治疗靶点。然而,在此类疗法进入临床之前,我们首先需要更好地了解非整倍体化时激活的分子机制以及非整倍体癌细胞中选择的应对机制。在这篇综述中,我们讨论了对非整倍体化的关键生物学反应、一些最近发现的非整倍体应对机制以及在癌症治疗中利用这些机制的一些策略。

更新日期:2020-09-02
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