Levine Michelle S, Bakker Bjorn, Boeckx Bram, Moyett Julia, Lu James, Vitre Benjamin, Spierings Diana C, Lansdorp Peter M, Cleveland Don W, Lambrechts Diether, Foijer Floris, Holland Andrew J
Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
European Research Institute for the Biology of Ageing, University of Groningen, University Medical Center Groningen, Groningen 9713 AV, the Netherlands.
Dev Cell. 2017 Feb 6;40(3):313-322.e5. doi: 10.1016/j.devcel.2016.12.022. Epub 2017 Jan 26.
Centrosome amplification is a common feature of human tumors, but whether this is a cause or a consequence of cancer remains unclear. Here, we test the consequence of centrosome amplification by creating mice in which centrosome number can be chronically increased in the absence of additional genetic defects. We show that increasing centrosome number elevated tumor initiation in a mouse model of intestinal neoplasia. Most importantly, we demonstrate that supernumerary centrosomes are sufficient to drive aneuploidy and the development of spontaneous tumors in multiple tissues. Tumors arising from centrosome amplification exhibit frequent mitotic errors and possess complex karyotypes, recapitulating a common feature of human cancer. Together, our data support a direct causal relationship among centrosome amplification, genomic instability, and tumor development.
中心体扩增是人类肿瘤的一个常见特征，但这是癌症的原因还是结果仍不清楚。在这里，我们通过创建在无其他基因缺陷情况下中心体数量可长期增加的小鼠来测试中心体扩增的后果。我们表明，在肠道肿瘤形成的小鼠模型中，增加中心体数量会提高肿瘤起始率。最重要的是，我们证明多余的中心体足以驱动非整倍体形成以及多个组织中自发性肿瘤的发生。由中心体扩增产生的肿瘤表现出频繁的有丝分裂错误并具有复杂的核型，重现了人类癌症的一个常见特征。总之，我们的数据支持中心体扩增、基因组不稳定和肿瘤发生之间存在直接因果关系。
