Cellular Stress in Aging and Cancer
Sturmlechner, Ines
DOI:
10.33612/diss.170212168
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Publication date:
2021
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Sturmlechner, I. (2021). Cellular Stress in Aging and Cancer. University of Groningen.
https://doi.org/10.33612/diss.170212168
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Two-step senescence-focused cancer therapies
Cynthia J. Sieben*
Ines Sturmlechner*
Bart van de Sluis
Jan M. van Deursen
* These authors contributed equally to this work.
Trends in Cell Biology, 2018 Sep;28(9):723-737.
Review
Two-Step
Senescence-Focused
Cancer
Therapies
Cynthia
J.
Sieben,
1,4Ines
Sturmlechner,
2,3,4Bart
van
de
Sluis,
3and
Jan
M.
van
Deursen
1,2,*
Damagedcells atriskof neoplastic transformationcan beneutralized by apoptosisorengagementofthesenescenceprogram,whichinduces perma-nentcell-cyclearrestandabioactivesecretomethatisimplicatedintumor immunosurveillance.Whilefromanevolutionary perspectivesenescenceis beneficialinthatitprotectsagainstmalignancies,theaccumulationof senes-centcellsintissuesandorganswithagingandatsitesofvariouspathologiesis largelydetrimental.Becauseinductionofsenescenceincancercellsis emerg-ingasatherapeuticconcept,itwillbeimportanttoconsiderthesedetrimental effects,includingtumor-promotingpropertiesthatmaydrivetheformationof secondarytumorsorcancerrelapse.Inthisreviewwediscussthecomplex relationshipbetweensenescenceandcancer,andhighlightimportant consid-erationsfortherapeutics.
SenescentCells:ModulatorsofAgingandCancer
Advancedageistheleadingriskfactorfornumerouschronicdiseasesincludingvarious typesofcancer[1].Althoughthecausesandmechanismsofagingremainpoorly under-stood,senescentcellshaveemergedasacentralcontributortoprematureandnatural aging[2]andtoage-relateddiseases[3–5].Variousstudiesinmicedemonstratethat senescentcellsrepresentadruggabletargettoextendhealthylifespanandameliorate variouschronicdiseases[2–4,6].Thesefindingshavepromptedcollectiveinterestinthe fundamentalbiologyofsenescentcells,notonlyincellculturebutalsointissuesandorgans acrossspecies,withtheultimategoalofidentifyingmolecularvulnerabilitiesfortherapeutic purposes[7](Box1).
Rationaltargetingofsenescentcells,particularlyinthecontextofcancer,requiresa com-prehensiveunderstandingofthemolecularandphysiologicalpropertiesofsenescentcells, theirdifferentphenotypicvariations,andtheircomplexassociationwithcancer,whichcanbe bothbeneficialanddetrimental.Acutelygeneratedformsofsenescentcells(acute senes-centcells;seeGlossary),thatariseduringwoundhealingorembryogenesisforexample,are thoughttoenhance organismalfitness byinhibitingneoplastic transformation[8] orby recruitingimmunecells[9].However,chronicallyexistingsenescentcellsduringaging andchronic diseasescanbedeleteriousfor theorganism, for instanceby creating a microenvironmentthatpromotesneoplasticgrowth[10],metastasis[11],or immunosup-pression[12].Inthefollowingsectionswediscussthevariousformsofcancer-associated senescentcellsinhumanandmousetissuesaswellastheirtherapeuticimplications.We proposethatsenescentcellremoval,senotherapy,isnotonlyaviabletherapeuticoptionfor agingandage-relateddiseasesbutalsoforcombination,two-stagecancertreatment– pro-senescencechemotherapyfollowedbysenotherapy.Thisapproachcouldmaximize che-motherapeuticefficiency,preventingcancerrelapseandmaintainingananti-tumortissue microenvironment.
Highlights
Senescentcells are a cell cycle-arrestedbuthighlybioactivecelltype. Althoughtheproportionofsenescent cellsintissuesisrelativelylow,these cellsarecausallyimplicatedinaging andinanever-expandinglistof dis-easesincludingcancer. Cancer-associated senescent cells canmodulateall stagesof tumor development,withtheircontributions beingeitherdetrimentalorbeneficial towards tumor initiation, growth, metastasis,orcancerrelapse. Although highlycontext-dependent, thesenescence-associatedsecretory phenotype(SASP)servesmany func-tionsinthetumormicroenvironment, includingmitogenicinduction,immune surveillance,orimmunedeterrence. Atwo-stepanticancertherapeutic con-cept,senescence-inducing chemother-apy followed by senotherapy, may representaviableoptiontomaximizether-apeuticefficiencyandpatientoutcome.
1BiochemistryandMolecularBiology,
MayoClinic,200FirstStreetSW, Rochester,MN55905,USA
2DepartmentofPediatricand
AdolescentMedicine,MayoClinic, 200FirstStreetSW,Rochester,MN 55905,USA
3DepartmentofPediatrics,Molecular
GeneticsSection,Universityof Groningen,UniversityMedicalCenter Groningen,AntoniusDeusinglaan1, 9713AVGroningen,TheNetherlands
4Theseauthorscontributedequallyto
thiswork
*Correspondence:
(J.M.vanDeursen).
TrendsinCellBiology,September2018,Vol.28,No.9 https://doi.org/10.1016/j.tcb.2018.04.006 723
©2018ElsevierLtd.Allrightsreserved.
SenescentCellTypesImplicatedinCancer
SenescentNeoplasticCells
Historically,cellularsenescencehasbeendescribedasatumor-protectivemechanismthat inhibitstheuncontrolledproliferationofcancer-pronecells.Activationofparticularoncogenes orthelossofparticulartumor-suppressorgenesinducesthesenescenceprogramtoestablish adurablecell-cyclearrest[8](Figure1A,KeyFigure).Thismechanismisdescribedinaplethora ofcellularsystemswithmultipleoncogenesinvitro,aswellasinmurinetissues,includingbut notlimitedtoliver(RASactivation[9]),lymphocytes(RASactivation[13]),skin(BRAFactivation
[14]),thyroidgland(BRAForRASactivation[11,15]),mammarygland(RASactivation[16]), prostate(PtenorSkp2loss[17,18]),colon(Csnk1a1loss[19]),andpituitarygland(Pttg1loss
[20]).Evidencefor‘oncogene-inducedsenescence’(OIS)inhumanprimarytumorshasalso beenreported.Forinstance,melanocyteswithoncogenicBRAFmutationsundergo senes-cenceandremainbenigninmelanocytenevi[21,22].Likewise,senescencemarkershavebeen identifiedinearly-stageprostatetumors[17]aswellascolonadenomas[10],astrocytomas
[23],andneurofibromas[24].
Inactivationofsenescencepathwaysinmice,forinstancethroughinactivationofthe Cdkn2a-encodedcell-cycleinhibitorsp16INK4Aandp19ARF(humanp14ARF),leadstoearlydeathfrom
tumors[16,25],illustratingwhynaturalselectionhasfavoredthesenescenceprogram. Fur-thermore,alterationofCDKN2Ainhumans,eithergeneticallyorepigenetically,isoneofthe mostfrequenteventsinneoplasticlesions[26,27],indicatingthatdisruptionofthesenescence programisamajoreventduringhumantumordevelopment.p16canalsobepredictiveof tumorsubtypebecausehighp16levelsdistinguishearly-stagesmallcelllungcancerfromlung adenocarcinoma[28,29],andearly-stage papillarythyroidmicrocarcinomafrompapillary thyroidcarcinoma[30].Tumorsubtypesoftenshowdistincttherapeuticresponseprofiles, suggestingthatp16levelscouldpredicttherapeuticefficacy[28].Inprostateoropharynx cancer,elevatedp16levelscorrelatewithasuperiorresponsetoradiationtherapy[31].On theotherhand,itmustbetakenintoconsiderationthatp16levelsmayincreaseoutsidethe contextofsenescence,forexampleowingtolossofRb1[32],anotherkeycell-cycleregulator withfrequentloss-of-functionmutationsinhumantumors[26].Overall,senescentcellsare foundinbothbenignandpremalignanttumors,suggestingthatcellularsenescenceisan evolutionarycancer-protectivemechanismdesignedtoenhanceorganismalfitness.
Therapy-InducedSenescentCells
Albeit metabolicallyactive, senescentcellsare cellcycle-arrested,and thereforecellular senescencehasbeenviewedasadesirableoutcomeduringcancertreatment(Figure1B). Tothisend,senescence-inducingcompoundshavebeendeveloped,includingCDK4/6 inhibitorssuchasabemaciclib,palbociclib,andribociclib.Becausethisclassofdrugshas
Glossary
Acutesenescentcells:senescent cellsthataregeneratedquicklyafter anenvironmentalinsultorstress(for exampleduringwoundhealing)or duringprogrammedsenescencein embryogenesis.Thesecellsare typicallyeliminatedbytheimmune systeminafastandefficientmanner. Becausethesecellsareonly temporarilypresentandare associatedwithphysiological processes,acutesenescentcellsare hypothesizedtobebeneficialforthe organism.
CDKN2A:thegeneencodingthe tumorsuppressorsp16INK4Aand
p19ARF(humanp14ARF),bothof
whichinhibitcyclin-dependent kinasesandthereforeregulatethe cellcycle.
Chronicsenescentcells:asubset ofsenescentcellsthatarenot efficientlyremovedorevadeimmune cellclearance,andtherefore accumulaterelativelyslowlyinseveral tissuesduringagingoratsitesof chronicpathologies.These senescentcellsareviewedas detrimentalfordiseaseprogression andaging.
Immunesurveillance: immunosurveillanceisacomplex processbywhichimmunecellsfrom theinnateoradaptiveimmune systemdetectandremove pathogensordamagedcells,which canincludesenescentcells. Inflammaging:ahypothesisthat tissuedeteriorationisassociatedwith low-gradetissueinflammation, usuallyinthecontextofagingand age-relatedaccumulationof senescentcellswhichsecrete pro-inflammatorycytokines. INK-ATTACtransgenicmice:a mousemodelcontaininganFK506 binding-protein–caspase8(FKBP– Casp8)fusionproteinandgreen fluorescentprotein(GFP)underthe controlofaminimalCdkn2a(p16) promoterfragmentthatis transcriptionallyactiveinsenescent cells,allowingeliminationof senescentcellsinthepresenceof thedimerizerAP20187(AP)which activatesFKBP–Casp8. PD1immunecheckpoint: programmedcelldeathprotein1 (PD1)isacell-surfacereceptorand immunecheckpointthatguards againstautoimmunitybypromoting
Box1.KeyAspectsofSenescentCells
Cellularsenescencereferstoamolecularprogramactivatedinresponsetoenvironmentalcuesorstressincluding,but notlimitedto,theendofreplicativelifespan/telomereerosion,DNAdamage,mechanicalstress,andoncogenicstimuli. Senescentcellsarecommonlycharacterizedbyadurablecell-cyclearrest,apoptosisresistance,andabioactive secretomereferredtoastheSASP.Combinationsofmultiplesenescencemarkersarewidelyusedtoidentifysenescent cells,suchasp16INK4A,p14ARF(murinep19ARF)(encodedbyCDNK2A),andp21CIP1/WAF1(encodedbyCDKN1A),DNA
damagemarkers(e.g.,g-H2AXfoci,53BP1foci),senescence-associatedb-galactosidaseactivity,chromatin altera-tionssuchaslaminBdeficiencyorheterochromatinfoci,andexpressionofseveralSASPfactors(proinflammatory cytokines,growthfactors,extracellularenzymes,andMMPs).Thereleaseofthesebioactivemoleculesaffectsand potentiallyharmsneighboringcellsorsignalstotheimmunesystem,andcollectivelymaycontributetotissue deteriorationorremodeling,chronicpathologies,andorganismalaging.Itshouldbenotedthatinthecaseofcancer, wherethegenomicregioncontainingCDKN2Aisfrequentlydeleted,itisimportanttoevaluateadditionalmarkersof senescencebecausep16INK4A-independentsenescencemayalsooccurinthesecases.
apoptosisinantigen-specificTcells whilesimultaneouslysuppressing apoptosisinregulatoryTcells. Signaltransducerandactivator oftranscription3(STAT3):a transcriptionfactorthatis phosphorylatedbyJanuskinases (JAKs)inresponsetocytokinesand growthfactors,triggering translocationtothenucleuswhereit actsasatranscriptionalactivatorand mediatescellgrowthandapoptosis. SRChomologyphosphatase2 (SHP2):alsoknownasPTPN11 (tyrosine-proteinphosphatase non-receptortype11),SHP2isan enzymeandsignalingmoleculethat regulatescellgrowth,mitoticcell cycle,differentiation,andoncogenic transformation.
KeyFigure
Cancer-Associated
Senescent
Cells
Affect
Tumors
in
Multiple
Ways
Age-related senescence (E) Stroma cell senescence Oncogene-induced senescence Immuno-senescence RAS Senescence during therapy
Healthy Ɵssue cell NeoplasƟc cell Senescent cell Senescent tumor cell Immune cell Senescent immune cell SASP factors Phenotypic transiƟons SASP signaling Blood vessel (A) (B) (C) (F) (D) senescenceParacrine
Figure1.Acutesenescentcellsthatariseduetooncogeneactivation(A)(oncogenicRASforexample)orchemotherapy (B)showtumor-suppressingproperties,includingcell-cyclearrestandSASPproductionthatmaypromote immuno-surveillance.However,prolongedpresenceofthesecells,inadditiontotumor-inducedorparacrinesenescenceinthe stroma(C,D)orage-relatedsenescence(E),canpromoteseveralhallmarksofcancer.Stromalsenescentcellsmayarise fromparacrinesignalsoriginatingfromtumorcells(C)(greyandwhitesecretedfactors)orothersenescentcells(D)(colored SASPfactors).Age-relatedsenescentcellsarehypothesizedtopromotebothneoplastictransformationofadjacentcells andproliferationoftumorcells(E).Immunosenescence(F)isacomplexprocess,butlargelyrendersimmunecells (especiallyTcells)unresponsivetoactivatingsignalsandalsopromotesaSASPwithprotumorigeniccapacities. Abbreviation:SASP,senescence-associatedsecretoryphenotype.
TrendsinCellBiology,September2018,Vol.28,No.9 725
shownpromiseintreatingseveralcancersinpreclinicalandclinicalstudies[33–35], high-throughputscreenshavebeenemployedtofindadditionaldrugtargetsthattriggersenescence incancercells[36].Studiesinmicesupportthebeneficialeffectsofsenescenceinductionin tumorcellsbecausethisnotonlyleadstotumorstallingbutalsoactivatesaSASP-mediated immuneresponse(Box1)thatcanresultineliminationofthesenescenttumorcells,aswellas neighboringneoplasticcells,ultimatelyleadingtotumorregression[9,37,38].
Conversely, accumulatingevidenceindicatesthat senescenttumorcells promotetumor relapse,aggressiveness,andmetastasis(Figure1B).Ithasbeenreportedthatp53-mediated senescenceinmammarytumorscanhinderchemotherapeuticefficiencyandpromoterapid cancerrelapse,comparedtoslowlyrelapsingtumorsinp53mutantmicethatfailtoarrestbut undergoapoptosisduetomitoticcatastrophe[39].Similarly,p16-positivepatienttumorsare associatedwithcancerrecurrence[40,41].Strikingly,arecentstudyshowsthat therapy-inducedsenescenceisassociatedwithstemcellandself-renewingfeatures,andcanpromote bothcancerinitiationandaggressiveness,inseveralmousetumormodelsincludingBcell lymphomaandTcellacutelymphoblasticleukemia[42].Inadditiontocancerrecurrence, senescentcellswithinthyroidtumorshavealsobeenlinkedtoinvasion,suggestingthatcancer metastasisispromotedbysenescentcellnon-autonomousfeatures[11].Importantly,while chronicsenescentcellsinducedbyradiationtherapyorchemotherapeuticdrugscontributeto localandsystemicinflammation,targetedremovalofthesecellsintransgenicmiceattenuates cancerrecurrenceanddetrimentalsideeffectsincludingbone marrowsuppressionand cardiacdysfunction[6,43].Therefore,althoughsenescenceinductionincancercellsisaviable therapeuticoptiontoreduceinitialtumorgrowth,chronicallypersistingsenescentcellsneedto beremovedtominimizeregressionriskandavoiddeleterioussideeffects.
SenescenceInductioninTissueAdjacenttoTumors
Thepresenceofsenescentcellswithintissuescanpromoteproliferationofneighboringcells, includingpreneoplasticcells[10].Thispropertyofsenescentcellshasbeenwellstudiedinvivo usingxenograftmodelsandcoinjectionofcancercellsandeithersenescentornon-senescent fibroblasts[12,44–46].Invitrostudiesshowthatsenescentcellnon-autonomouseffects,via secretionofSASPfactors(furtherdetailedinalatersection),inducegrowth,angiogenesis,and invasivepropertiesinneighboringcells[10,47,48].Establishedtumorsorneoplasticcellscan alsoinducecellularsenescenceinneighboringcells(Figure1C).Indeed,senescentcellshave beenidentifiedinthestromaofhepatocellularcarcinoma[49]andovariancancer[50],and usingap16–luciferasemousemodel,onegroupshowedthatinjectionoftumorcellsinduced senescenceinthestromasurroundingtumors[51].
Stromalsenescentcellsdrivetumorgrowthinseveralstudies,andthegeneexpressionprofiles ofcancer-associatedfibroblastsandsenescentcellsaresimilar,suggestingthatsenescent cellsdriveneoplasticcellproliferationthroughsimilarparacrinemechanisms[52,53].Infact, increasedp16levelsinthestromasurroundinghumanmammaryductalcarcinomainsitu lesionspredictdiseaserecurrenceindependentlyofothertypicalhistologicalmarkers[54]. Recentstudieshavealsoshownthatsenescentcellscanpromotetumorgrowthby establish-inganimmunosuppressivemicroenvironmentviasecretingcytokinesthatrecruit myeloid-derivedsuppressorcells,whichinhibitTlymphocyte-mediatedtargetingoftumorcells[55]. Overall,senescentcellsareinducedbyneighboringneoplasticcellsortumors,andsupporta protumorigenicmicroenvironmentandincreasedriskofrelapse.
Inaddition,senescentcellscanalsopotentiatetheirowneffectsbyinducingsenescencein neighboringcellsthroughparacrinemechanisms(bystander effect)viatheSASPorgap
junction-mediatedcell–cellcontact(Figure1D)[56,57].Indeed,severalstudieshave demon-stratedthiseffectinvitrousingsenescentcellconditionedmedia,andhaveshownthat numerousSASPfactorsorsignalingpathways,includingTGFB1[58,59],reactiveoxygen species(ROS)-activatedNF-kBsignaling[60],IL-8andCXCL1[61],andcGAS–STING signal-ing[62],canmediatetheinductionofparacrinesenescence.Further,anothergroupshowed thatshort-termexposureofnormalcellstoSASPfromsenescentcellsinducesexpressionof stemcellmarkersconferringregenerativecapacity;however,prolongedexposureinduces senescence[63],suggestingthatonlyshort-termexposuremaybebeneficial.Inductionof senescenceinneighboringcellshasalsobeendemonstratedinvivo,inpituitarystemcell clustersinmousemodelsofpediatriccraniopharyngioma[64]andinischemicretinalcellsina mousemodelofischemicretinopathy[65].Senescentcellsclustershavealsobeenidentifiedin thethymusofagedmice[66],hepatocytesfrommouselivers[56],andintervertebraldiscsof patientssufferingfromintervertebraldiscdegeneration[67].Together,paracrinesenescence inductionbyneighboringsenescentcellsrepresentsamechanismforsenescentcellsto potentiatetheireffects,andmayamplifynegativeimpactsoncancer(Figure1D),aging, andotherage-relateddiseases.
Aging-RelatedSenescentCells
Agingisamajorriskfactorforcancer,andmosttumorsarediagnosedinagedpatients[68].In addition,5yearsurvivalformanycancertypesdramaticallydeclineswithage[68,69]. Epidemio-logicalstudiesshowthatfamilialfactorscorrespondtobothreducedcancerandlongevity,and mostgeneticanddietarymodificationsinmicethatimpactonagingalsohaveanimpactoncancer
[69,70].Further,severalprogeroidsyndromes(Hutchinson–Gilfordprogeriasyndrome,Werner syndrome,Bloomsyndrome,xerodermapigmentosum,ataxiatelangiectasia,andmosaic varie-gatedaneuploidysyndrome)arealsoassociatedwiththedevelopmentofcancer[71]. Althoughhistoricallycanceraggressivenesshasbeenthoughttodecreasewithage,several tumortypesincludingacutemyeloidleukemiaandovariancancerhaveaworseprognosiswith increasingage[72,73].Experimentalevidenceforarelationbetweenagingandcancerfrom animalmodelsisvariable,andappearstobetumororcelltype-dependent[69].Inprostate cancerandmelanomaxenograftexperiments,nochangeingrowthorfastergrowthinyoung micewasobserved,respectively[74,75].However,inthesestudies12-month-oldmicewere usedas‘aged’mice,buttheseverityofage-relatedtissue deteriorationorpresenceof senescentcellsatthisagemaybelimited.However,implantationofneoplasticliverepithelial cellsintoliversofyoungandoldratsresultedinreducedproliferationandmoreapoptosisin youngrats[76].Thissuggeststhatdifferencesbetweentumortype,celltype,and/orsiteof implantationmayexplainthevariationinresults.
Inothergeneticapproaches,continuedsenescentcellremovalinnaturallyagingmice (INK-ATTACtransgenicmice)throughoutadulthoodwasfoundtoextendlifespananddelaytumor latency[2],suggestingadetrimentalroleforage-relatedsenescentcellsintumorprogression. Thisresultisfurthersupportedbytimedsomaticp53deletioninyoungandoldmice,where reducedtumorlatencywasobservedinagedmice[77].Further,usinganinducibleconditional mousemodelexpressingthecellcycleinhibitorp27Kip1tomimicskinaging,otherresearchers
discoveredthepresenceofstromalsenescentcellsandincreasedrecruitmentofsuppressive myeloidcellswhichinhibittumorimmunesurveillanceandpromotetumorformation[12]. Collectively,thesestudiesshowthataccumulationofsenescentcellsintissueswithaging promotes tumorformationandgrowth (Figure1E),andhighlightsthesecellsasoptimal therapeutictargetsnotonlyfortheameliorationofage-relateddeteriorationbutalsoforcancer preventionandtreatment.
TrendsinCellBiology,September2018,Vol.28,No.9 727
CancerandtheAgingImmuneSystem
Boththeadaptiveandinnateimmunesystemsarecapableofinfiltratingandclearingtumor cells.WhileTcells(CD4+helperandCD8+cytotoxic),tumor-associatedmacrophages,and
naturalkiller(NK)cellspreventtumorgrowthbytargetingantigenictumorcells,regulatoryT cellsthatsecreteimmunosuppressivecytokinesaswellasmyeloidandstromalcellssuppress Tcellresponsesinlesionsthathavelostimmunogenicity[9,78,79].Interestingly,thesesame immunecelltypesareeffectiveineliminatingsenescentcells[9,37,38,80,81].Theimmune systemundergoesprofoundchangeswithagingasreflectedbyincreasedsusceptibilityto infection,autoimmunity,impairedresponsetovaccination,andcancerdevelopment[82,83]. Withincreasingage,boththeabilityoftheadaptiveimmunesystemtomountTcell-mediated responsesandtheregulationoftheinnateimmunesystemdecline,whichmayimpactonboth senescentandtumorcellclearance[84,85].
Interestingly,theaccumulationofagedimmunecells,referredtoasimmunosenescence, increaseswithageinbothBandTcellpopulations(Figure1F)[86].WefocushereonTcell immunosenescencebecauseTcellsfunctioninimmunosurveillanceoftumorsandsenescent cells.Tcellimmunosenescencecanbeinducedbymultiplemechanismsincluding,butnot limitedto,repeatedorchronicT cellstimulation(viruses,pathogens,tumorantigens,or immunogenicself-antigens)andaderegulatedinflammatoryenvironment[86,87].Senescent Tcellsarenonresponsivetostimulation,butaremetabolicallyactiveandproducecytokines includingIL-6andTNF-a[86].SenescentTcellscanbeprotumorigenicthroughtheirabilityto suppressproliferationofresponderTcells[88],butcanalsomodulatemacrophagecellfate andcontributetoantitumoralfunctions[89].
Oneof thehallmarksof canceristheabilityof tumor cellsto escapefromimmune surveillance[90].Severalrecentstudieshaveshownthatimmunosurveillanceoftumor andsenescentstromalcellsisanimportanttumorprotectionmechanism.Ithasbeen shownthatoncogene-inducedsenescenthepatocytessecretchemokines,whichfacilitate clearanceby theadaptiveimmunesystem(CD4+T cell-mediated),whereasimpaired
immunesurveillanceresultedinthedevelopmentofhepatocellularcarcinomas[9].This suggeststhatdecreasedimmunesurveillance,asobservedwithage,maydrivetumor formation.Indeed,inamousemodelofsquamouscellcarcinoma,conditionalinductionof mutantHRASinkeratinocytesresultedindysplasticchangesand50%tumorincidencein agedmiceonly,whichshowedincreasedcellularsenescenceindermalimmunecells[91]. Bycontrast,twostudiesdemonstratedthatsenescentcellswithintumorsfacilitatedNKcell recruitmentandtumorelimination,suggestingthatsenescentcellsmayprovidebeneficial immuneattractionproperties[37,80].Together,theseresultssuggestthatpresenceof senescentcellsmaybeabenefitordetrimenttoneoplasticcells/tumorsbyavertingor attractingimmunecells.
Inaddition,theimmunosuppressivenatureofthetumormicroenvironmentlimitstheabilityof immunecellstoinfiltrateandtargettumorcells[92].Senescentcellswithintumorstroma,for example,maydeterimmunecellinfiltrationanddrivetumorigenesis.Onestudyshowedthat myeloid-derivedsuppressorcells(MDSCs)promotedanage-relatedincreaseinlungcancer growthinmice,andthatthesecellsincreasewithageinthecirculationofhumansandinthe spleensofmice[93].Further,inamodelofskinaging,senescentstromalcellsweresufficientto recruitandincreaseMDSCs,whichinhibitTcellresponsesandpromotetumorgrowth[12]. Overall,theagingprocessincreasesthesenescentcellburdenandimpairsimmunefunction, whichinturn escalatessenescent cellaccumulationandinferiorneoplasticsurveillance, establishingaprotumorigenicenvironment(Figure1F).
TheSASPandCancer
Senescentcellsrestrictandcontributetocancerviabothcell-autonomous(restrictionofcell proliferationortransformation)andcellnon-autonomousmechanisms(SASP)thatcanresultin extracellularmatrixremodeling,growthstimulation,orsuppressionofadjacentcellsand signalingtotheimmunesystem.Senescence-associatedparacrinesignalingseemstobe context-dependent,withthetypeofsenescencestimulusandcelltypehavingdramatic consequencesontheSASPprofile[47,94].
TheestablishmentandregulationoftheSASPcanbeorchestrated,atleastinvitro,bymultiple signalingpathwaysandtranscriptionfactornetworks,includingNF-kBsignaling[95],thep38 MAPKpathway[96],thecGAS–STINGpathway[62,97],inflammosomeactivation[57],TGF-b signaling[98],JAK–STATsignaling[55],PI3K–AKT–mTORsignaling[99],GATA4activation
[100],andC/EBP-bactivation[10](Figure2).Whichofthesesignalingpathwaysandnetworks areactiveseemstobedependentonsenescentcellmaturation[63,98]andorigin[42]. Extensivecrosstalkamongpathwaysandnetworkshasbeenobserved[99,101].EachSASP signalingpathwaymaydrivetheexpression,translation,orproteinstabilityofnumerousSASP factors.However,onlyafewofthesefactorshavebeenmechanisticallylinkedtophysiological eventsintissuesordiseases,andthemechanisticactionofsinglecomponentsisstilllargely basedonstudiesperformedinculturedcells.WedescribebelowselectSASPfactorsto illustratetheircontext/potentialinimpactingcancer-associatedprocesses(Figure2). IL-1aisanimportantSASPinitiatorandisactivatedintherapy-induced[99,101], oncogene-induced[102],andage-relatedsenescentcells[2].IL-1adrivesautocrineproinflammatory signalingincludingNF-kBactivationandtheexpressionofkeycytokinessuchasIL-6andIL-8
[99].IL-1acanactlocallyasamembrane-boundcytokinethatmayrecruithematopoieticcells orbecleavedbyextracellularproteasesandpromotesystemicinflammation.IL-1asignaling maythereforenotonlycontributetosenescentcellimmunosurveillancebutalsototissue inflammaging.Studiestodeterminetheroleofsenescentcell-derivedIL-1aintumorgrowth haveyettobeconducted[103].
IL-6andIL-8aretwoofthemostinvestigatedproinflammatorySASPfactors,andhavebeen linkedtooncogene-inducedsenescentcells,senescentstroma[10–12,15,104],andmurine senescentcellsduringnaturalaging,progeria,anddisease[2,4,105].Inadditiontopromoting aninflammatoryresponseandimmunosurveillancetocontrollivertumorprogression[80], CXCR2receptoractivationviaIL-6andIL-8reinforcessenescence andcell-cyclearrest throughelevatedROSproductionandactivationoftheDNAdamageresponse[61,101].In someinstances,however, stromalcell-derivedIL-6 canactinimmunosuppression [12]. AlthoughfunctionsascribedtoIL-6andIL-8 suchasprofibroticsignaling[106]or pro-proliferativesignaling[107]areunexploredinthecontextofsenescence,investigatingthese characteristicsmaybeofintegralimportanceinthecontextofcancerandcancer-associated senescence.
ChemokinessuchasCXCL1/GROaarebroadlyexpressedinseveralsenescencecontexts. CXCL1isnotonlyhighlyexpressedinoncogene-inducedsenescentcellsinvitroandinmice
[50,104]butalsoinhumanovariancancersamples[50].SecretionofCXCL12by cancer-inherent, likelyoncogene-induced,senescentcells promotesthyroidtumorinvasionand metastasisinmice[11],andthecytokineCCL2/MCP-1hasbeenlinkedtoOISintheliver andimmunesurveillanceofpremalignanthepatocytes[38]orsenescentlivertumorcells[37]. However,inthecontextofestablishedhepatocellularcarcinoma,CCL2amongothersrestricts NKcellfunctionthroughtherecruitmentofimmunosuppressivemyeloidcells,andfacilitatesthe
TrendsinCellBiology,September2018,Vol.28,No.9 729
establishmentofadvanceddisease[38].Ontheotherhand,CXCL1canalsobesecretedby tumorcellsandconfersparacrinestromalsenescencethat,inturn,couldpromotetumor growth[50].Whilethesestudiesillustratethatsenescentcell-derivedchemokinesareintegral SASPcomponents,theirphysiologicalcontributionstocancerareofacomplexand context-dependentnature.
Growthfactorsorextracellularvesicleswithgrowth-stimulatorypropertiesaresecretedby senescentcellsandmaycontributetotumorinitiation,growth,andangiogenesis[47,108]. Vascularendothelialcellproliferationmaybemediatedbysenescentcellsofvariousorigins
Oncogene-induced
senescent cells
Age-associated
senescent cells
Senescent cells
during therapy
Senescent
stromal cells
IL-6, IL-1α, MMPs
CXCL1, HGF
IL-1α, IL-6/8,
CCL2,
CXCL1/12,
MMPs
IL-6, MMPs,
osteoponƟn
IL-1α, CCL2
Healthy
Ɵssue cells
NeoplasƟc cells
Phenotypic transiƟons
SASP signaling
SASP factors
Secreted factors (from non-senescent cells)
Figure2.SecretoryDiversityofCancer-AssociatedSenescentCells.SelectedSASPcomponentswith tumor-modulatingactivitiesforeachofthediscussedsenescencetypesaredepicted.Whileage-associatedsenescentcells, oncogene-inducedsenescentcells,andtherapy-inducedsenescentcellsoftenseemtosecretecytokinesand chemo-kines(includingIL-6,CCL2,etc.),theprotumorigenicactivityofstromalsenescentcellsbenefitsmostlyfromthesecretion ofgrowthfactors(suchasosteopontin)andmatrixmetalloproteinases(MMPs).Tumorcellsthemselvesarealsoableto secretebioactivefactorsthat,insomeinstances,arecausallyimplicatedinthedevelopmentofstromalsenescentcells. Abbreviations:HGF,hepatocytegrowthfactor;SASP,senescence-associatedsecretoryphenotype.
throughsecretionofpro-angiogenicVEGF,resultingintumorvascularization[45].Osteopontin (OPN),asecretedglycoprotein,ishighlyproducedbysenescentstromalcellsinmurineskin papillomas,andcoinjectionofOPN-deficientsenescentcellsrestrictstumorgrowthcompared toOPN-expressingsenescentcells[109].Conversely,hepatocytegrowthfactorderivedfrom tumorcells orascitic fluidofan ovariancancer-patientcan alsoinducesenescence in mesothelialcells,andthismaymodulateovariancancerdevelopmentandpotentially metas-tasis[110,111].
Matrixmetalloproteinases(MMPs),secretedenzymesthatprocessanddegradeextracellular matrix(ECM)components,contributetotissueremodelingandareoftenreleasedbysenescent cells.ThisclassofSASPfactorsiswelldescribedinmultipletissueswithage[2,112]and age-relateddiseases[3,4],aswellasinthyroidtumorsassociatedwithsenescentcells[11].While destructionoftheECMbarrierpersemayfacilitatetumorgrowthandcellinvasion,growth factorsandcytokinesthataresequesteredbyECMcomponentscanalsobeliberatedbyMMP activity[113].Indeed,senescentcell-derivedMMPswereshowntosupporttumorgrowth[44]
andpromoteVEGF-stimulatedtumorvascularizationofmurinexenografts[114].Further, stromalcell-derivedMMP1cancleaveprotease-activatedreceptorsontumorcellstoenable migrationandtumorcellinvasion[115];however,whetherthismechanismappliestosenescent cell-derivedMMPsremainstobeexplored.Therefore,whiletumor-inherentsenescentcells couldrendertumortissuepermissivetocancergrowth,vascularization,orcellinvasion, age-associatedsenescentcellsmayrendertargettissuepermissivetometastases.
Overall,theSASPofage-relatedsenescentcellsandofsenescentcellsinestablishedtumors appearstobemostlydetrimentalbecauseitcatalyzesseveralhallmarksofcancer,andremoval ofsenescentcellsduringnaturalagingdelaystumorlatency[2].Onekeyfeatureistheinterplay betweentumorcells,cancer-associatedsenescentcells,andtheimmunesystem orchestrat-ingimmuneresponses.Althoughonlyfewstudiesaddressthisrelationship,itisapparentthat senescentcellandtumorimmunesurveillanceiscomplexandoftencontext-dependent. Molecularmechanistic insightsintothe implicatedevents, proteins,and kineticswillbe necessarytounderstandandpredicttherapeuticoutcome.Althoughdissectingtheidentity andoriginofdonorandrecipientcellsduringparacrinesignalingistechnicallychallenging, recentadvancesinsingle-cellsequencingtechniquesandsingle-cellproteomicswillaidethese effortsandaddressthenotionthattargetingofsenescentcellsortheirsecretomeincancer patientsmayrepresentaviabletherapeuticoptionthatshouldbeconsideredasasupplement tochemotherapy.
SenotherapyasanAnticancerStrategy
Althoughthecentralobjectiveofchemo-andradiationtherapiesistopreventtheproliferationof cancercellsthroughtheinductionofcellularsenescenceorcelldeath[116],thepersistenceof therapy-inducedsenescentcellsaftertreatmentisdetrimental.Theuseofsenotherapyin combinationwithcurrentlyusedcancertherapiesshouldbetakenintoconsiderationtocontrol thisproblem[43].Severalcancertypesarediscussedherewhichrepresentsuitablecandidates forconsiderationofcombinationcancerandsenotherapies(Table1).
Indeed,treatmentwiththeCDK4/6inhibitorpalbociclibisinitiallyeffectiveininhibiting mela-nomatumorgrowth;however,prolongedtreatmentinducedsenescenceandSASP produc-tioninstromalcells,whichbecametumor-promoting[117].Inaddition,inhibitionofSRC homologyphosphatase2(SHP2)preventedandarrestedmammarytumorgrowthinmice throughtheinductionofsenescence;however,theactivationofsignaltransducerand activatoroftranscription3(STAT3)andSASPsecretionsuppressedimmunesurveillance
TrendsinCellBiology,September2018,Vol.28,No.9 731
Table1.Senescence-AssociatedCancerTypesandTherapeuticPotential
Tissue/tumortype Model Senescentcelltype Potentialsenotherapeutic
outcome(aspect)
Refs Brain
Adamantinomatouscraniopharyngioma Mouse,human Oncogene-induced,age-related Beneficial(initiation) [64]
Breast
Mammarytumors Mouse Therapy-induced Beneficial(recurrence) [39]
Xenograft(breastcancer) Mouse,coinjection (tumorandsenescentcells)
Therapy-induced Beneficial(growth) [44]
Xenograft(mammaryepithelialcancer) Mouse,coinjection (tumorandsenescentcells)
Replicative,oncogene-induced, andp16overexpression
Beneficial(vascularization) [45]
Mammaryductalcarcinoma Human Tumor-induced Beneficial(recurrence) [54]
Liver
Hepatocellularcarcinoma Mouse Oncogene-induced(andothers?) Detrimental,earlystages (immunosurveillance)
[9,37,38]
Beneficial,latestages (immunosurveillance)
Hepatocellularcarcinoma Mouse Geneticp53
reactivation
Detrimental (immunosurveillance)
[80]
Hepatocellularcarcinoma Human Age-relatedortumor-induced? Unclear [49]
Hepatictumors Mouse,tumorcellinjection Age-related Beneficial(growth) [76]
Lung
Lungcancer Mouse,tumorcellinjection Age-related Beneficial(growth) [93]
Lymphoma/leukemia
Bcelllymphoma Mouse,tumorcellinjection Therapy-induced Beneficial(initiation,growth) [42]
Tcellacutelymphoblasticleukemia Mouse,tumorcellinjection Therapy-induced Beneficial(initiation,growth) [42]
Multiple
Lymphoma,sarcoma,carcinoma (age-relatedcancerinmice)
Mouse Age-related Beneficial(growth,initiation?) [2,77]
Xenograft(breast,pancreatic, endometrial,andlungcancer)
Mouse,tumorcellinjection Tumor-induced Unclear [51]
Xenograft(humanepidermalkeratinocytes, immortalizedmousemammaryepithelial cells,humanbreastcancer)
Mouse,coinjection (tumorandsenescentcells)
Oncogene-induced,replicative Beneficial(initiation,growth) [46]
Ovary
Ovariancarcinoma Human Tumor-induced Beneficial(growth) [50]
Prostate
Prostatecarcinoma Human Unclear Beneficial(recurrence) [40,41]
Prostatecancer Mouse Ptendeletion Beneficial(immunosurveillance,
growth,andchemoresistance)
[55]
Skin
Skinpapillomas Mouse Tumor-induced Beneficial(growth) [109]
Skin(squamouscellcarcinoma) Mouse Age-related Beneficial(initiation,growth?) [91]
Skin(squamouscellcarcinoma) Mouse,coinjection (tumorandsenescentcells)
Geneticp27overexpression Beneficial(immunosurveillance, growth)
[12]
Thyroid
[118].Further,twomousestudiesshowedthatremovalofsenescentcellsaftercancertherapy alleviatedtheirdetrimentaleffects,including reducedbonemarrowsuppression,cardiac dysfunction,cancerrecurrence,andimprovedphysicalactivityandstrength[6,43].Together, theseresultsunderpintherelevanceandpotentialbenefitofsenotherapyfollowingcancer therapeutics.
Threeprinciplecategoriescanbeconsideredforsenotherapy:permanentremovalof senes-centcells(senolysis),immune-mediatedsenescentcellclearance,andSASPneutralization[7]. Althoughsenescentcellshavebeeneliminatedwithoutnegativeconsequencesduringaging anddisease[2,4,105],acutelygeneratedsenescentcellsinadultsexhibitsomebeneficial effectsinwoundhealing[2,119]andtissueregeneration[63].Senolyticdrugswhichtargetthe antiapoptoticresponseinsenescentcells,suchassignalingthroughBCL-2familymembers (navitoclax/ABT-263 orABT-737), haveprovedto beeffectiveininducingcelldeathin senescentcells;however,thesecompoundsareunlikelytomeetrequiredsafetystandards owingtotherisksofthrombocytopeniaandneutropenia[7,120,121].However,theseriskscan beminimizedbyshort-termtreatment,andpotentiallybylocalizeddelivery,whereapplicable. Effectivetargetingofsenescenttumorcellshasbeenachievedusinginhibitionoflysosomal ATPases,therebyexploitingthehighmetabolicactivityofcyclophosphamide-or adriamycin-inducedsenescentlymphomacellsinmice[122].
Treatmenttoenhanceimmuneactivitycouldalsobeharnessedtoimprovetheantitumor activityofsenescentcell-recruitedimmunecells[123].Thiscouldbeachievedthroughtheuse ofipilimumab,anantibodythatenhancesactivationofcytotoxicCTLA-4receptor,orwith antibodiesagainstthePD1immunecheckpoint,bothofwhichareinclinicaluseforthe treatmentofmelanoma[124].SASPmodulationmayalsobeemployed,andcanbeachieved byblockingpro-SASPsignalingorinhibitingindividualSASPcomponents[7].Blocking pro-SASPsignalingmaybecomplexbecauseperturbationofthesepathwaysistumorigenicin somecases,forexampleIL-6isnecessarytomaintainthesenescentcellstate[101].In addition,SASPreductionthroughNF-kBinhibitioninalymphomamousemodeldisrupts immunosurveillancefollowingtherapy-inducedsenescence,andleadstotreatmentresistance andrelapse[95].Similarly,inhibitionofmTORC1,acomponentofthePI3K–AKT–mTOR pathway,withrapamycindiminishesp53translationinPten-deficientsenescentcellsand promotesmurineprostatetumorigenesis[125].Ontheotherhand,STAT3inhibitionhad beneficialeffectsinalleviatingdetrimentalSASPeffects,andresultedinreducedsecretion ofimmunosuppressive cytokines,triggering astrongCD8+ Tlymphocyte responseand
prostatetumorregression[55].Together,thissuggeststhatinhibitionofpro-SASPsignaling ispathway-dependent,andfurtherinvestigationintotheefficiencyandriskofthesestrategiesis required.InhibitionofselectedSASPcomponentscanalsobebeneficialbecauseofreduced off-targeteffects.PerhapsthemostprominentSASPfactors,forwhichapproveddrugsare available,includeIL-1a(IL-1receptordruganakinra,currentlyusedfortreatmentofrheumatoid arthritis),andIL-6(IL-6antibodysiltuximab,currentlyusedfortreatmentofCastlemandisease; IL-6receptorinhibitortocilizumab,currentlyusedfortreatmentofrheumatoidarthritis)[126– 128].Thesestrategieshavenotyetbeentestedinpreclinicalmodelsofcanceroraging,but representpromising targetsfor futurestudy.Together, several suitableapproaches are availablefortargetingsenescentcellsincombinationwithchemotherapyorinthecontext ofagingtopromoteeffectivetherapy,minimizerelapse,anddelayorpreventcanceronset; however,furthertestingofthesestrategiesincancerisrequired.
Inaddition,carefulconsiderationofthetimelineforsenotherapyincombinationwithcancer therapyshouldbetakenintoconsiderationbecausesenescentcellshavebothbeneficialand
TrendsinCellBiology,September2018,Vol.28,No.9 733
detrimentaleffectsontumorinitiation,growth,andrelapseinacell/tumortype-dependent fashion.Withcurrentknowledge,incorporationofsenotherapymaybebeneficial(i)before cancertherapyto increasetherapeuticefficacyby removingexistingsenescentcells,(ii) followingcyclesofcancertherapytoimprovetherapeuticoutcome,and(iii)afterfinaltreatment toreduceriskofrecurrenceandalleviatethenegativeimpactsofindirectsenescenceinduction duringtherapy.Inallcases,senescentcellremovalbysenolysisorimprovingimmunetargeting wouldbemostefficacious;however,ifmodulationofparticularSASPfactorscanprove beneficial,withminimaloff-targeteffects,thismayalsobeaviableoption.Inallinstances, however,additionalstudyusingpreclinicalanimalmodelswillbenecessarytodeterminethe safetyandefficiencyofthesestrategies.
ConcludingRemarksandFutureDirections
Cellularsenescenceisafeatureofcancerthatcanbeinducedbymultiplemechanismsinand aroundtumors,andcanhavebothbeneficialanddetrimentaleffectsontumorinitiation,growth, therapeuticefficacy,andtumor recurrence.However, thefeatures of thesedifferentsenescentcell types,aswellasthemechanismsfortheirphenotypicimpactonneoplasticcells,remain incompletelyunderstood,andin-depthinvivoanalysisiscurrentlylacking(seeOutstanding Questions).Althoughthesestudiesaretechnicallychallenging,itisdifficulttotranslateinvitro findings.Further,giventhecomplexandimportantroleofimmunesurveillanceintumorigenesis andcellularsenescence,experimentationinimmunocompetentanimalmodelsisrequired.In addition,theroleofsenescentcellsindifferenttumortypesappearstoberelativelyvariable,and furtheringourunderstandingofthesedifferencesisanimportantconsiderationforbothcancer andsenotherapy.Withcurrentknowledge,itseemsthatthedetrimentaleffectsofsenescentcells incancerappeartooutweighthebeneficialeffectsthatareobservedinsomeinstances. Nevertheless,increasingourunderstandingofthedifferencesbetweentheSASPofsenescent cellsderivedfrommultiplemechanisms,andhowthesecomponentscontributetoimmune attractionanddeterrence,willbecrucialforconsiderationofcombinationcancerand senother-apy.Althoughadditionalstudieswillbenecessarytodeterminethesafetyandefficiencyof combinationcancerandsenotherapy,thisconceptshowsgreatpromiseinimprovingcurrent cancertherapeuticsandoverallthehealthandoutcomesofcancerpatients.
Acknowledgments
The authorswouldliketoacknowledgethefollowingfunding andsupportsources:NIH(R01CA166347and R01CA96985),theGlennFoundationforMedicalResearch,MayoClinicCenterforBiomedicalDiscovery,andtheMayo ClinicGraduateSchoolofBiomedicalSciences.
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