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: 9.92). 04/2007; 17(5):431-7. DOI: 10.1016/j.cub.2007.01.049
Source: PubMed

ABSTRACT 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, Jul 22, 2015
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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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    ABSTRACT: Many mitotic factors were shown to be activated by Ran guanosine triphosphatase. Previous studies in Xenopus laevis egg extracts and in highly proliferative cells showed that mitotic chromosomes were surrounded by steep Ran guanosine triphosphate (GTP) concentration gradients, indicating that RanGTP-activated factors promote spindle assembly around chromosomes. However, the mitotic role of Ran in normal differentiated cells is not known. In this paper, we show that although the steep mitotic RanGTP gradients were present in rapidly growing cell lines and were required for chromosome congression in mitotic HeLa cells, the gradients were strongly reduced in slow-growing primary cells, such as HFF-1 fibroblasts. The overexpression of RCC1, the guanine nucleotide exchange factor for Ran, induced steeper mitotic RanGTP gradients in HFF-1 cells, showing the critical role of RCC1 levels in the regulation of mitosis by Ran. Remarkably, in vitro fusion of HFF-1 cells produced cells with steep mitotic RanGTP gradients comparable to HeLa cells, indicating that chromosomal gain can promote mitosis in aneuploid cancer cells via Ran.
    The Journal of Cell Biology 01/2013; 200(2). DOI:10.1083/jcb.201206142 · 9.69 Impact Factor
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    • "Tetraploidy can be experimentally induced in p53 null cells by transient inhibition of the actin cytoskeleton or by virus-mediated cell fusion and has been shown to promote tumorigenic transformation (Fujiwara et al., 2005; Duelli et al., 2007). Tetraploidization has also been suggested to be one of the outcomes of chromosome nondisjunction (Shi and King, 2005), possibly through a lagging chromosome blocking the cleavage furrow (but see Weaver et al., 2006). "
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    ABSTRACT: Tetraploidization has been proposed as an intermediate step toward aneuploidy in human cancer but a general mechanism for the induction of tetraploidy during tumorigenesis is lacking. We report that tetraploidization occurs in p53-deficient cells experiencing a prolonged DNA damage signal due to persistent telomere dysfunction. Live-cell imaging revealed that these cells have an extended G2 due to ATM/ATR- and Chk1/Chk2-mediated inhibition of Cdk1/CyclinB and eventually bypass mitosis. Despite their lack of mitosis, the cells showed APC/Cdh1-dependent degradation of the replication inhibitor geminin, followed by accumulation of Cdt1, which is required for origin licensing. Cells then entered a second S phase resulting in whole-genome reduplication and tetraploidy. Upon restoration of telomere protection, these tetraploid cells resumed cell division cycles and proliferated. These observations suggest a general mechanism for the induction of tetraploidization in the early stages of tumorigenesis when telomere dysfunction can result from excessive telomere shortening.
    Cell 04/2010; 141(1):81-93. DOI:10.1016/j.cell.2010.01.031 · 33.12 Impact Factor
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    • "Fusions may also cause malignant transformation by inducing chromosomal instability [18]. Additionally, other biological roles of syncytin, like its immunomodulatory and nitric oxide-stimulating effects [5], may affect the prognostic outcome. "
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    ABSTRACT: The endogenous retroviral envelope protein syncytin is involved in cell fusions and has also been associated with immunomodulatory functions. Syncytin is currently known to be expressed in the placenta, testis and brain as well as in breast and endometrial carcinomas. Using a newly developed monoclonal syncytin antibody we have assessed syncytin expression in a retrospective series of 140 colorectal cancer patients. Variable degrees of syncytin expression were detected in both colonic and rectal tumors and the prognostic impact of such expression was analysed with the Kaplan-Meier method and the Cox proportional hazard model. Interestingly, increased syncytin expression was associated with decreased overall survival in rectal but not in colonic cancer patients. Thus, the prognostic impact of syncytin expression appears to vary with the tumor type.
    Cancer letters 04/2009; 280(1):44-9. DOI:10.1016/j.canlet.2009.02.008 · 5.02 Impact Factor
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