Cell Biology International 29 (2005) 1012e1018www.elsevier.com/locate/cellbi

Hypothesis

Mitotic catastrophe and endomitosis in tumour cells: An evolutionarykey to a molecular solution

Jekaterina Erenpreisa a,*, M. Kalejs a, M.S. Cragg b,c

a Lab. Tum. Cell Biol., Biomedicine Centre of the Latvia University, Ratsupites 1, Riga LV-1067, Latviab University of Southampton, Southampton, UK

c WEHI, Melbourne, Australia

Abstract

Following genotoxic insult, p53 mutated tumour cells undergo mitotic catastrophe. This is characterised by a switch from mitosis to the endo-cycle. The essential difference between mitosis and the endocycle is that in the latter, DNA synthesis is uncoupled from cell division, whichleads to the formation of endopolyploid cells. Recent data suggests that a return from the endocycle into mitosis is also possible. Furthermore,our observations indicate that a particular type of endocycle known as endomitosis may be involved in this return. Here we review the role ofendomitosis in the somatic reduction of polyploidy during development and its postulated role in the evolution of meiosis. Finally, we incor-porate these evolutionary data to help interpret our most recent observations in the tumour cell system, which indicate a role for endomitosisand meiotic regulators, in particular p39mos in the segregation of genomes (somatic reduction) of these endopolyploid cells.� 2005 International Federation for Cell Biology. Published by Elsevier Ltd. All rights reserved.

Keywords: Mitotic catastrophe; Tumours; Endomitosis; Somatic reduction; Meiotic regulators

1. Introduction

‘Treasure your exceptions’ (F. Schrader)

Following genotoxic insult, p53 mutated tumour cells un-dergo a process known as mitotic catastrophe (Hartwell andKastan, 1994). This is characterised by a switch from mitosis(which is halted due to a profound arrest in metaphase) to theendocycle. Endocycles are also seen within normal tissues andare surprisingly common in the plant and animal kingdoms.Interestingly, the appearance of chromosomes during endo-cycles is highly varied. At one extreme they can appear fullypolytenic as highly extended multinemic chromosomes, atthe other extreme, during true endomitosis (as described byGeitler, 1937, 1939) they are displayed as multiple individualcondensed chromosomes (or as diplochromosomes) within anintact nuclear envelope; partial polyteny, with some degree ofmultinemic chromosome compaction is also common (Nagl,

* Corresponding author. Tel.: þ371 7 808 220; fax: þ371 7 442 407.

E-mail address: katrina@biomed.lu.lv (J. Erenpreisa).

1065-6995/$ - see front matter � 2005 International Federation for Cell Biolog

doi:10.1016/j.cellbi.2005.10.005

1990; Zybina and Zybina, 1996; Edgar and Orr-Weaver,2001). Interestingly, all of these various forms of endocycle,including endomitosis, can also be observed in tumours(Levan and Haushka, 1953; Therman and Kuhn, 1989). In par-ticular we and others have described the appearance of endo-polyploid giant cells after genotoxic damage in tumourslacking wild type p53 function as a result of mitotic catastro-phe (Illidge et al., 2000; Castedo et al., 2004).

Previously, mitotic catastrophe and endopolyploidy havebeen considered a reproductive dead-end. However, in recentyears, we, and others, have provided data suggesting that thisis not the case (Illidge et al., 2000; Erenpreisa et al., 2000;Erenpreisa and Cragg, 2001; Walen, 2002, 2004). Importantly,this data has now been confirmed in several independent labo-ratories with the use of direct video-imaging techniques study-ing the fate of individual cells, showing that after mitoticcatastrophe a small proportion of endopolyploid tumour cellscan survive, segregate successfully and return to mitosis(Prieur-Carrillo et al., 2003; Ianzini and Mackey, 2002, 2005;Sundaram et al., 2004; Mackey et al., 2003; Ianzini et al.,2002, 2005). These data indicate that tumour cells can, albeit

y. Published by Elsevier Ltd. All rights reserved.

1013J. Erenpreisa et al. / Cell Biology International 29 (2005) 1012e1018

with relatively low frequency, successfully switch from the en-docycle back to mitosis. The question then arises as to how thisis possible and which molecules regulate it? We have addressedthis problem using insights gained from a knowledge of howendocycles are regulated throughout evolution and appliedthis to the tumour cell setting. Several aspects of these variousendocycles will be discussed and may provide keys to how thisproblem is solved. First, we will discuss how and why the endo-cycle is initiated in tumour cells and how this parallels that seenin normal phylo- and onto-genesis.

2. Mitotic catastrophe and endomitosis occur not onlyin tumours, but in normal development

Mitotic catastrophe occurs in tumours following genotoxicinsult or mitotic spindle damage and is apparently selected asan alternative to rapid apoptosis (Roninson et al., 2001). Sub-sequently, aberrant mitoses become aborted, restitute into in-terphase and the cells become endopolyploid. In this way,mostly 4C polyploid cells arise. However, higher levels ofpolyploidy, (at least up to 64C) are also observed and achievedthrough subsequent iterative endocycles. Importantly, a signif-icant proportion of the endopolyploid cells (particularly fromradioresistant cell-lines) appear to derive through endomitosiswhere condensed chromosomes are observed within intact nu-clear envelope. These appear to initiate from either 4C, butmore commonly, from 8C precursors, the latter developingfrom two aborted mitoses (personal observation on lymphoidtumours). Interestingly, exactly the same sequence of poly-ploidisation events and ploidy numbers have been describedby researchers studying developmental polyploidy in varioustaxonomic forms (Nagl, 1978; Brodsky and Uryvaeva, 1985;Zybina and Zybina, 1996).

Anisimov and colleagues revealed a similar mechanism ofreproduction in gland cells and neurons of the mollusc S. lauta(Anisimov and Kirsanova, 2002; Anisimov, 1997). The mech-anism involves a switch from normal (complete) proliferativemitosis to an abnormal (incomplete) restitutional mitosis, fol-lowed by classical endomitosis (Geitler, 1937, 1939, 1953). Asinitially described by Geitler (1937), during classical endomi-tosis chromosomes are duplicated (endoreplicate), and pro-ceed through condensation and de-condensation phasesas endoprophase, endometaphase, endo-anaphase and endo-telophase whilst remaining static, without spindle formationor dissolution of the nuclear envelope.

The appearance of aberrant mitoses, (arrested in metaphaseor more rarely in anaphase) or unequal segregation of chromo-somal material leading to polyploidisation and endomitosishas also been observed during development. In fact, Geitler(1939) himself first noticed it in development of Water-hopper.Likewise, Anisimov (1997) described a strikingly high propor-tion of aberrant mitoses, up to 60%, during polyploidisationprocesses in the mollusc S. lauta. Similarly, up to 70% of a-cytokinetic mitoses were found at the stage of polyploidisationin the liver of newborn rats (Kudryavtsev, 1991, PhD theses inRuss., cited from Anisimov, 1997), and up to 80% of atypicalmetaphases at the polyploidisation stage in the mink

trophoblast (Zybina et al., 1994). Presence of not only aberrantpolyploidising mitoses but also cell death from arrested meta-phases was also found during the normal development of thebone growth plate of embryonic chicken. Here the strikingsimilarity to mitotic catastrophe in tumours after genotoxicdamage was noted (Erenpreisa and Roach, 1999). Anisimov(1997, 1999, 2005) highlighted the sequence of aborted poly-ploidising mitosis and classic endomitosis as mutually com-patible mechanisms of cell endopolyploidy. Clearly then,aberrant mitoses, endopolyploidy and endomitosis are reason-ably commonplace and occur throughout evolution. Next wemust consider how somatic reduction might occur.

3. Endomitosis is possibly linked to the evolutionof meiosis

Somatic reduction of polyploidy in higher organisms isquite rare and most polyploid cells terminally differentiateand degenerate. However, somatic reduction can indeed beachieved in higher organisms and numerous examples are ap-parent (see reviews of Huskins, 1944 and Nagl, 1978). For ex-ample, in the mammalian trophoblast whole genomessegregate in the giant nucleus before death of these cells(Nagl, 1978; Zybina and Zybina, 1996, 2005). Furthermore,a small number of reduction divisions of octaploid cells areknown to occur in the fox placenta (Zybina et al., 2001). How-ever, although clearly possible, it should be noted that somaticreduction in higher organisms is still poorly understood (Edgarand Orr-Weaver, 2001; Storchova and Pellman, 2004). For thisreason we have analysed the polyploid reduction processesthat occur in lower organisms, such as protozoa. Some proto-zoans involve cycling polyploidy in their life-cycles, alternat-ing between polyploidisation and de-polyploidisation phases(Raikov, 1982), making study of their genome reduction pro-cesses more straightforward. Furthermore, it is intriguing tonote that certain aspects of the tumour cell response to geno-toxic insult, involving polyploidy, depolyploidisation and seg-regation of genomes is reminiscent of the events of the asexuallife-cycle of these protozoans (Erenpreisa et al., 2000).

In most protozoans, a fully-fledged sexual process (involv-ing meiosis and syngamy) exists (Raikov, 1995), however, insome, the sexual life-cycle is not permanent and occasionallythey revert to a more primitive process involving polyploidy/depolyploidy cycles. The interaction between these processesin the usually haploid flagellate Barbulanympha and other pro-tozoans led Cleveland (1947) to suggest that this processformed the basis for the evolution of meiosis from mitosis.This idea is illustrated by the scheme presented in Fig. 1. Asreported by Cleveland, polyploidy in Barbulanympha is invari-ably reduced by meiosis, and no degeneration results. The im-portant part of this asexual life-cycle is that it is a two-step(somatic) meiosis where ‘chromosomes are synapsed and goto poles as dyads, in the first division, and as singles, in thesecond’ and where ‘meiosis is neither preceded nor followedby any kind of syngamy’ (Cleveland, 1947). A notable obser-vation of Cleveland was that this meiosis is preceded by a mo-nopolar endomitosis (Fig. 2, step 3). In fact, Cleveland even

1014 J. Erenpreisa et al. / Cell Biology International 29 (2005) 1012e1018

Fig. 1. The original scheme of Cleveland (1947) kindly supplemented by Dr. H. Zacharias Langwendel; (zacharias@ki.comcity.de) with a DNA-replication phase

(in red), as DNA replication was not yet known in 1947. It shows the steps of evolution of meiosis from mitosis. Step 3 is deduced from polyploid forms of Bar-bulanympha showing that endomitosis is a prerequisite of a-sexual meiosis (somatic reduction).

included endomitosis as the first step in meiosis. Endomitosisalso precedes the somatic reduction and segregation of the pri-mary polyploid nucleus of the radiolarian Aulocantha into iso-spores (not gametic cells) as reported by Grell (1953). In fact,both Cleveland (1947) and Grell (1953) and later Grell andRuthmann (1964) all described the classical features of endo-mitosis initially reported by Geitler (1937, 1939).

In his 1953 publication, which included investigation ofmore than 4000 Aulocantha specimens, Grell concluded thatendomitosis was undertaken in preparation for the subsequentreduction divisions of the polyploid nucleus. Endomitosis wasobserved in 9.1% of samples, yet somatic reduction was pres-ent in only 2.6%. So, like in tumours, it is clear that this is nota frequent and therefore easily observable process. In subse-quent work, Grell and Ruthmann (1964) went on to demon-strate that axial structures were present between chromatidsin the endomitotic chromosomes. After much dispute, theseaxial structures in the endomitotic chromosomes were agreedto represent the evolutionary predecessors of the meiotic syn-aptonemal complex. It was subsequently agreed that duringendomitosis pairing of somatic bivalents probably occurs(Cachon et al., 1973). For this reason, endomitosis hasbeen coined ‘meiosis without karyogamy’ (discussion rev. byRaikov, 1982). Interestingly, chromosomal pairing with true syn-aptonematic complexes is observed during the somatic reductionof the Pyrsonympha flagellate (Hollande and Carruette-Valentin,1970). Unfortunately over time, with rare exceptions (Becaket al., 2003) knowledge of this work on endomitosis and its

relationship to meiosis has been forgotten. Moreover, the exis-tence of endomitosis as a specific kind of endocycle was forsome time disputed (Therman et al., 1983; Brodsky andUryvaeva, 1985; Anisimov, 1999) and molecular aspects oftrue endomitosis have not been well studied. Next, we shallconsider what is currently known about the cytogenetic andmolecular regulation of endomitosis.

4. Cytogenetic and molecular features of endomitosis

The accepted wisdom of how endocycles are regulated isbased upon our knowledge of how mitosis is regulated. In short,endocycles are possible only when mitosis is suppressed. Thisoccurs through down-regulation of the activity of the main driverof mitosis, the metaphase promoting complex (MPF) e whichis composed of cyclin B and cdk1 (Grafi, 1998; Edgar andOrr-Weaver, 2001). Without this activity and the activity ofthe MPF-induced anaphase promoting complex, the cell isunable to compact, segregate, or move chromosomes.

Before continuing with this molecular analysis we must firstnote, as outlined earlier, there are important differences in thetypes of endocycles that cells undertake. In polytenic endo-cycles, DNA repeatedly duplicates but chromosomes remainuncoiled, probably due to the down-regulation of the mitoticmolecular machinery (mostly cyclin B/Cdk1). In fact, evencentromere and telomere heterochromatin sequences may beunder-replicated due to an aborted late S-phase (Nagl, 1995;Lilly and Spradling, 1996; Edgar and Orr-Weaver, 2001).

1015J. Erenpreisa et al. / Cell Biology International 29 (2005) 1012e1018

This is in contrast with the situation in endoreduplicating endo-mitotic cells where the genomes seem to be fully replicated(Zybina and Zybina, 1996). Furthermore, in endomitotic endo-cycles chromatin is condensed albeit to a variable extent whichis a classical mitotic feature (Nagl, 1978, 1990). In fact, in tu-mour cell-lines high plasticity of endomitotic endochromo-somes, from fully dispersed (Figs. 2a,b) to partially polytenic(Figs. 2c,d) is found, much as it was observed in tumours invivo (Therman and Kuhn, 1989) and in polyploid protozoans(Raikov, 1982). The importance of chromosome condensationfor de-polytenisation of partly interwoven multi-stranded chro-mosomes, and as a pre-requisite of genome segregation hasbeen suggested by several authors (Grell, 1953; Nagl, 1978;Zybina and Zybina, 1996a, 2005; Bier, 1957).

Another difference between polytenic and endomitotic en-docycles is that endomitotic tumour cells replicate telomeres(Fig. 2c) and centromeres (Fig. 2d) whilst truly polytenic

tumour cells with extended decondensed chromatin do not(the latter also never segregate sub-cells, personal observations).

The truly endomitotic and partially polytenic endopolyploidtumour cells induced following gamma-irradiation expresslarge amounts of nuclear cyclin B1 (Figs. 2a,b and 3a). This ap-pears to be at least partly regulated by the MAPK pathway asthe number of polyploid cells (particularly with ploidy over8C) containing cyclin B1 is reduced by the addition of theMEK inhibitor UO126 (unpublished). Interestingly, endopoly-ploidy is also decreased by MEK inhibition in polyploid mega-karyocytes (Rojnuckarin et al., 1999). The fact that theendomitotic endopolyploid tumour cells possess nuclear cyclinB1 and display chromosome condensation, indicates that theMPF is active in these cells. However, other known phosphor-ylating activities of the MPF such as mitotic spindle assemblyand nuclear envelope disassembly, are not apparent. Clearlythen, in endomitotic cells, MPF function is not typical and

Fig. 2. Features of endomitotic tumour cells induced post-mitotic catastrophe. Apparent are the condensed chromosomes and intact nuclear envelope (smooth

nuclear outlines), along with high nuclear concentration of cyclin B1 (FITC) counterstained with Propidium iodide (red), shown as panels (a) and (b) on the

same cells. Panel (c) shows the distribution of telomeres detected by FISH; Panel (d) shows kinetochore staining (using immunofluoresce with the CREST-antibody

(FITC), with DNA counterstained with DAPI (blue) and Beta-actin stained with falloidin-Texas red (red); Panel (e) demonstrates the formation of several meta-

phase/anaphase plates directly from endomitosis (DNA staining by the Feulgen-type reaction). Panels a)ed) are of Namalwa cells 5e8 days after irradiation with

10 Gy. Panel e) is of HeLa cells following similar treatment on day 8. Bars ¼ 10 mm. NB: Image (e) was obtained in a joint experiment with Dr. F. Ianzini, Iowa

University, USA.

1016 J. Erenpreisa et al. / Cell Biology International 29 (2005) 1012e1018

Fig. 3. Localisation of mos and cyclin B in endomitotic tumour cells post mitotic catastrophe. lmmunofluorescent detection of p39mos protein (FITC) and cyclin B

(blue) with DNA counterstained with 7AAD (red). A partial co-localisation and co-ordinated regulation of both proteins is apparent, in accord with the extent of

compaction/de-compaction of the partially polytenic endochromosomes: (a) endometaphase; (b) endotelophase. Images are of Namalwa cells irradiated 7 days

previously with 10 Gy. Bars ¼ 10 mm.

somehow partially abrogated. Abnormal cyclin B/cdk1 func-tion during mitotic catastrophe was also noted by Castedoet al. (2004). Instead of progressing through mitosis, the endo-mitotic tumour cells which are mostly in endometaphase seemto activate the spindle checkpoint and thus prevent the degrada-tion of cyclin B1. Presumably then, during the mitotic catastro-phe and endomitosis of these endopolyploid tumour cells,another alternative non-mitotic signaling pathway must be inoperation. It is intriguing therefore that an analogous require-ment for these activities (spindle arrest and partial condensa-tion of chromosomes) is also present during meiosis, where itis regulated by the MOS/MAPK pathway. During meiosis,mos is translationally up-regulated, where it stimulates the firstdivision (reductional) of the cell and then further acts as a cyto-static factor to maintain the oocyte in metaphase arrest at mei-osis II until fertilization occurs (Tachibana et al., 2000). Theseseparate functions are attributed to two different downstreamtargets of the Mos/MAPK pathway, cdk1 and Rsk90, respec-tively (Phillips et al., 2002). In addition, Mos directly interactswith kinetochores thereby interrupting mitosis (Sagata, 1997).

For this reason, we recently assessed the expression of Mosin our lymphoid tumour cells before and after irradiation. In-triguingly, we found that both by western blotting and immu-nostaining, Mos was significantly upregulated in p53-mutatedbut not wild type cells (paper submitted). These studies showedthat partially polytenised endomitotic nuclei from endopoly-ploid cells contained large amounts of both Mos and cyclinB1, a proportion of which was colocalised (Fig. 3a). Further-more, rare endotelophases from these cells showed co-operativedown-regulation of both Mos and cyclin B1 coincident with de-condensation of the multinemic chromosomes (Fig. 3b).

In addition to Mos, we also discovered that other meiosis-specific genes were up-regulated in these tumour cells follow-ing mitotic catastrophe (Plakhins et al., 2005; Kalejs et al.,submitted). Therefore, although not formally proven, it is likelythat the appearance of mitotic catastrophe and endomitosiscan be explained by the expression of important meiosis-

specific regulators during aberrant mitosis. For example, inaccord with its functions during meiosis, p39Mos could triggerthe MEK/MAPK/Rsk90 pathway to switch off mitoticprogression causing activation of the spindle checkpoint(Kosako et al., 1994; Tachibana et al., 2000) and allow poly-ploidisation in the absence of p53 function. In turn, down-regulation of the anaphase promoting complex signaledthrough the spindle checkpoint prevents degradation of cyclinB1, accounting for its nuclear accumulation and the condensa-tion of the chromosomes, all of which are hallmarks of the sus-tained metaphase arrest caused by Mos (Maller et al., 2002).Furthermore, another function of the MPF, karyokinesis, isdirectly blocked by Mos through inactivation of kinetochores,and indirectly, through spindle checkpoint proteins. Withinthis scheme cyclical down-regulations of the Mos/MAPK cas-cade would allow S-phase and recombination to proceed.Recombination might be crucial both for reduction division(Petronczki et al., 2003) and also in surviving genotoxic dam-age. In support of this notion, we previously demonstratedDNA repair by homologous recombination in the endopoly-ploid tumour cells and provided evidence that this activityenhanced the survival of these cells (Ivanov et al., 2003).

Following recombination, it is currently unknown whichmolecular regulators are subsequently involved in the processleading to the segregation of the polyploid genome. However,it is clear that they do finally segregate nuclei which can as-semble metaphase plates again (Fig. 2e) which then resumemitosis, as documented by us in an accompanying article(Erenpreisa et al., 2005).

5. Conclusion

The response of p53 non-functional tumour cells to geno-toxic insult involves mitotic catastrophe and the induction ofpolyploidy. Although previously the induction of polyploidywas deemed a reproductive dead-end we, and others have indi-cated that this is not always the case. Through a series of

1017J. Erenpreisa et al. / Cell Biology International 29 (2005) 1012e1018

defined complex nuclear rearrangements the endopolyploid tu-mour cells can successfully switch from the endocycle back tomitosis, through a process of somatic (genome) reduction.

In an attempt to discover the molecular regulators of the so-matic reduction which occurs in these endopolyploid tumourcells, we took note of the fact that features reminiscent of mi-totic catastrophe are also observed during normal develop-ment. This observation suggests that mitotic catastrophe isnot simply a dysregulated deviation from the mitotic cyclecaused by DNA damage but rather a programmed event. In-deed, both during ontogenetical development and in p53 mu-tated tumour cells, this response is linked to a specific formof the endocycle, endomitosis. Endomitosis was originally de-fined as ‘meiosis without karyogamy’ and is also observed innumerous phylogenetic and ontogenetic studies. Importantly,in the life cycles of several protozoa it is seen as a prerequisiteof asexual meiosis enabling somatic reduction of polyploid nu-clei. We therefore propose that endomitosis facilitates a similarfunction in endopolyploid tumour cells. Although current dogmasuggests that the endocycle is simply a mitotic cycle withsuppressed mitosis-engine machinery, the appearance of con-densed chromosomes in the endomitotic cells does not fitwith this paradigm. Instead it indicates that an additionalmolecular pathway is in operation. Again, in accordancewith the evolutionary data mentioned above and recent exper-imental data in the tumour cell system, we suggest that keymeiotic regulators, in particular, p39mos are involved in theinduction of mitotic catastrophe and subsequent endomitosis.Furthermore, we suggest that meiotic regulators may alsoprovide the molecular basis for somatic reduction and the re-turn to mitosis of endopolyploid tumour cells.

Acknowledgments

Dr. Helmut Zacharias (Langwedel, Germany) is acknowl-edged for his help in the adaptation of the Cleveland scheme,both in its translation from old German-written articles and hisinterest in the problem. Thanks also to Dr. Harry Scherthan(BW Institute of Radiobiology, Munich, Germany) for hishelp in the telomere PNA FISH staining.

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