Sheltzer Jason M, Ko Julie H, Replogle John M, Habibe Burgos Nicole C, Chung Erica S, Meehl Colleen M, Sayles Nicole M, Passerini Verena, Storchova Zuzana, Amon Angelika
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA; David H. Koch Institute for Integrative Cancer Research, Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
David H. Koch Institute for Integrative Cancer Research, Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Cancer Cell. 2017 Feb 13;31(2):240-255. doi: 10.1016/j.ccell.2016.12.004. Epub 2017 Jan 12.
Aneuploidy is a hallmark of cancer, although its effects on tumorigenesis are unclear. Here, we investigated the relationship between aneuploidy and cancer development using cells engineered to harbor single extra chromosomes. We found that nearly all trisomic cell lines grew poorly in vitro and as xenografts, relative to genetically matched euploid cells. Moreover, the activation of several oncogenic pathways failed to alleviate the fitness defect induced by aneuploidy. However, following prolonged growth, trisomic cells acquired additional chromosomal alterations that were largely absent from their euploid counterparts and that correlated with improved fitness. Thus, while single-chromosome gains can suppress transformation, the genome-destabilizing effects of aneuploidy confer an evolutionary flexibility that may contribute to the aggressive growth of advanced malignancies with complex karyotypes.
非整倍体是癌症的一个标志，尽管其对肿瘤发生的影响尚不清楚。在这里，我们使用经过基因工程改造以携带单条额外染色体的细胞，研究了非整倍体与癌症发展之间的关系。我们发现，相对于基因匹配的整倍体细胞，几乎所有三体细胞系在体外培养和异种移植中生长都很差。此外，几种致癌途径的激活未能减轻非整倍体诱导的适应性缺陷。然而，经过长时间生长后，三体细胞获得了额外的染色体改变，而这些改变在其整倍体对应细胞中基本不存在，并且与适应性改善相关。因此，虽然单条染色体的增加可以抑制细胞转化，但非整倍体的基因组不稳定效应赋予了一种进化灵活性，这可能有助于具有复杂核型的晚期恶性肿瘤的侵袭性生长。
