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MOS, Aneuploidy and the Ploidy Cycle of Cancer Cells

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MOS, Aneuploidy and the Ploidy Cycle of Cancer Cells Oncogene (2010) 29, 5447–5451 & 2010 Macmillan Publishers Limited All rights reserved 0950-9232/10 www.nature.com/onc REVIEW MOS, aneuploidy and the ploidy cycle of cancer cells J Erenpreisa1 and MS Cragg2 1Latvian Biomedicine Research and Study Centre, Riga, Latvia and 2Tenovus Laboratory, Cancer Sciences Division, Southampton University School of Medicine, General Hospital, Southampton, UK After DNA or spindle damage, p53-defective tumor cells the level of aneuploidy could be reduced in cancer cells undergo a complex cycle of reversible polyploidy. How (Vitale et al., 2010). In this study, isolated tetraploids, this process occurs and more importantly, why, has induced in diploid p53À/À HCT 116 colon cancer cells by recently become the focus of several research groups, nocodazole treatment, were shown to undergo multi- prompting this review in which we discuss two related polar and bipolar cell divisions accompanied by a phenomena that accompany the reversible polyploidy of gradual decrease in genomic instability and return to tumor cells: the induction of meiosis genes such as MOS para-diploidy over 2–3 weeks. The process was shown and the decrease in genomic instability observed during to be inhibited by functional p53. Intriguingly, the the reversion from polyploidy to para-diploidy. The isolated transition tetraploid clones enriched with the reversible polyploidy likely provides the means through reverted para-diploid fraction caused the most rapid which the balance between increased chromosome in- tumor growth when inoculated into nude mice. stability (CIN), driving genetic variation and decreased As such, the cells had undergone reversible polyploidy CIN, necessary for perpetuating these malignant clones, is (2n/4n/B2n), increasing and then suppressing the maintained. These concepts are integrated with recent chromosome instability (CIN) and recovering more findings that many meiotic and self-renewal genes become rapid growth. activated during reversible polyploidy and lead us to the The evidence that endopolyploid tumor cells (ETC) hypothesis that tumor cell immortality may be achieved induced by genotoxic treatment are capable of returning through germline-like transmission. to para-diploidy and have access to additional means Oncogene (2010) 29, 5447–5451; doi:10.1038/onc.2010.310; of survival, resulting in increased resistance to DNA- published online 2 August 2010 damaging agents is growing (de la Hoz and Baroja, 1993; Illidge et al., 2000; Ianzini and MacKey, 2002; Keywords: polyploidy; MOS; aneuploidy; DNA Prieur-Carrillo et al., 2003; Chu et al., 2004; Sundaram damage; tumor resistance; life cycle et al., 2004; Puig et al., 2008), resulting in greater attention from the wider scientific community (Storchova and Pellman, 2004; Vakifahmetoglu et al., 2008; Wheatley, 2008; Martin et al., 2009; Forer, 2009; Lee et al., 2009). Introduction Lee et al. (2009) recently provided an excellent summary of the ‘purpose’ of endopolyploidy in onto- Somatic polyploidy (endopolyploidy) is generally rare in genesis and adaptation to various stresses. However, the normal mammalian cells (Nagl, 1978), yet frequently authors ended the section devoted to the reversible found in human tumors, particularly as aneuploidy endopolyploidy of tumor cells with the sentence: ‘What (Haroske et al., 2001; Ho¨glund et al., 2002). A key might be the mechanism of de-polyploidisation which molecular regulator of this phenomenon is p53, whose seems so counterintuitive? It is unclear’. Here, we shall deficiency is permissive for the bypass of mitotic consider exactly this point. catastrophe and the creation and survival of tetraploid cells, a metastable intermediate between normal diploidy and oncogenic aneuploidy (Storchova and Pellman, Reversible polyploidy and reversible aneuploidy 2004; Castedo et al., 2004, 2006; Ganem and Pellman, of tumor cells 2007; Thompson and Compton, 2010). A new strand to this story came to light very recently When Martin Raff claimed that the purpose of cell life is in an article published in EMBO Journal, showing that death (Raff, 1992), he meant, of course, the apoptosis of a single cell within a multicellular organism, in the Correspondence: Dr J Erenpreisa, Latvian Biomedicine Research and context of insufficient prosurvival signaling. He was Study Centre, Riga LV-1067, Latvia. right, this is how multicellular organisms maintain E-mail: [email protected] or Dr MS Cragg, Tenovus Laboratory, fidelity. The situation is radically different when Cancer Sciences Division, Southampton University School of considering a tumor cell whose very hallmarks are Medicine, General Hospital, Southampton SO16 6YD, UK. E-mail: [email protected] autonomy and independence from prosurvival signals Received 26 May 2010; revised and accepted 22 June 2010; published (Hanahan and Weinberg, 2000). Therefore, our first online 2 August 2010 observations made just over a decade ago, relating to the MOS and cancer cell cycle J Erenpreisa and MS Cragg 5448 reversible polyploidy of human lymphoma cell lines share homology to checkpoints, such as the spindle induced after ionizing irradiation (Illidge et al., 2000), checkpoint (Page and Orr-Weaver, 1997; Nebreda and lead us to intuitively suggest that this phenomenon had Ferby, 2000; Nasmyth, 2001). This hypothesis would something in common with the life-cycle regulations of explain why Vitale et al. (2010) revealed that the proto- autonomous unicellular organisms that in a chain of oncogene and main meiotic kinase Mos was upregulated ongoing clonal generations are also essentially immortal in colon cancer cells after spindle damage. Earlier, (Erenpreisa et al., 2000; Erenpreisa and Cragg, 2007). upregulation of Mos after treatment with tubulin- In this context, the life cycle should be the ‘means’, with disrupting agents was shown in ovarian carcinoma cells immortality the ‘purpose’ of this regulation. It therefore (Ling et al., 1998) and our observations also revealed the follows that to reach immortality, a tumor cell should Mos–mitogen-activated protein kinase pathway to be uncouple from ‘death-linked’ regulations of normal activated in irradiated p53-mutant lymphoma cells, mitotic checkpoints and become aligned to the cell allowing us to predict that the depolyploidization of systems for perpetuating life cycles. tumor cells was meiosis-like and should reduce aneu- To perpetuate, cells need to propagate. It is clear that, ploidy (Erenpreisa and Wheatley, 2005; Erenpreisa although genetic change and tumor progression require et al., 2005). CIN (which results in miss-segregation of chromosomes Vitale et al. concluded from their studies that p53 and aneuploidy), limitless accumulation of CIN ulti- deficiency, upregulation of Mos and multipolar divi- mately interferes with a cells capacity to divide (Cahill sions have a decisive role in generating unstable et al., 1999; Duesberg et al., 2006; Weaver and Cleve- tetraploid intermediates capable of reducing CIN and land, 2007; Chandhok and Pellman, 2009). In a recent repopulating the para-diploid fraction. What evidence paper (Vitale et al., 2010), a decrease in aneuploidy do we have for this? First, Mos protein was not through unstable transient tetraploidy to para-diploidy upregulated by nocodazole in the wild-type p53 cells; was reported for the first time. What then links second Mos depletion depressed recovery of the most reversible genomic instability to reversible polyploidy? malignant para-diploid descendents from transient One obvious solution would be a ploidy cycle. tetraploid cells; third, overexpression of Mos was found to favor multipolar divisions. However, at least till now the general opinion was that multipolar mitoses of cancer cells randomly segregate genetic material and The ploidy cycle inevitably increase aneuploidy (Therman and Kuhn, 1989; Stewenius et al., 2005; Gisselsson et al., 2008). The ploidy cycle, whereby the genome number per cell rises and falls in sequence, has developed through evolution to lessen the mutational load and cost of Multipolar divisions in ploidy reduction aneuploidy under natural selection (Kondrashov, 1994, 1997). It includes the doubling(s) of ploidy (asexual by The problem then becomes how multipolar divisions can endoreduplication or sexual by fertilization) and its participate in the reduction of aneuploidy? One possi- halving in reduction division(s). The ploidy cycle bility relates to the fact that supernumary centrosomes provides the potential for orderly reduction which needs can coalesce in ETC, converting multipolar into bipolar (1) cohesion of sister chromatids; (2) omission of DNA spindles, thus providing higher fidelity segregation of replication; and (3) pairing and recombination of genetic material as a basis for this. The process of homologous chromosomes, which is usually present centrosome coalescence is regulated largely by HSET, but may be optional for somatic reduction (Kondrashov, an otherwise nonessential kinesin motor (Goshima 1997). Kondrashov (1994, 1997) also showed that the et al., 2005; Quintyne et al., 2005; Gergely and Basto, ploidy cycle has the advantage of decreasing the 2008; Kwon et al., 2008). In their paper, Vitale et al. mutational load as compared with permanent diploidy noticed that Mos has affinity to centrosomes; the or permanent polyploidy and therefore should appear in coalescence of supernumary centrosomes was shown evolutionary development when this property is re- here to be HSET-dependent, indicating that the proto- quired. Among other advantages, polyploidy
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