A Virus Causes Cancer by Inducing Massive Chromosomal Instability through Cell Fusion

Cold Spring Harbor Laboratory, One Bungtown Road, Cold Spring Harbor, NY 11724, USA.
Current Biology (Impact Factor: 9.57). 04/2007; 17(5):431-7. DOI: 10.1016/j.cub.2007.01.049
Source: PubMed


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.

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Available from: Dominik Duelli
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    • "For example, p53 −/− tetraploid mouse cells formed tumours when transplanted into immunocompromised mice, which was not detected with the isogenic diploid cells [10]. Tetraploid cells generated by virus induced cell-cell fusion can proliferate and induce transformation [11] [12]. Mutation of adenomatous polyposis coli (APC) in colorectal cancer resulted in tetraploid genomes in vivo due to cytokinesis failure [13]. "
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    • "Remarkably, fused mitotic HFF-1 cells displayed steep RanGTP gradients comparable with mitotic HeLa cells (compare Fig. 4 B and Fig. 1 E), demonstrating that chromosomal gain is sufficient to drive the formation of a steep mitotic RanGTP gradient. Virus-induced cell fusion (Duelli et al., 2007), mitotic slippage, or cytokinesis failure is thought to produce unstable tetraploid precursors of aneuploid cancer cells (Ganem et al., 2007; Vitale et al., 2011). The chromosomal gain-driven mitotic RanGTP gradient in such intermediates could selectively promote proliferation of intermediates expressing Ran-regulated mitotic factors. "
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