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 provides oncogene Mos may also have some function relating to tumor cells with durability against genotoxic damage this process. To address this point further, it is (Castedo et al., 2006; Lee et al., 2009) and, indeed, important to first describe the normal biological roles reversible polyploidy seems to be operating during the of Mos during meiosis (Figure 1). response to it (Illidge et al., 2000; Sundaram et al., 2004; Puig et al., 2008). The asexual ploidy cycle is thought to have lead to the evolution of the sexual cycle, alternating syngamy and Roles of Mos in meiosis meiosis (Cleveland, 1947; Raikov, 1982; Kondrashov, 1997). Furthermore, meiosis almost certainly evolved The Mos–mitogen-activated protein kinase pathway is from mitosis (Hurst and Nurse, 1991; Wilkins and required in germline cells (Page and Orr-Weaver, 1997), Holliday, 2009), possibly for the purpose of reducing in particular for the initiation and progression of oocyte polyploidy. This shared evolution may be central to the maturation. Here, Mos binds to tubulin and has a role ability of polyploid cells to revert back to mitosis as they in the bipolar meiotic spindle formation (Zhou et al.,

Oncogene MOS and cancer cell cycle J Erenpreisa and MS Cragg 5449 Apoptosis

fer tilization DNA MOS/MAPK synthesis p90 Rsk MOS M

Meiotic MOS MAPK MPF MOS-MPF partheno- prophase genesis

S Meiosis I Meiosis II metaphase- Cleavage divisions arrested mature oocyte Figure 1 Scheme indicating the participation of Mos in the principal steps of female meiosis: In meiosis I, Mos directly phosphorylates microtubules and organizes the spindle, regulating the contraction and favoring bipolar separation of homologous chromosomes; in interkinesis, Mos prevents DNA synthesis; in meiosis II, Mos activates the spindle checkpoint (in co-operation with cytostatic EMI proteins) and uncouples it from apoptosis. Arrest in metaphase II prevents parthenogenesis of the mature oocyte until fertilization. (Figure based on data from Page and Orr-Weaver 1997; Nebreda and Ferby, 2000; Extavour, 2009.)

1991; Yew et al., 1993; Verlhac et al., 1996). At early DMC1 (Ivanov et al., 2003; Erenpreisa et al., 2009; meiosis I, Mos induces nucleation of multiple centro- Ianzini et al., 2009). Although not yet proven experi- somes in the vicinity of condensing bivalents. Further mentally, the involvement of Rec8 and DMC1 implies activation of mitosis-promoting factor Cdk1/cyclin B by pairing of homologous chromosomes—a pre-requisite Mos triggers contraction of bivalents and signals the for their orderly segregation (Nasmyth, 2001). In multiple centrosomal microtubule arrays to form a addition, fluorescent in situ hybridization studies on bipolar prespindle (Choi et al., 1996). Here, the bipolar irradiated HeLa cells revealed sister centromeric spindle of the first meiotic division is responsible for cohesions in ETC, not only in bipolar mitoses but also segregation of the paired homologs to two opposite in tri- and tetrapolar mitoses (Erenpreisa et al., 2009 and poles along with the cohesed sister chromatids— unpublished data). the latter a condition of somatic reduction as well (see Interestingly, particularly high levels of Mos and above; Kondrashov, 1994). This multipolar prephase may cyclin B were found in endomitotic nuclei of ETC be linked to the difficulty of establishing robust mono- (Erenpreisa et al., 2005) and aberrant expression of Mos orientation of both sister chromatids and pulling residu- was previously reported in lung cancer (Gorgoulis et al., ally cross-linked homologs in opposite directions by the 2001). Furthermore, overexpression in somatic cells of meiotic spindle (Nasmyth 2001; Petronczki et al., 2003). v-Mos causes an oocyte phenotype (Fukasawa et al., Mos also has a key role in regulating the omission of 1994). Moreover, in our experiments with two lympho- S-phase between the first and second meiotic divisions. ma cell lines, we could identify a proportion of Here, Mos favors the accumulation of Cdk1/cyclin B, endopolyploids that entered cell division having omitted thereby condensing chromosomes in interkinesis in the the preceding S-phase (Erenpreisa et al., 2008, 2009)— environment akin to G2 of the mitotic cycle, preventing this is yet further evidence of meiosis-like behavior and replication licensing, the second condition for reduction somatic reduction division. division. This activity reaches a peak in metaphase II Many meiotic genes have now been observed to be wherein Mos/MEK-primed p90 Rsk (in co-operation upregulated in genotoxically stressed lymphoma, with cytostatic Emi proteins) induces meiosis-specific HeLa and breast cancer human cell lines including activation of the spindle checkpoint uncoupled from MOS, REC8, SGO1 and SPO11 (Erenpreisa et al., 2005; apoptosis (Wu and Kornbluth, 2008; Extavour, 2009; Kalejs et al., 2006; Ianzini et al., 2009; Erenpreisa et al., Wilkins and Holliday, 2009). The question then arises 2009). It is interesting to note then, that mutations in whether these activities (cohesion of sister chromatids in genes involved in homologous recombination, sister the first division and subsequent omission of S-phase chromatid cohesion and spindle formation were before the second) are applicable to somatic ETCs? amongst the few revealed as polyploidy-specific lethal in a large-scale genetic screen in yeast (Storchova´ et al., 2006). Meiotic-like processes in ETC

Cohesion of sister centromeres by the meiotic cohesin Conclusions and perspectives Rec8 was found in ETC of a human lymphoma cell line undergoing reduction divisions (Erenpreisa et al., 2009) In summary, the data indicate that there is a structural, after a period of intensive homologous DNA repair molecular and evolutionary basis for orderly reduction involving the mitotic/meiotic recombinases Rad51 and divisions of ETC in the context of an asexual ploidy

Oncogene MOS and cancer cell cycle J Erenpreisa and MS Cragg 5450 (2010) and features the ectopic expression of meiotic DNA damage Mitotic proteins in the absence of p53. Previously, we and others catastrophe speculated that reversible polyploidy may induce self- renewal by promoting ‘stemness’ in p53-deficient tumor Mitotic cells as an alternative to mitotic catastrophe (Erenpreisa M cycle and Cragg, 2007; Rajaraman et al., 2006, 2007). In agreement with these expectations, we have recently reported that the key stem-cell genes responsible for pluripotency and self-renewal (that is, OCT4 and Germline p53 NANOG) are upregulated in parallel to meiotic genes transmission dysfunction during the reversible polyploidy of tumor cells (Salmina et al., 2010). Altogether, we believe that these data provide an impetus for rethinking the biological nature Ploidy of genotoxic resistance and self-renewal of tumor cells cycle and suggest that the immortality of tumor cells is DNA transferred, through the ploidy cycle, to a germline-like repair state (Figure 2). Meiotic gene Self-renewal up-regulation gene up-regulation Conflict of Interest Figure 2 Hypothetical scheme of the cancer life cycle. Under endogenous or exogenous genotoxic stress, p53 dysfunctional somatic tumor cells bypass mitotic catastrophe and initiate the The authors declare no conflict of interest. ploidy cycle (reversible polyploidy), doubling genomes and activating self-renewal and meiotic genes, thereby instigating cohesion of sister chromatids, recombination and DNA repair, and reduction divisions to renew ‘stemness’ in the next generation Acknowledgements of somatic tumor cells. Parasexual nuclei/cell fusions may be part of the cycle. We thank many collaborators and colleagues for helpful discussions, in particular Kirsten Walen, Helmut Zacharias, cycle. This enables the decrease of CIN associated with Evgenia Zybina and Dmitry Perminov and apologize to those the reversion from tetraploidy reported by Vitale et al. authors not cited here due to space restrictions.

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