Abstract
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.
Highlights
Aneuploidy, an abnormal number of chromosomes in cells, affects the majority of cancers, ranging from 26% in thyroid carcinoma to 99% of the glioblastomas and testicular germ cell tumours [1,2]
This leads to the activation of cyclic GMP-AMP synthase, a major cytosolic nucleic acid sensor with dsDNA as its ligand [103,104,105,106]. cGAS activation generates cyclic dinucleotide cyclic GMP-AMP, which in turn activates a Type I Interferon response and initiates NF-κB signalling via the adaptor Stimulator of Interferon Genes (STING) [107,108]
We discussed the paradoxical role of the consequences of aneuploidy as tumour-promoting or tumoursuppressing features
Summary
Aneuploidy, an abnormal number of chromosomes in cells, affects the majority of cancers, ranging from 26% in thyroid carcinoma to 99% of the glioblastomas and testicular germ cell tumours [1,2]. Defects in SAC genes such as Mad, Mad, BUB3 and BUBR1 lead to CIN and aneuploidy [6,7,8,9]. Despite being a hallmark feature of cancer cells, aneuploidy will initially cause growth defects to untransformed cells [13,14,15,16]. The fact that aneuploidy is initially toxic to cells but yet frequently occurring in cancer is referred to as the aneuploidy paradox and suggests that aneuploid cells must develop aneuploidy-tolerating mechanisms to cope with CIN and adopt a malignant fate [25]. CIN will yield a progeny of cells with variable aneuploid karyotypes that drive tumour evolution and that can help cells to adapt to the initial growth defects imposed by aneuploidy and challenges of the tumour microenvironment. We aim to give an overview of the initial stresses that aneuploidy imposes on cells, some of the mechanisms that can lead to aneuploidy tolerance and how these mechanisms can potentially be exploited in aneuploid cancer therapy
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