A virus causes cancer by inducing massive chromosomal instability through cell fusion
A virus causes cancer by inducing massive chromosomal instability through cell fusion
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DOI：
10.1016/j.cub.2007.01.049
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发表时间：
2007-03-06
期刊：
影响因子：
9.2
通讯作者：
Lazebnik, Yuri
中科院分区：
文献类型：
--
作者：
Duelli, Dominik M.;Padilla-Nash, Hesed M.;Lazebnik, Yuri
染色体不稳定性（CIN）是许多实体癌恶性特性及其逃避治疗能力的基础，它本身也可能导致癌症[1,2]。CIN是由蛋白质缺陷维持的，如肿瘤抑制因子p53[3-5]，它可以保护基因组的完整性，但散发性癌症中CIN的主要原因仍不确定[6,7]。主要的怀疑是解除端粒维持或有丝分裂的突变，然而这种突变尚未在大多数散发性癌症中被发现。或者，CIN可能是由瞬时事件引起的，该事件使基因组不稳定，但不会永久影响有丝分裂或增殖机制[5,8]。在这里，我们展示了一种原本无害的病毒，通过融合细胞周期被癌基因解除调控的细胞，迅速引起大量染色体不稳定。这种融合和癌基因之间的协同作用使正常的二倍体人成纤维细胞“随机化”，以至于每个被分析的细胞都有独特的核型，一些细胞在小鼠中产生侵袭性的、高度非整倍体的、异质的和可移植的上皮癌。由于许多病毒具有融合性，这项研究表明，病毒，包括那些与致癌作用无关的病毒，可以通过融合细胞引起染色体不稳定，从而导致癌症。
Chromosomal instability (CIN) underlies malignant properties of many solid cancers and their ability to escape therapy, and it might itself cause cancer [1, 2]. CIN is sustained by deficiencies in proteins, such as the tumor suppressor p53 [3-5], that police genome integrity, but the primary cause of CIN in sporadic cancers remains uncertain [6,7]. The primary suspects are mutations that deregulate telomere maintenance, or mitosis, yet such mutations have not been identified in the majority of sporadic cancers [6]. Alternatively, CIN could be caused by a transient event that destabilizes the genome without permanently affecting mechanisms of mitosis or proliferation [5, 8]. Here, we show that an otherwise harmless virus rapidly causes massive chromosomal instability by fusing cells whose cell cycle is deregulated by oncogenes. This synergy between fusion and oncogenes "randomizes" normal diploid human fibroblasts so extensively that each analyzed cell has a unique karyotype, and some produce aggressive, highly aneuploid, heterogeneous, and transplantable epithelial cancers in mice. Because many viruses are fusogenic, this study suggests that viruses, including those that have not been linked to carcinogenesis, can cause chromosomal instability and, consequently, cancer by fusing cells.