How cell death shapes cancer - Nature

Tumorigenesis initiated by repeated cell attrition and repopulation, as confirmed in different genetic models, ... Cell 2000; 100: 57–70. Skiptomaincontent Thankyouforvisitingnature.com.YouareusingabrowserversionwithlimitedsupportforCSS.Toobtain thebestexperience,werecommendyouuseamoreuptodatebrowser(orturnoffcompatibilitymodein InternetExplorer).Inthemeantime,toensurecontinuedsupport,wearedisplayingthesitewithoutstyles andJavaScript. Advertisement nature celldeath&disease review article Howcelldeathshapescancer DownloadPDF DownloadPDF Subjects ApoptosisCancertherapyOncogenesis AbstractApoptosishasbeenestablishedasamechanismofanti-cancerdefense.MembersoftheBCL-2familyarecriticalmediatorsofapoptoticcelldeathinhealthanddisease,oftenfoundtobederegulatedincancerandbelievedtoleadtothesurvivalofmalignantclones.However,overtheyears,anumberofstudiespointedoutthatamodelinwhichcelldeathresistanceunambiguouslyactsasabarrieragainstmalignantdiseasemightbetoosimple.Thisisbasedonparadoxicalobservationsmadeintumorpatientsaswellasmousemodelsindicatingthatapoptosiscanindeeddrivetumorformation,atleastundercertaincircumstances.Onepossibleexplanationforthisphenomenonisthatapoptosiscanpromoteproliferationcriticallyneededtocompensateforcellloss,forexample,upontherapy,andtorestoretissuehomeostasis.However,this,atthesametime,canpromotetumordevelopmentbyallowingexpansionofselectedclones.Usually,tissueresidentstem/progenitorcellsareamajorsourceforrepopulation,someofthempotentiallycarrying(age-,injury-ortherapy-induced)geneticaberrationsdeleteriousforthehost.Thereby,apoptosismightdrivegenomicinstabilitybyfacilitatingtheemergenceofpathologicclonesduringphasesofproliferationandsubsequentreplicationstress-associatedDNAdamage.Tumorigenesisinitiatedbyrepeatedcellattritionandrepopulation,asconfirmedindifferentgeneticmodels,hasparallelsinhumancancers,exemplifiedintherapy-inducedsecondarymalignanciesandmyelodysplasticsyndromesinpatientswithcongenitalbonemarrowfailuresyndromes.Here,weaimtoreviewevidenceinsupportoftheoncogenicroleofstress-inducedapoptosis. Facts Duringcancerdevelopment,clonalselectionisfacilitatedbytheacquisitionofmutationsinoncogenesandtumorsuppressorsandbytheselectionof'winner'cells. Apoptosisof(pre)-cancerouscellsgeneratesvacantnichesthatpotentiallybecomerepopulatedbymoreaggressivesub-clones.Thereby,apoptosisincreasesproliferativepressureandpromotesclonalselection,thusdrivingtumorevolution. Dyingcellscanpromotecelldivisionofneighboringcells. OpenQuestions Doesapoptosisdrivemalignanttransformationinpre-malignantconditionssuchastherapy-relatedmyelodysplasticsyndromesorcongenitalbonemarrowfailuresyndromes? Canresistancetoapoptosisdelaytheriskof(further)malignanttransformationwithinfullyestablishedtumorsorinpre-malignanttissues? Howcanunnecessarytissuedamageandinflammatoryresponsebeavoidedintumorpatientsaswellasinpatientspresentingwithpremalignantconditions? Twoconceptsinthefieldoftumorigenesisarewidelyaccepted.First,canceristheresultofsequentialgeneticchangesthat,eventually,transformnormalintomalignantcells,amodelthathasbeenreferredtoasmultistepcarcinogenesis.1Second,specificbiologicalprocesseshavetobederegulatedduringtumorevolutiontoenableandsustaintumorigenesis.Theseprocesseshavebeensummarizedas'hallmarksofcancer'byHanahanandWeinberg2intheyears2000and2011,respectively,andamongthose,evasionfromcelldeathisstillregardedasanessentialmechanismrequiredformalignanttransformationandtumormaintenance.Thougheverydogmahasitsday,doubtisthedrivingforcebehindscientificprogress.Inthisreview,wechallengethecurrentparadigmaticviewthatincreasedsurvivalisunambiguouslypromotingtumorigenesis.Wewilldiscusstheroleofapoptosisanditsderegulationduringtheinduction,progressionandmaintenanceofmalignantdisease.Finally,weproposetoadoptthecurrentviewthatresistancetocelldeathconstitutesagenuinehallmarkofcancer,aswebelievethatthismayactuallybelimitedtocertainsettings.ApoptosisderegulationincancerThoughcellscancommitsuicidebymultipleways,mostcelldeathinvertebratesismediatedbythemitochondrial(intrinsic)pathwaythatisinitiatedbyaplethoraofsignals,suchasDNAdamage,growthfactordeprivation,developmentalcuesaswellasmanystandardanti-cancertherapies.TheinitiatorsofthispathwaybelongtotheBCL-2family(Figure1)andthebalancebetweenanti-andpro-apoptoticfamilymembers,theso-called'Bcl-2rheostat'determineswhetheracellwillliveordieanapoptoticdeath.Figure1CytotoxicagentsimpacttheBcl-2rheostat.Thepro-andanti-apoptoticBCL-2familyproteinscloselyinteractatthemitochondrialmembraneandregulatetheintrinsicapoptosispathway.Cellularstresscausesactivationofpro-apoptoticBCL-2proteinsfromtheBH3-onlysub-group(BIM,PUMAetc.).Thesebindtoandinhibittheiranti-apoptoticantagonists(BCL-2,MCL-1etc.),thusreleasingandactivatingthedownstreameffectorsBAKandBAX.Mitochondrialmembranepermeabilization(MOMP)istriggered,andpro-apoptoticmoleculesreleasedintothecytoplasmactivatecaspases(inmoredetailreviewedbyLabietal.120).ConventionalcytotoxicagentsinterferewithupstreamsignalingpathwaysconvergingattheBCL-2familylevel.Incontrast,BH3-mimeticsdirectlyinhibitpro-survivalBCL-2proteinsFullsizeimageOnthebasisofthe'hallmarksofcancer'conceptmentionedabove,GreenandEvan3proposedthatthecorechangesconvertinganormalcellintoamalignantonemightbesimplyincreasedproliferationcoupledtodecreasedcelldeath.Indeed,itisfullyestablishedthattumorcellsdampentheapoptoticresponse,asonlydefectivedeathpreventstheireffectiveeliminationbyintrinsicanti-cancermechanismsoranti-cancertherapy.4Progressivecounteractionofpro-deathsignalsisaconsequenceofexogenousaswellas(epi)geneticchangesintherichsetoffactorsregulatingapoptosis.Thoughmutationsingenesencodingforcorecomponentsofthecell-deathmachinery,forexample,BCL-2familyproteins,aredescribedinliterature,theyarenotparticularlycommon.OneprominentexceptionoccursinB-cellfollicularlymphomawherefusionsbetweenBCL-2andtheimmunoglobulinheavychaingeneareregularlydetectedthusraisingBCL-2proteinlevels.5,6,7Morecommonly,upstreamsignalingpathwaysconvergingattheleveloftheBCL-2familyarederegulatedwithintumorcellssecondarilyleadingtoanimbalanceintheBCL-2rheostattiltingthebalanceinfavorofsurvival.ThetumorsuppressorgeneTP53isfrequentlymutatedinhumancancerandhasearlybeenlinkedtoapoptosis.8,9,10ActivateduponDNAdamage,hypoxiaoroncogeneactivation,TP53initiatescellcyclearrestandDNArepairor,inirreversiblydamagedcells,senescenceorapoptosis,withPUMAandNOXAbeingthemainpro-apoptotictargetgenes.11,12,13,14,15Loss-of-functionmutationsinTP53resultinapoptosisresistanceandarefrequentlyassociatedwithadvancedtumorstageandpoorprognosis.16,17BesidesTP53,othercomponentsoftheDNAdamagecheckpointpathwayarefrequentlyinactivatedinhumancancer(e.g.,MDM2,ARF,RB1).18,19Commonmutationsinoncogenescausingtheirgrowthfactor-independentactivationcanbefoundintheRAS-signalingpathway,suchasmutationsintheRASgenesitself(i.e.,HRAS,NRAS,KRAS)orupstream/downstreamcomponentsofgrowthfactorsignalingpathways(e.g.,FLT3,CKIT,EGFR,PTPN11,CBL,NF1etc.).20ThemainBCL-2playersrepresseddownstreamofthesepathwaysarePUMA,BADandBIM,BH3-onlyproteinsthatarekeptinactivebyAKTsignaling.21,22Incolorectalcancers,theadaptorproteinpaxillinhasbeenreportedtopromotesurvivalandchemo-resistanceoftumorcellsbyincreasingBCL-2proteinstabilityandabundance.23Thec-MYC-oncogenecaninducetumorsinitswild-typeformandisoverexpressedinmosthumantumorentities.24Paradoxically,athighlevelsitpromotesapoptosisinvolvingBCL-2familyproteins.Manyothermutatedoncogenesortumorsuppressorshavebeendescribedtoderegulateintrinsicapoptosissignalingbutdetailedinformationontheirmaindownstreamapoptoticeffectorsisoftenlacking.Besidescell-intrinsicpro-survivalsignals,supportfromtheenvironmentiscriticallyrequiredfortumorcellsurvival.Forexample,chroniclymphocyticleukemiacellssurvivewellinalymph-nodenicheinvivobutrapidlyundergoapoptosisexvivo.Thisindicatesthat(i)thedownstreamapoptosismachineryisusuallyfunctionalinthesecells,and,that(ii)theyareready-to-dieandassuchstrictlydependentonniche-derivedpro-survivalsignals.25Indeed,highlevelsoftheBH3-onlyproteinsBIM,BMFandNOXAweredetectedinprimaryhumanchroniclymphocyticleukemiacells.26,27,28,29Co-culturewithfeederorT-helpercellsaswellasadditionofcytokinesstronglydelaysexvivoapoptosisbyincreasingexpressionofanti-apoptoticBCL-2proteins.25,30,31BCL-2proteinsastargetsforanti-cancertherapiesAlthoughresistancetocelldeathisanimportantfeatureofcancers,itiscertainlynottruethattumorsarefullyresistanttocelldeath.32Iftrue,anti-cancertherapieswouldinvariablyfail.Themajorityoftoday’stherapeuticregimensaimtodirectlykilltumorcellsandoftensuccessfullyreducestumormass.Dependingonthetreatmentscheme,differentbutoftenoverlappingpathwaysareengagedleadingtoapoptosisand/ornecrosis(i.e.,DNAdamage,oxidativeormetabolicstress,andothers).Notunexpectedly,clinicaltrialsusetheamountoftreatment-inducedcelldeathwithintumorstopredictprognosisanddecideonfurthertreatmentintensity(i.e.,steroid-responseinpediatricacutelymphoblasticleukemia).33Mostconventionalcytotoxicagentsactbyactivatingtheintrinsicapoptosispathway(Figure1).DNAdamagingagents(i.e.,etoposideoralkylatingagents)aswellasγ-irradiationinduceapoptosisbyTP53-mediatedactivationofPUMAandpossiblyalsoNOXA.12,13Incontrast,steroidskillacutelymphoblasticleukemiacellsbyactivationofBIM,PUMAand/orBMF,34andimatinibhasbeenshowntokillBCR-ABL-positivechroniclymphocyticleukemiacellsinaBIM-andBAD-dependentmanner.35Alternatively,apoptosissusceptibilityofchroniclymphocyticleukemiacellscanbeincreasedbytheCXCR4antagonistplerixaforbecauseofmobilization-dependentlossofsurvivalsignalsinlymph-nodeniches.25,36Thereby,pro-survivalsignalswithintumorcellsdropandtheBCL-2rheostatfavorsinductionofapoptosis.Recently,specificcompoundsthatinduceapoptosisdirectlyattheBCL-2levelhavebeendeveloped(Figure1).These'BH3-mimetics'(i.e.,ABT-737,ABT-263,ABT-199andObatoclax)mimicBH3-activitybybindingandinhibitingpro-survivalBCL-2proteins.37Theyholdbigpromiseforanti-cancertherapy,eitheraloneorincombinationwithothermodalities.Amongallpro-survivalBCL-2proteins,onlyBCL-2,BCL-xLandBCL-WareboundwithrelevantaffinitiesbyABT-737andABT-263.38,39Accordingly,resistanceoftumorcellsiscommonlycausedbyhighlevelsofMCL-1and/orBFL1/A140andthustargetingthesetwoproteinshasbecomeincreasinglyinteresting.TheapoptosisparadoxintumordevelopmentCompleteapoptosisresistancecoupledwithunleashedproliferationwouldmakeanytumorgrowtoamassofunbearablesizeinaveryshortperiodoftime,afactinconsistentwiththeusuallylonglatencyofmalignantdisease.Anuncontrollablyproliferatingcellhastoundergoonly40populationdoublingsuntilaclinicallydetectabletumormasscomprisingapproximately109cellsappears.Thislesionwouldrequireonly10furtherdoublingstoproduce1012cells,themaximaltumorsizecompatiblewithhumanlife.41Assuchrapidgrowthisrare,evolvingtumorsmustbecharacterizedbyadynamicinterplaybetweenproliferation,celldeathand/orsenescence.Thisfeaturecontributestointra-clonalheterogeneityoftumorsthatconsistofsubpopulationsofcellsdisplayingvariableratesofdeath,divisionandaggressiveness.42,43Asdiscussedearlier,fullytransformedcellsmighthaveacquiredmutationsincreasingcelldeaththresholdsandinhibitingtheirclearance.44Buthowdoapoptosisandacquiredapoptosis-resistanceactuallyimpactontheprocessofmalignanttransformation?Isapoptosisresistancesufficienttotransformacell?Whenandwhydotransformingortransformedcellsrequiremechanismstoevadeapoptosis?And,aretheresituationswhereapoptosisresistanceratherreducestheriskof(further)malignanttransformation?TheinvolvementofBCL-2itselfinneoplastictransformationwasnailedin1985whenatranslocationjuxtaposingtheBCL-2geneandtheimmunoglobulinheavychaingenet(14;18)wasregularlyfoundinhumanfollicularlymphoma.5,6,7Thiswasthefirstevidencethatsomeoncogenesratherpromotecellsurvivalthanstimulateproliferation.Onlylaterwelearnedthatapoptosisinhibitionperseishardlyeversufficienttotransformacell,inlinewiththeabove-mentionedmulti-stepcarcinogenesismodel.BCL-2transgenicmicedeveloptumorsonlyatlowpenetranceandwithlonglatency,45andonlyafractionofallpersonsharboringthet(14;18)translocationinbloodcellssubsequentlydevelopfollicularlymphoma,andonlyafteralong-lastinglatencyperiod.46ThetumorigenicpotentialofBCL-2becomesonlyevidentwhenoverexpressedincombinationwithoncogenessuchasc-MYC.Thoughpromotingunleashedproliferation,c-MYCcanonlyefficientlyimmortalizecellsinthepresenceofsufficientpro-survivalsignalssuchasthoseprovidedbyoverexpressionofBCL-2.47,48Thisneedarisesbecausehighlevelsofc-MYCdrivecelldeath.Thus,apoptosisisanimportantbarriertouncontrolledproliferationandaformoftumorsurveillancecurtailingMYC-driventransformation.Consequentstudiesdemonstratedthatc-MYCsynergizeswithanyoftheanti-apoptoticBCL-2proteinsintransformingleukocytesinoverexpressionmodelsinvivo,49whereasthedependenceappearsmoreselectiveatthelevelofendogenouspro-survivalproteins.50Consistently,thelossofvariouspro-apoptoticBH3-onlyproteinsresultsinaccelerationofc-MYC-drivenlymphomagenesis.51,52,53Similarsynergiesbetweenc-MYCandanti-apoptoticBCL-2proteinshavebeenobservedinothertissuessuchasthepancreasorthemammarygland.54,55Furthermore,apoptosisisnotonlyinducedbyc-MYCoverexpressionbutalsobyactivity-gainofotheroncogenesorthelossoftumorsuppressors.However,thisisbeyondthescopeofthisreviewandwasdiscussedelsewhere.4,56Surprisingly,ampledatafromhumantumorsandmousemodelsactuallyindicatethatthe'simple'viewonapoptosisbeingakeymechanismofanti-cancerdefensesuffersfromoversimplification.StudiesonhumantumorsparadoxicallypointedoutastrongcorrelationbetweenhighBCL-2levelsandfavorableprognosis(Table1).TheseobservationsindicatethatBCL-2overexpressionisroutinelyobservedinhumantumorsandthatitcanbeassociatedwithalessaggressivediseasecourse.Alongthatline,theincreasedexpressionofpro-apoptoticBAXhasbeencorrelatedwithanincreasedriskofrelapseinchildhoodacutelymphoblasticleukemia.57Gurovaetal.58demonstratedthatclonalexpansionoftransformedTP53-deficientfibroblastsinvitroandinamousetumormodelwassuppressedbyBCL-2overexpression.Intriguingly,BCL-2-overexpressingtumorscontainedgeneticallystablecellsandwereabletorestricttheexpansionofotherwiserapidlygrowingandgeneticallyinstableTP53-deficientcells.Inanotherstudy,BAXoverexpressionintheT-celllineageenhancedlymphomagenesisinTP53-deficientmiceinadose-dependentmanner,andeveninitiatedlymphomaformationonaTP53-proficientbackground.59Inaccordancewithdatadiscussedbefore,BAX-drivenapoptosisledtoincreasedchromosomeinstability,andco-expressionofBCL-2wasabletodelaylymphomagenesis.Table1Invarioustumors,highBCL-2levelscorrelatewithgoodprognosisFullsizetableInsum,theseresultssupportahypothesisinwhichahigherrateofapoptosiswithinatumor,eitheratearlystageorduringprogression,orboth,mightpromotegeneticinstabilitycausingmoreaggressivedisease.AfarewellfromtheclassicviewontheroleofapoptosisincancerHowcouldapoptosispromotetumorigenesis?CancerdevelopmentcanbeviewedasaDarwinisticprocessofsomaticcellevolution,wherebyinitially'healthy'cellsacquiremultiple(epi)geneticlesionsdrivingclonalselection.Thisprocessisfacilitatedbytheacquisitionofmutationsinoncogenesandtumorsuppressorsandbytheselectionforcellswithsuperiorfitness.Undercontinuousselectionpressure,apoptosiscouldbeamajordriverofclonalexpansionbygeneratingvacantniches(Figure2).Thesenichesbecomerepopulatedbymoreaggressivesub-cloneswithcertaincompetitiveadvantages.Inthatrespect,apoptosiswouldbeadriveroftumorevolutionandahallmarkofaggressivedisease.Thiscouldbeespeciallyrelevantduringearlystepsoftumorigenesis.Pre-malignantlesionscanstablypersistforanextendedperiodoftimewhilestilltoosmalltobeclinicallyrelevant.Figure2Howapoptosisshapescancer.(a)Inproliferativetissues,injuryisfollowedbyrapidregenerationandrestorationofnormallysizedandshapedstructures.IntheDrosophilawingimaginaldisc,apoptoticcellsinducecompetitiveproliferationbysecretionofmitogenicfactorsinacaspase-dependentmanner.(b)Intissueswithaberrantcells,tissueinjury(e.g.causedbyDNAdamageinMDSpatients)andconsecutiveproliferationenablesoutgrowthofmoreaggressiveclones.Thisfostersmalignanttransformation.(c)Withinestablishedtumors,chemo-orradiotherapyinducesapoptosisbutleadstodeath-inducedproliferationoftherapy-survivingcells.Followingthegenerationofspace,proliferationismediatedbymitogensderivedfromapoptoticcells(suchasPGE2).Asproposedinmathematicalmodels,thisresultsinincreasedsub-clonalvariabilitywithahigherriskoftumorprogression,chemoresistanceandrelapseFullsizeimageProof-of-principleexperimentsexploringcellcompetitionandcompensatoryproliferationinD.melanogasterlarvaldevelopmentsuggestadualroleforapoptosisduringearlytumorigenesiswiththeneedtodampenintrinsicpro-apoptoticsignalstopromotetumorcellsurvivalononehand,andthebenefitfromthedeathofsurroundingcellsontheotherhand.60,61ThiscanbedescribedasatypeofDarwinian-likeselectionthatgenerates'winner'and'loser'cellsthusleadingtolong-termoutgrowthofcertaincellsoverothers.Inparticular,preventingapoptosisofsurroundingwild-typecellsimpairsthegrowthofotherwisehighlyproliferatingclones,bothinthecasesofDMYC-inducedsuper-competition60andMinute-inducedcell-competition.61IthasonlyrecentlybeenshownthatthiscompetitionreliesonTOLLsignalinginducingNFκB-dependentapoptosisin'loser'cellsandtheirsubsequentengulfmentby'winner'cells.62,63Alongthisline,anaturalcellcompetitionhasbeendescribedforthymicprogenitorcellsinthemouse.Youngcellsrecentlyimmigratedfrombonemarrowdisplace'older'progenitorsalreadyresidinginthethymus.The'older','loser'cells,expresslowerBCL-2levelsandaremoresusceptibletoapoptosis.Consequently,reductionofnaturalcompetitioninhealthythymictissuecausesT-celllymphoma.64,65Mathematicalmodelsallowforanapproximationofhowintrinsiccellpropertiesinfluencegrowthdynamicsandclonalexpansion.66,67Enderlingetal.68predictthatspontaneouscelldeathyieldsatumorsizereductionintheshortterm,butultimatelyenhancestumorigenesisinthelongterm.Theyconcludethattumorscanremaindormantforlongintervalsdespiteconstantcellularturnoverandthathighapoptosisratesperturbtheintrinsictumordynamicsandshiftthepopulationtowardsmoreaggressivesubclones.69Wodarzetal.70describetherelationbetweendeathrateandthegenerationofmutantcellswithinapopulationafterafirstwaveofclonalexpansion.Intheirmathematicalmodel,theyfindthatlesscelldeathcorrelateswithfewercelldivisionsduringclonalexpansion,thusleadingtoalessvariablecellpopulation.Incontrast,highdeathratescorrelatewithmorecelldivisionsduringexpansioncausingtheappearanceofmanydifferentmutants(Figure2).Withincreasingsub-clonalvariability,theriskthatindividualcellsovercomeselectivebarriers(i.e.growthinhibition)andprogresstowardsmalignancyincreases.70Weareputtingforwardthequestionwhethertheseinsilicomodelsoncelldeath-stimulatedtumorprogressionfindtheircounterpartsinvivo.Death-drivenproliferationfacilitatestissueregenerationandtumorigenesisOnepieceofevidenceinfavorofthesemathematicalmodelscomesfromtwostudiesonthymicT-celllymphomawheregeneticablationofthepro-apoptoticBH3-onlyproteinPUMAabolishedtumorformation.71,72Inthismousemodel,lymphomagenesisisinducedbyrepeatedroundsofsub-lethalγ-irradiationandstronglyacceleratedbyTP53deficiency.73Repeatedγ-irradiationinducesamassivewaveofapoptosisinthehematopoieticcompartmentthatisdependentontheTP53target,PUMA.13Initially,thesestudiesaimedatconfirmingthetumorsuppressorpotentialofPUMA,aswassuggestedbythefactthatitslossacceleratedMYC-inducedlymphomagenesis.53,74Unexpectedly,PUMAdeficiencyprotectedmiceefficientlyfromthymiclymphoma.WhydoesdeletionofPUMAabrogatelymphomaformationwhereaslossofitsactivator,TP53,doestheopposite?Twostudiesonthecompetitionofhematopoieticprogenitorsshedlightonpossiblyunderlyingmechanisms.Hematopoieticstemcells(HSCs)carryingdamagedDNAintroducedbysub-lethalirradiationcaneffectivelyreconstitutemyelo-ablatedmice.However,theyareoutcompetedwhentransplantedinacompetitivesettingwithTP53-deficientHSCs.75,76AstransplantationoflethallyirradiatedrecipientsrequiresHSCexpansionforhematopoieticregeneration,itistemptingtospeculatethatselectivepressureduringrepopulationprovidesthebasisforoncogenicmutationstoappear.Thistheoryisbackedupbyastudyusingtamoxifen-inducedTP53expressiononaTP53-deficientgeneticbackground.WhenTP53expressionwaslimitedtothetimeofirradiation,DNAdamageledtostrongapoptosisofhematopoieticcellsandsubsequentlytocancerdevelopment.Incontrast,whenTP53expressionwasonlyallowedatlatertimepoints,noapoptosiswasinducedbyirradiationbutalsonocancermanifested.Thus,thetumor-preventivefunctionofTP53isnotcriticalduringtheacuteeliminationofdamagedcellsbutratheressentialatlatertimepointswhencellsthatsurvivedirradiationdespitecarryinggeneticaberrationsdrivetumorprogression.77TheobservationsinPUMA-deficientmiceareconsistentwiththeseresultsandsuggestthatTP53-dependentapoptosistriggeredduringanacuteDNAdamageresponseisnotonlyirrelevantfortumorigenesis,butevenpromoteslymphomaformation.Thisisunderlinedbythefindingthatresistancetoradiation-inducedlymphomainPUMA-deficientmicecanbeovercomebyPUMA-independentapoptosisinduction,thatis,byglucocorticoidtreatmentuponirradiation.72Thetumor-initiatingcellsinthistumormodelarehematopoieticstemorprogenitorcells,becauseT-cellspecificoverexpressionofpro-survivalBcl-xLfailedtopreventirradiation-inducedlymphomagenesisdespiteprotectingthymocytesandperipheralTcellsfromdeathwhereasmiceoverexpressingBCL2throughouthematopoiesisphenocopiedPUMA-deficientmice.71,72Strikingly,inwild-typemice,persistingPUMA-andTP53-dependentapoptosisisstilldetected1weekafterirradiationspecificallyinhematopoieticprogenitorsascomparedwithmoredifferentiatedcellsindicatingexcessivepressurewithintheproliferatingprogenitorcompartmenttocompensateforthecellloss.78Theassociationbetweendeath-drivenproliferationandcancerisbestestablishedinmousemodelsofhepatocellularcarcinoma(HCC).Inhumans,HCCalmostinvariablydevelopsinthecontextofchronicliverinflammationthatislinkedtotissueinjuryandcelldeathcausedbyviralhepatitis,chronicalcoholconsumption,excessivehepatosteatosisorenvironmentaltoxins.79Theregenerativeresponseisaccompaniedbyareleaseofpro-inflammatoryfactorsbydyinghepatocytesandsubsequentexpansionofun-differentiatedprecursorssuchastissuestemcells.GiventhestrongimpactofapoptosisonHCCdevelopment,Qiuetal.80investigatedtheroleofPUMAinamousemodelofcarcinogen-inducedlivercancer.TheyfoundthatPUMAwasactivatedbyJNK1andcriticallymediatedcarcinogen-treatment-inducedapoptosis.Importantly,PUMAdeficiencydecreasedthemultiplicityandsizeofemergingtumors.81Twofurtherstudiescouldshowthatliver-specificMcl-1deletioninducedspontaneoushepatocyteapoptosis,chronicproliferationandfinallycausedHCC.Noteworthy,inthismousemodel,HCCdevelopedintheabsenceofcarcinogentreatmentordetectableinflammationandhepatocytesofHCC-likelesionsshowedahighdegreeingenomicinstability.82,83MechanismscouplingcelldeathandproliferationThediscussedmousemodelsindicatethatapoptoticcellspromotecelldivisionsofneighboringcells,aprocessthatcanbetermeddeath-drivenproliferation,buttheunderlyingsignalingeventsremainelusive.84Onlyrecently,evidencehasemergedhowapoptoticcellscanpromotetheproliferationofsurroundingcells.Planariansregeneratecompleteindividualsfromthesmallestofbodypartsuponinjury85byaprocesstermedcompensatoryproliferation.86,87Apoptosismediatedbypro-deatheffectorslikethecaspase-likegene3(DjCLg3)isnotrestrictedtothewoundbutoccursinprimarilyunaffectedtissueandisthusactivelyinvolvedindrivingfullrestorationofbodypieces.88InHydra,headregenerationafteramputationrequiressecretionofWnt3bydyingcells,thusinitiatingβ-catenin-drivenproliferationofsurroundingcells.BlockingapoptosisbycaspaseinhibitorspreventsheadregenerationandcanbeovercomebyexogenousWnt3.89IntheDrosophilawingimaginaldisc,ahighlyproliferativetissue,radiation-inducedapoptosisisfollowedbyrapidtissueregenerationtoformadultstructuresofnormalsizeandshape(Figure2).Mechanistically,activityoftheinitiator-caspaseDroncinapoptoticcellspromotesJNKandWinglesssignalingpathways,thuscausingthesecretionofmitogensDecapentaplegic(Dpp)andWingless(Wg)topromotetissueregeneration.90,91,92Keepingapoptosis-initiatedcellsartificiallyalivebyinhibitingdownstreameffectorcaspasespreventedinjury-induceddeath.Persistenceofsuch'undead'cellsresultedinexcessiveproliferationandhyperplasticovergrowthduetocontinuousandinappropriatesecretionofmitogens.IncontrasttoproliferatingtissueswhereDronc-initiatedapoptosisinducedDppandWgexpression,apoptosis-inducedproliferationincommittednon-dividingphotoreceptorneuronsinDrosophilalarvaerequiredactivityoftheeffectorcaspasesDrICEandDcp-1,whichsubsequentlyforcecellcycleentrymediatedbyHedgehog(Hh)signaling.93Extrapolatingtohumantumors,theabilityofapoptoticcellstoactivelypromoteproliferationofsurroundingcells,forexamplebysecretingmitogens,mightbeofmajorsignificance.Wespeculatethatcell–cellcommunicationlikelycouplesproliferationandcelldeatheitherpassivelyorthroughsignalsactivelyelicitedbyapoptoticcells.Insupportofthelatter,arecentstudyinxenotransplantedmicesuggeststhatdyingcellsdirectlyinduceproliferationofneighboringcells.Uponradiotherapy-inducedtumorcellapoptosis,caspase-3activityledtotheactivationofiPLA2andsubsequentreleaseofprostaglandinE2byapoptotictumorcellsandneighboringstroma.ProstaglandinE2inturnservedaspromoteroftumorcellsurvivalandproliferation.94Inthismodel,thenetresponsetotherapywasdeterminedbyradiation-inducedtumorcellapoptosisandprostaglandinE2-drivencellsurvivalandproliferation.Anadditionallayerofcommunicationbetweendyingandproliferatingcellsisprovidedbyimmuneandinflammatorycells.Dyingcellsactivatemacrophages,dendriticcells,neutrophilsandmastcellsthatsecretemitogeniccytokinessuchasIL1,IL6orTNFα.95Thus,nexttotheirmajorfunctionofimmunesurveillance,96theimmuneandinflammatorysystemsalsofostermalignanttransformationundercertaincircumstances.95Insum,weproposethatunderstandingtheimpactofdeath-drivenproliferationontumorigenesis,eitherdirectlyormediatedbyinflammatorysignals,canopenanewavenuetoimprovetherapyandpotentiallypreventcancerdevelopment.FromanimalmodelstohumandiseaseTheanimalmodelsdiscussedearlierindicatethattoomuchapoptosiscompromiseshealthyorpremalignanttissuesbyincreasingproliferativepressureandclonalselectionfosteringoutgrowthofmalignantclones.Butdotheseobservationsreflecttumorigenesisasitoccursinhumans?Andifyes,whichtissuesandcancertypescouldbeaffected?Theconceptofapoptosis-drivencancercanbeappliedtotherapy-inducedsecondarytumorsthatoriginatefromdistincttissuesthantheprimarytumors.Thesetumorsariseasaconsequenceofgenomicinstability97likelyprovokedbyrepeatedcyclesofexcessiveapoptosisandsubsequentproliferationduringtherapy.Typically,theycompromisetissueswithhighregenerativecapacity(i.e.,breast,intestine,rectum,skinorthyroidgland)andfrequentlypresentintheareaofpreviousirradiation.Adultsurvivorsofchildhoodcancerhaveasixfoldincreasedrisktodevelopsecondarytumorslaterinlife.98Thisiseitherduetounderlyinggenetic(e.g.,germlinemutationsincancersusceptibilitygenes99)and/orenvironmentalfactors(e.g.,nicotineabuse)thatpredisposethesepatientstotumorsortoprevioustherapiesincludingchemotherapyorirradiation.Patientswhosufferfromacombinationofanunderlyinggeneticpredispositionandearlierapplicationofchemotherapyorradiationtherapyhaveanexcessivelyhighrisktodevelopsecondarytumors.100Bonemarrow,aradiosensitivetissue,101frequentlygivesrisetosecondarymalignanciesassuggestedbytheabove-describedmousemodelofirradiation-inducedlymphomagenesis.71,72However,thymiclymphomasarerareinhumansanddonotoccurastherapy-inducedmalignancies.Incontrast,inhumans,exposuretoradio-orchemotherapyratherincreasestherisktodeveloptherapy-relatedmyelodysplasticsyndromes(MDS).102MDSareclonalmalignanciesoriginatingfromdefectivebone-marrow-derivedHSCs,inwhichcriticaldrivermutationsprovidethemwithaselectiveadvantage(Figure3).Thisdiseaseischaracterizedbyineffectivehematopoiesiscausingperipheralcytopenia(s)andbonemarrowdysplasia.Abnormalclonalprogenitorcelldifferentiationandincreasedsusceptibilityofimmatureprogenitorstoapoptosisunderliethesesymptoms.TherisktodevelopMDSincreaseswithage,suggestingthataccumulationofgeneticdamageinfluencespathogenesis.Exposuretoalkylatingagents,chemo-orradiotherapyofcancerpatientsdramaticallyincreasestherisktodeveloptherapy-relatedMDS(lifetimeriskof2–10%).102MDShasahighpropensitytoprogresstoMDS-relatedAML(MDR-AML).Diseaseprogressionischaracterizedbyanincreasedpercentageofbonemarrowblastcellsandcytogeneticabnormalities(reviewedbyCoreyetal.102).Figure3TheriseandfallofapoptosisduringMDSpathogenesis.Therapy-relatedmyelodysplasticsyndrom(MDS)iscausedbyrepeatedcyclesofradio-orchemoradiotherapy(i.e.,includingalkylatingagents)thatleadtobonemarrowattritionandsubsequentregeneration.Inchildrenandadolescents,MDScandeveloponthebasisofcongenitalbonemarrowfailuresyndromesuchasFanconianemiaandDyskeratosiscongenita.MDSfrequentlyprogressestoMDS-relatedAML(MDR-AML).ThestepwiseevolutionofMDSisreflectedbytheFABclassification,whichdistinguishesbetweenrefractoryanemia(RA),RAwithexcessblasts(RAEB),RAEBintransformation(RAEB-T)andMDR-AMLFullsizeimageInanalogytotherapy-relatedMDSofadults,childrenandadolescentscandevelopsecondaryMDSandMDR-AMLonthebasisofcongenitalbonemarrowfailuresyndromes(Figure3).Thesesyndromesarecausedbygenemutationsaffectingdiversecellularpathwaysbutallresultinginprematurefailureofhematopoiesis.Inindividualswiththesecongenitalconditions,HSCsbecomeprematurelyexhaustedandareexcessivelysusceptibletoapoptosisorsenescence.103ThemostfrequentbonemarrowfailuresyndromesareFanconianemia,causedbymutationsinDNArepairgenes,anddyskeratosiscongenita,characterizedbyprematuretelomereshortening.103,104FanconianemiaanddyskeratosiscongenitahaveaninherentrisktotransformintoMDS,withprevalenceof30–40%and10–15%,respectively.105Additionally,patientswiththesesyndromesareatrisktodevelopothermalignancies,withthosechildrenhavingthehighestriskthatpreviouslyweresubjectedtochemotherapeuticagentsorirradiation.105Both,therapy-relatedandsecondaryMDSarecausedbycumulativeHSCinjuryviaDNAdamageoroxidativestress.Inpatientswithoranimalmodelsofbonemarrowfailuresyndromesandlow-riskMDS,HSCsareexceptionallysusceptibletoapoptosis.106,107,108Thisindicatesthat,inlinewiththeaforementionedanimalmodels,excessiveapoptosisgeneratesvacantcellcompartmentsthatsubsequentlyarerepopulatedbymorecompetitiveHSCs.Proliferativepressureisfurtherincreasedbyperipheralcytopeniasandfeedbackloopstothebonemarrow.Thus,apoptosismightbeamajordriverofdiseaseprogressionduringearlystagesofMDSandfinaltransformationtofull-blownAML.ThepathophysiologyofFanconianemia,dyskeratosiscongenitaandtherapy-relatedMDSsuggeststhatchronicHSCapoptosiscanbeattributed,atleastinpart,tochronicDNAdamagecheckpointsignaling,withATM/ATR,CHK1,CHK2andTP53beingcentralplayers.109Thesecheckpointspreservegeneticstabilityandactasabarriertomalignanttransformation,110thusevolvingtumorcellsareinneedtoinactivatethem.Accordingly,theamountofapoptoticCD34+HSCsgraduallydecreasesduringfurtherprogressiontoMDR-AML.ThepressuretoinactivateDNAdamagecheckpointsignalingisreflectedbythefactthattherapy-relatedAMLmorefrequentlyharborTP53mutationsthanAMLdevelopingdenovo111andthatclonesharboringTP53mutationsareselectedduringmalignanttransformationoftherapy-relatedAML.112Similarly,CHK1andCHK2arestronglyactivatedinMDS,butalmostcompletelyinactivatedinMDR-AMLcells.113WehavelearnedfromanimalmodelsofbonemarrowfailureandMDSaswellaspatients’subgroupsthatcellswithactivatedcheckpointsignalingdisplaycompetitivedisadvantages.Accordingly,checkpointabrogationrescuesproliferationandsurvivalofHSCs,butalsoincreasestheriskofmalignanttransformation.109,114,115Whatif,insteadofcheckpointabrogation,apoptosiswouldbeinhibitedinearly-stageMDSwhereasallotherpathwaysdownstreamoftheDNAdamagecheckpointremainactive?Onthebasisofobservationsmadeinthemurinethymiclymphomamodel,wewouldexpectanincreaseinbonemarrowcellularity,thusrelaxingproliferativepressureanddelayingfurthertransformationfromMDStoMDR-AML.Indeed,thefirstMDSmousemodelavailablesupportsthisconcept:Slapeandcolleagues116recentlyshowedthatBCL-2overexpressioninNHD13micecorrectsmacrocyticanemiaanddelaysleukemictransformation.Furthermousemodelswillberequiredtoelucidatetheroleofapoptosissusceptibilityorresistance,respectively,forpathogenesisandprogressionofbonemarrowfailuresyndromesandMDStoAML.PerspectivesMovingawayfromtheparadigmaticviewprevailingthelastdecades,therelationshipbetweencelldeathandcancergetsfarmorecomplexthanoriginallyanticipated.Beyonddoubt,thetraditionalviewthatintrinsicdeathofpotentiallydangerouscellsispreventivetotumordevelopmentstillholdstrueinmanyaspects.However,itdisregardsthefactthatcellsareplacedinandinteractwiththeirenvironment.Atthefirstglance,thedualfunctionofapoptosisintumorigenesisisachallengingconcept,buttheseconflictingrolesarenotincompatiblewithcommonbeliefsandmightalsodependonthetissueandthesequenceofeventsduringtransformation.Thebalancebetweenproliferation,senescenceanddeathlikelyadaptsduringtumorprogression.Tumorinitiationmustbeaccompaniedbytheoddsurvivalofsingle'initiated'cellsthatcarrydrivermutations.Recently,lighthasbeenshedontheprocessofinitiationofhematologicalmalignancies.DrivermutationsconferringHSCswithselectiveadvantages(i.e.,inDNMT3A,JAK2,ASXL1,TET2andothers)leadtoclonalexpansioninagedindividuals,whodonot(yet)sufferfromleukemiaorMDS.117Duringfurthertumorprogression,cancercellsfrequentlyrespondtotheiralteredstatebyundergoingprogrammedcelldeathandremainhighlydependentoncertainsurvivalsignalsfromtheirenvironment.118,119Withinagrowingtumor,apoptosiswillpreferentiallyeliminatethosesub-cloneswiththehighestapoptosissensitivitywhereassparingthemoreresistantcells.Thus,celldeathimposesahugeselectionpressurefavoringclonalexpansionofmoreaggressivesub-clones.Hence,evenfullyestablishedtumorsarerarelycompletelyresistanttoapoptosis,anddeathinducedbyhypoxiaorchemotherapeuticsincreasesproliferativepressureandclonalselectionpavingthewayfortherapy-refractoryorrelapsingcancers.Inlightofthesefindings,itbecomesapparentthatstandardanti-cancertherapiesfaceadilemmabyaimingatinducingtumorcelldeath.Hence,webelievethatweareinneedforbettertreatmentstrategiestoavoidunnecessarytissuedamageandinflammatoryresponsesintumorpatientsaswellasinpatientspresentingwithpremalignantconditionssuchasbonemarrowfailureorviralhepatitis.Wearestillonlybeginningtounderstandthecomplexmechanismsinvolvedintumordevelopmentandprogression,andthusfurtherresearchisnecessarytounderstandthecontributionofapoptosisinshapingtumors,asaprerequisitetogenerateamorecomprehensivepictureontumorigenesisandallowmoreeffectivetherapeuticintervention. 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AdditionalinformationEditedbyGMelinoRightsandpermissions CellDeathandDiseaseisanopen-accessjournalpublishedbyNaturePublishingGroup.ThisworkislicensedunderaCreativeCommonsAttribution4.0InternationalLicence.Theimagesorotherthirdpartymaterialinthisarticleareincludedinthearticle’sCreativeCommonslicence,unlessindicatedotherwiseinthecreditline;ifthematerialisnotincludedundertheCreativeCommonslicence,userswillneedtoobtainpermissionfromthelicenceholdertoreproducethematerial.Toviewacopyofthislicence,visithttp://creativecommons.org/licenses/by/4.0 ReprintsandPermissionsAboutthisarticleCitethisarticleLabi,V.,Erlacher,M.Howcelldeathshapescancer. CellDeathDis6,e1675(2015).https://doi.org/10.1038/cddis.2015.20DownloadcitationReceived:05December2014Revised:28December2014Accepted:02January2015Published:05March2015IssueDate:March2015DOI:https://doi.org/10.1038/cddis.2015.20SharethisarticleAnyoneyousharethefollowinglinkwithwillbeabletoreadthiscontent:GetshareablelinkSorry,ashareablelinkisnotcurrentlyavailableforthisarticle.Copytoclipboard ProvidedbytheSpringerNatureSharedItcontent-sharinginitiative Furtherreading Hypomethylation-mediatedupregulationoftheWASF2promoterregioncorrelateswithpoorclinicaloutcomesinhepatocellularcarcinoma HyeRiAhn GeumOkBaek SoonSunKim JournalofExperimental&ClinicalCancerResearch(2022) Spontaneousactivityofthemitochondrialapoptosispathwaydriveschromosomaldefects,theappearanceofmicronucleiandcancermetastasisthroughtheCaspase-ActivatedDNAse AladinHaimovici ChristophHöfer GeorgHäcker CellDeath&Disease(2022) Tannicacidenhancescisplatineffectoncellproliferationandapoptosisofhumanosteosarcomacellline(U2OS) MohamadZahidKasiram HermiziHapidin SarinaSulong PharmacologicalReports(2022) AND-gatecontrastagentsforenhancedfluorescence-guidedsurgery JohnC.Widen MartinaTholen MatthewBogyo NatureBiomedicalEngineering(2021) TheBH3-onlyproteinNOXAservesasanindependentpredictorofbreastcancerpatientsurvivalanddefinessusceptibilitytomicrotubuletargetingagents GerlindeKarbon ManuelD.Haschka AndreasVillunger CellDeath&Disease(2021) DownloadPDF Advertisement Explorecontent Researcharticles Reviews&Analysis News&Comment Videos Collections FollowusonTwitter Signupforalerts RSSfeed Aboutthejournal JournalInformation AbouttheEditors Openaccesspublishing Contact ForAdvertisers PressReleases AboutthePartner UpcomingConferences Publishwithus ForAuthors&Referees Submitmanuscript Search Searcharticlesbysubject,keywordorauthor Showresultsfrom Alljournals Thisjournal Search Advancedsearch Quicklinks Explorearticlesbysubject Findajob Guidetoauthors Editorialpolicies