New Dimensions in Cancer Biology: Updated Hallmarks of ...

The original hallmarks (2000) · Self-sufficiency in growth signals. · Insensitivity to growth suppressive signals. · Ability to evade programmed ... SkiptoContent × AdvancedSearch Searchfor: Select"Patients/Caregivers/Public"or"Researchers/Professionals"tofilteryourresults.Tofurtherrefineyoursearch,toggleappropriatesectionsonoroff. Patient/Caregivers/Public Researchers/Professionals AACRFoundationAACR'sImpactAboutCancerGetInvolvedInnovatorsinDiscoveryPatientAdvocacyProgressAgainstCancerSurvivorJourneysWaystoGiveAACRBlogAACRFellowsAACRHistoryAACRNewsroomStoriesoftheAACRAwardsandLectureshipsEducationandTrainingInMemoriamLeadership/GovernanceMeetingsMembershipPolicy/GovtAffairsResearchResearchFunding ClearFilters × CancerResearchCatalystTheOfficialBlogoftheAmericanAssociationforCancerResearch Home»CancerResearchCatalyst»NewDimensionsinCancerBiology:UpdatedHallmarksofCancerPublished NewDimensionsinCancerBiology:UpdatedHallmarksofCancerPublished January21,2022 bySilviaLicciulli,PhD ThenewyearbringsanewchapterintheholybookofcancerbiologywiththepublicationintheAACRjournalCancerDiscoveryofHallmarksofCancer:NewDimensions,anupdatetothe“HallmarksofCancer”series.Thelatesteditionwassalutedwithgreatenthusiasmbythescientificcommunityasthenewpieceofaniconicsaga,withmanyscientiststakingtoTwittertosharetheirexcitementaboutseeingtheirfieldofstudyacknowledgedamongthefundamentalsofcancerbiology.  Theoriginalarticleoftheseminalserieswaspublishedin2000byRobertWeinberg,PhD,FAACR,fromtheWhiteheadInstituteforBiomedicalResearchandtheMassachusettsInstituteofTechnology,andDouglasHanahan,PhD,FAACR,fromEPFL,theSwissFederalInstituteofTechnologyinLausanne.Theauthors,bothcancerresearchpioneers,organizedstate-of-the-artknowledgeoncancerintoalogicalframeworkthatrecapitulatedtheextraordinarycomplexityofthediseaseinasmallsetoffundamentaltraitssharedbymost,ifnotall,humancancers.Inaddition,theyintroducedtheconceptof“enablingcharacteristics,”ormeansthatenablepremalignantcellstoacquirethesixhallmarksofcancer.  Thislandmarkreviewsoonbecameanessentialresourceforcancerresearchers,withtensofthousandsofcitations,providingacomprehensivefoundationforunderstandingandstudyingcancerbiology.Toaccountfornewdiscoveriesandprogressinthefield,theauthorsprovidedafirstupdatein2011,addingtwoemerginghallmarksandanewenablingcharacteristic.  In“HallmarksofCancer:NewDimensions,”Hanahanfurtherrevisitedthelist,proposingonenewemerginghallmarkandtwoadditionalenablingcharacteristics.   Readontolearnmoreaboutthehallmarksofcancer,howtheywereexpandedovertime,andthelatestadditions.  Theoriginalhallmarks(2000)  Writingabouttheoverwhelmingcomplexityofthescientificliteratureoncancerin2000,WeinbergandHanahanforecastedthat,ratherthanaddingmoreinformationinachaoticfashion,researchinthenextquartercenturywouldbringaconceptualshifttowardsamorelogicalapproachtodeciphersuchcomplexity“intermsofasmallnumberofunderlyingprinciples.”Theoriginal“HallmarksofCancer”reviewwastheauthors’effortandcontributiontothisshift,leadingtotheenumerationofsixcore“rules”thatorchestratethemultistepprocessofthetransformationofnormalcellsintomalignantcells:  Self-sufficiencyingrowthsignals.Whilenormalcellsdependonexternalgrowthsignalsforproliferation,cancercellscangeneratemostofthegrowthsignalsbythemselves,greatlyreducing,oreliminating,theirdependenceonexternalstimuli.Acorollarytothisobservationwasanewviewofcancerasacomplextissueinwhichmalignantcellsco-optthesurroundingnormalcellstoprovidethenecessarygrowthsignals,servingasactivecollaborators,ratherthanpassivebystanders. Insensitivitytogrowthsuppressivesignals.Multipleantiproliferativesignalsmaintainthehomeostasisinnormaltissues,pushingcellsoutofthecellcycleandintoatemporaryquiescentstate,orsendingthemintotheirterminal,post-mitoticdifferentiationstate.Transformedcellsevadetheseantiproliferativesignalsbysubvertingthemechanismsthatcontrolcellcycleprogression—forexample,bydisruptingthepRbpathway,andoverexpressinggrowth-stimulatingfactorssuchasc-myc. Abilitytoevadeprogrammedcelldeath.Apoptosisisamajoranticancerbarrier,asbecomingimmortalisanotherwaythroughwhichcancercellscontinuetoexpandinnumber.Further,theauthorsproposedthattheredundancyincelldeathmechanismscouldbeexploitedfortherapeuticpurposes. Enablingreplicativeimmortality.Inorderforcancertogrow,malignantcellshavetoproliferateindefinitely.Whilenormalcellspossessalimitedproliferativepotentialandwillstopdividingatsomepointifculturedinvitro,cancercellshavelostthatrestrainmechanism,governedbytelomereshortening.Tobecomeimmortal,malignantcellsrelyonthetelomeraseenzymetomaintainthelengthoftheirtelomeresaboveacriticalthresholdthatallowsthemtogoondividing.  Sustainedangiogenesis.Thegrowingtumortissuehasincreasedoxygenandnutrientneedsand,tokeepexpanding,itneedstotriggertheformationofnewvasculaturebyreleasingpro-angiogenicsignals.Atthetimetheauthorscodifiedthisfeature,ithadbeenestablishedthattumorsgothroughan“angiogenicswitch”thatallowsthemtogrowfrommicroscopictomacroscopiclesions. Tissueinvasionandmetastasis.Metastasisisthecauseofthevastmajorityofcancerdeaths.Theabilitytoinvade,settlein,andgrowindistanttissuesisthereforeoneofthemainfeaturesofcancerandreliesonmodificationsinthecancercellinteractionswiththeirsurroundingenvironmentthroughe-cadherin,integrins,andotheradhesionmolecules,andtheproductionofmatrix-degradingproteases.  Theacquisitionofmultiplemutationsthroughthelossofoneormoremechanismsdesignatedtoprotectinggenomeintegritywaspresentedbytheauthorsasanenablingcharacteristicthatallowscancercellstoreachthesix“biologicalendpoints”illustratedabove.  WeinbergandHanahandescribedthesixcapabilitiesacquiredbycancercellsasthesuccessfulbreachingofjustasmanyanticancerdefensemechanismswiredintoourcells,andsuggestedthesecharacteristicsweresharedbythemorethan100distincttypesofcancerknownatthetime.Thus,thehallmarksofcancerprovidedafewunifyingconceptstowardwhichfuturecancerresearchcouldgravitate.  “Thenextgeneration”(2011)  In2011,WeinbergandHanahanpublishedanupdatediscussingtheprogressmadeovertheprecedingdecadeintheknowledgeaboutthesixoriginalhallmarks.Theyalsoincorporatedtwoemerginghallmarks:  Reprogrammingenergymetabolism.Whilenormalcellsuseoxygentoprocessglucoseandproduceenergy,malignantcellscanswitchtoaerobicglycolysiseveninthepresenceofoxygen(whatisknownastheWarburgeffect).Thoughthismechanismislessefficient,itisfasterandoriginatesseveralintermediateprecursorsusedbycancercellsasbuildingblockstomakeproteins,DNA,andlipidstosupporttheirfastproliferation.Othercancercellscanuselactateastheirmainenergysource. Evadingimmunedestruction.HanahanandWeinbergdiscussedevidencesupportingthecentralroleplayedbytheimmunesystemasabarriertotumorigenesis,includingstudiesinmousemodelsdemonstratingthatcarcinogen-inducedtumorsdevelopedandgrewmorerapidlyinimmunodeficientmice,especiallyiftheylackedcytotoxicandhelperTcellsornaturalkillercells,andobservationsthathumantumorswithhighimmuneinfiltrationhadbetterprognosis.   The2011editionalsoidentifiedtumor-promotinginflammationasanewenablingcharacteristic.Whileimmuneinfiltrateswerehistoricallyconsideredasignoftheimmunesystemreactingagainstthetumor,atthetimethesecondreviewwaspublished,thetumor-promotingeffectofcertaininflammatorycellshadbecomeclear.Theauthorsdiscussedhowinflammationfavorsmultiplehallmarkcapabilitiesbyprovidinggrowth,survival,andproangiogenicfactors,andreleasingchemicals,suchasreactiveoxygenspecies,thatcancauseadditionalmutationsinthenearbycancercells.   Thereviewalsocontainsaparagraphonthetumormicroenvironment,whichinthepreviousdecadehadbecomethesubjectofextensiveresearchshowingthat,whenstudyingthebiologyofatumor,oneneedstoconsiderboththecancercellsandthemicroenvironmenttheyconstructaroundthem.   “NewDimensions:”ExpandingtheFrontiersofCancerBiology(2022)  Tenyearslater,Hanahangoesbacktothehallmarksoncemore,recognizingthegreatprogressmadeinthestudyofcancerthroughbigdata,andreaffirmingtheimpactofthehallmarksofcancerinconceptualizingthenewdiscoveriesand“helpingtodistillthiscomplexityintoanincreasinglylogicalscience.”Inthelatestarticle,thetwohallmarksaddedasemergingin2011weredefinitivelyincorporatedascorehallmarks,asresearchinthepast10yearshaslargelyconfirmedtheimportanceofmetabolicreprogrammingandavoidingimmunedestructionincancer.Inaddition,Hanahanproposedanadditionalemerginghallmark:  Phenotypicplasticityanddisrupteddifferentiation.Terminaldifferentiationinnormalcellsisassociatedwithapermanentproliferationarrest,andincreasingevidenceindicatesthatmalignantcellsevadedifferentiationandunlockwhatisknownasphenotypicplasticitytocontinuetogrow.Inotherwords,theycanchangetheiridentityintosomethingthatismoreinclinedtoproliferate.Thiscanhappenindifferentways:Cellsthatareapproachingfulldifferentiationcande-differentiatebacktoaprogenitor-likestate;neoplasticcellsoriginatingfromanundifferentiatedprogenitorcellcanhaltthedifferentiationprocessandremaininthatpartiallydifferentiated,progenitor-likestate;andcellsthatwerecommittedtoacertaindifferentiationphenotypecanswitchdevelopmentalprograms,ortransdifferentiate,acquiringtraitsthatarenotassociatedwiththeircelloforigin.Hanahannotesthat,asitistrueforotherhallmarkcapabilities,cellularplasticityisnota“novelinvention”ofcancercells,butratheramalignanttwistonexistingmechanismsthatsomenormalcellscanactivatetorepairandregeneratenormaltissues.  “HallmarksofCancer:NewDimensions”providesanupdatetothelandmark“HallmarksofCancer”series.GraphicfromCancerDiscovery. Thenewarticlealsohighlightstwonewenablingcharacteristics:  Non-mutationalepigeneticreprogramming.Globalchangesintheepigeneticlandscapeareindeedrecognizedasacommonfeatureofmanycancers.Reproducingwhathappensduringnormalembryogenesisanddevelopment,cancercellscanreprogramalargenumberorgene-regulationnetworkstoaltergeneexpressionandfavortheacquisitionofhallmarkcapabilities. Themicrobiome.Ourbodyiscolonizedbyavastarrayofmicroorganisms—nearly40trillioncells—thatliveinandonus.Theirprofoundcontributiontohumanhealthanddiseaseisnowappreciated.Forexample,researchershavefoundthatsomeofthesemicroorganismscanexertprotectiveordeleteriouseffectsoncancerdevelopment,progression,andresponsetotherapy.  Theneweditionacknowledgedtheimportanceofsenescentcellsasinstrumentalcomponentsofthetumormicroenvironment.Whileinthe2000editiontheauthorsdiscussedsenescenceasapossibleanticancerbarrier,theydidnotruleoutthepossibilityofitbeinganartifactofcellculturethatdidnotrepresentarealcellphenotypeinvivo.Morethantwodecadeslater,theroleofcellularsenescenceintissuehomeostasisandcanceriswellrecognized,andsignificantmorphologicalandmetabolicfeaturesassociatedwithithavebeenuncovered.Researchhasalsoshownhow,incertaincontexts,senescentcellscanstimulatetumordevelopmentandmalignantprogression.Therefore,Hanahanproposedthatsenescentcellsshouldbeincludedassignificantcomponentsofthetumormicroenvironment.  Intheconcludingremarks,Hanahanexplainshow,whilesomeofthehallmarksarenowwellvalidated,thenewestfeaturesaddedasemerginghallmarksaremeanttoserveas“trialballoons”tostimulatedebatewithinthecancerresearchcommunityandinspirenewinvestigationsthatwillkeeprefiningourunderstandingofcancerbiology.  Ontothenextdecadeofdiscoveries.  SearchCancerResearchCatalyst Searchfor: SubscribeViaEmailGetthelatestblogpostsdeliveredtoyourinbox. 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