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

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, Sep 29, 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 · 9.83 Impact Factor
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    • "Nude mice (Taconic, Hudson, NY) were housed, maintained, and injected with indicated breast cancer cell lines according to RFUMS IACUC guidelines, and as described [101]. In brief, 5 million cells of indicated cell lines were injected in 100 µl BD Matrigel (BD Biosciences, San Jose, California) into the right flank of mice, and monitored for tumor growth. "
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    ABSTRACT: MicroRNAs (miRNAs) in body fluids are candidate diagnostics for a variety of conditions and diseases, including breast cancer. One premise for using extracellular miRNAs to diagnose disease is the notion that the abundance of the miRNAs in body fluids reflects their abundance in the abnormal cells causing the disease. As a result, the search for such diagnostics in body fluids has focused on miRNAs that are abundant in the cells of origin. Here we report that released miRNAs do not necessarily reflect the abundance of miRNA in the cell of origin. We find that release of miRNAs from cells into blood, milk and ductal fluids is selective and that the selection of released miRNAs may correlate with malignancy. In particular, the bulk of miR-451 and miR-1246 produced by malignant mammary epithelial cells was released, but the majority of these miRNAs produced by non-malignant mammary epithelial cells was retained. Our findings suggest the existence of a cellular selection mechanism for miRNA release and indicate that the extracellular and cellular miRNA profiles differ. This selective release of miRNAs is an important consideration for the identification of circulating miRNAs as biomarkers of disease.
    PLoS ONE 10/2010; 5(10):e13515. DOI:10.1371/journal.pone.0013515 · 3.23 Impact Factor
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    • "Recently, the view that oncogenic virus-induced cell fusion may contribute to oncogenesis is appealing as all well-known human oncogenic viruses, including HPV, Hepatitis B virus, Hepatitis C virus, Epstein-Barr virus, Kaposi sarcoma virus and human T-lymphotropic virus type 1, have fusogenic activity [9-11]. Researches show that although most tetraploid cells resulting from non-oncogenic-induced cell fusion would undergo p53-dependent cell cycle arrest or apoptosis, they, however, survive and might be more prone to chromosomal instability (CIN) if p53 or apoptosis is perturbed [12,13]. It is notable that all oncogenic viruses mentioned above also possess proteins with these abilities [9]. "
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    ABSTRACT: Cervical cancer is strongly associated with high-risk human papillomavirus (HPV) and viral oncoproteins E5, E6 and E7 can transform cells by various mechanisms. It is proposed that oncogenic virus-induced cell fusion may contribute to oncogenesis if p53 or apoptosis is perturbed simultaneously. Recently, HPV-16 E5 was found to be necessary and sufficient for the formation of tetraploid cells, which are frequently found in precancerous cervical lesions and its formation is strongly associated with HPV state. We propose that high-risk HPV E5-induced cell fusion is a critical initiating event in the early stage of HPV-associated cervical cancer. Our hypothesis can be tested by comparing the likelihood for colony formation or tumorigenic ability in nude mice between normal HaCaT cells expressing all three oncogenic proteins and E5-induced bi-nucleated HaCaT cells expressing E6 and E7. Moreover, investigating premature chromosome condensation (PCC) in HPV-positive and negative precancerous cervical cells is another way to assess this hypothesis. This viewpoint would change our understanding of the mechanisms by which HPV induces cervical cancer. According to this hypothesis, blocking E5-induced cell fusion is a promising way to prevent the progression of cervical cancer. Additionally, establishment of a role of cell fusion in cervical carcinogenesis is of reference value for understanding the pathogenesis of other virus-associated cancers.
    Virology Journal 09/2010; 7(1):238. DOI:10.1186/1743-422X-7-238 · 2.18 Impact Factor
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