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2011_Cell_Hallmarks of Cancer-The Next Generation.pdf

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2013-12-28 0人阅读 0 0 0 暂无简介 举报

简介:本文档为《2011_Cell_Hallmarks of Cancer-The Next Generationpdf》,可适用于自然科学领域

LeadingEdgeooo,rMausthiotgaeecellsbutinsteadmustencompassthecontributionsofthethenewfrontieroftherapeuticapplicationoftheseconceptssubsequenttothispublication,newobservationshaveservedbothtoclarifyandtomodifytheoriginalformulationofthehallmarkcapabilitiesInaddition,yetotherobservationshaveraisedArguablythemostfundamentaltraitofcancercellsinvolvestheirabilitytosustainchronicproliferationNormaltissuescarefullycontroltheproductionandreleaseofgrowthpromotingsignalsquestionsandhighlightedmechanisticconceptsthatwerenotintegraltoouroriginalelaborationofthehallmarktraitsMotithatinstructentryintoandprogressionthroughthecellgrowthanddivisioncycle,therebyensuringahomeostasisofcell‘‘tumormicroenvironment’’totumorigenesisInthecourseofremarkableprogressincancerresearchSustainingProliferativeSignalingINTRODUCTIONWehaveproposedthatsixhallmarksofcancertogetherconstituteanorganizingprinciplethatprovidesalogicalframeworkforunderstandingtheremarkablediversityofneoplasticdiseases(HanahanandWeinberg,)Implicitinourdiscussionwasthenotionthatasnormalcellsevolveprogressivelytoaneoplasticstate,theyacquireasuccessionofthesehallmarkcapabilities,andthatthemultistepprocessofhumantumorpathogenesiscouldberationalizedbytheneedofincipientcancercellstoacquirethetraitsthatenablethemtobecometumorigenicandultimatelymalignantWenotedasanancillarypropositionthattumorsaremorethaninsularmassesofproliferatingcancercellsInstead,theyarecomplextissuescomposedofmultipledistinctcelltypesthatparticipateinheterotypicinteractionswithoneanotherWedepictedtherecruitednormalcells,whichformtumorassociatedstroma,asactiveparticipantsintumorigenesisratherthanpassivebystandersassuch,thesestromalcellscontributetothedevelopmentandexpressionofcertainhallmarkcapabilitiesDuringtheensuingdecadethisnotionhasbeensolidifiedandextended,revealingthatthebiologyoftumorscannolongerbeunderstoodsimplybyenumeratingthetraitsofthecancervatedbythesedevelopments,wenowrevisittheoriginalhallmarks,considernewonesthatmightbeincludedinthisroster,andexpanduponthefunctionalrolesandcontributionsmadebyrecruitedstromalcellstotumorbiologyHALLMARKCAPABILITIESCONCEPTUALPROGRESSThesixhallmarksofcancerdistinctiveandcomplementarycapabilitiesthatenabletumorgrowthandmetastaticdisseminationcontinuetoprovideasolidfoundationforunderstandingthebiologyofcancer(FigureseetheSupplementalInformationfordownloadableversionsofthefiguresforpresentations)InthefirstsectionofthisReview,wesummarizetheessenceofeachhallmarkasdescribedintheoriginalpresentationin,followedbyselectedillustrations(demarcatedbysubheadingsinitalics)oftheconceptualprogressmadeoverthepastdecadeinunderstandingtheirmechanisticunderpinningsInsubsequentsectionsweaddressnewdevelopmentsthatbroadenthescopeoftheconceptualization,describinginturntwoenablingcharacteristicscrucialtotheacquisitionofthesixhallmarkcapabilities,twonewemerginghallmarkcapabilities,theconstitutionandsignalinginteractionsofthetumormicroenvironmentcrucialtocancerphenotypes,andwefinallydiscussHallmarksofCancer:ThDouglasHanahan,,*andRobertAWeinberg,*TheSwissInstituteforExperimentalCancerResearch(ISREC),SchTheDepartmentofBiochemistryBiophysics,UCSF,SanFranciscWhiteheadInstituteforBiomedicalResearch,LudwigMITCenterfoMA,USA*Correspondence:dhepflch(DH),weinbergwimitedu(RAW)DOIjcellThehallmarksofcancercomprisesixbiologicalcmentofhumantumorsThehallmarksconstitcomplexitiesofneoplasticdiseaseTheyincludesuppressors,resistingcelldeath,enablingreplicavatinginvasionandmetastasisUnderlyingthesethegeneticdiversitythatexpeditestheiracquisitmarkfunctionsConceptualprogressinthelaspotentialgeneralitytothislistreprogrammindestructionInadditiontocancercells,tumorscontainarepertoireofrecruited,ostensiblynormmarktraitsbycreatingthe‘‘tumormicroenvironmoftheseconceptswillincreasinglyaffectthedevCell,March,ªElsevierIncRevieweNextGenerationlofLifeSciences,EPFL,LausanneCH,SwitzerlandCA,USAolecularOncology,andMITDepartmentofBiology,Cambridge,pabilitiesacquiredduringthemultistepdevelopteanorganizingprincipleforrationalizingtheustainingproliferativesignaling,evadinggrowthiveimmortality,inducingangiogenesis,andactiallmarksaregenomeinstability,whichgeneratesn,andinflammation,whichfostersmultiplehalldecadehasaddedtwoemerginghallmarksofofenergymetabolismandevadingimmuneexhibitanotherdimensionofcomplexity:theylcellsthatcontributetotheacquisitionofhallnt’’Recognitionofthewidespreadapplicabilitylopmentofnewmeanstotreathumancancercedar高亮cedar高亮cedar高亮cedar高亮cedar高亮cedar高亮cedar高亮cedar高亮cedar高亮cedar高亮numberandthusmaintenanceofnormaltissuearchitectureandfunctionCancercells,byderegulatingthesesignals,becomemastersoftheirowndestiniesTheenablingsignalsareconveyedinlargepartbygrowthfactorsthatbindcellsurfacereceptors,typicallycontainingintracellulartyrosinekinasedomainsThelatterproceedtoemitsignalsviabranchedintracellularsignalingpathwaysthatregulateprogressionthroughthecellcycleaswellascellgrowth(thatis,increasesincellsize)oftenthesesignalsinfluenceyetothercellbiologicalproperties,suchascellsurvivalandenergymetabolismRemarkably,thepreciseidentitiesandsourcesoftheproliferativesignalsoperatingwithinnormaltissueswerepoorlyunderstoodadecadeagoandingeneralremainsoMoreover,westillknowrelativelylittleaboutthemechanismscontrollingthereleaseofthesemitogenicsignalsInpart,theunderstandingofthesemechanismsiscomplicatedbythefactthatthegrowthfactorsignalscontrollingcellnumberandpositionwithintissuesarethoughttobetransmittedinatemporallyandspatiallyregulatedfashionfromonecelltoitsneighborssuchparacrinesignalingisdifficulttoaccessexperimentallyInaddition,thebioavailabilityofgrowthfactorsisregulatedbysequestrationinthepericellularspaceandextracellularmatrix,andbytheactionsofacomplexnetworkofproteases,sulfatases,andpossiblyotherenzymesthatliberateandactivatethem,apparentlyinahighlyspecificandlocalizedfashionThemitogenicsignalingincancercellsis,incontrast,betterunderstood(LemmonandSchlessinger,Witschetal,HynesandMacDonald,Perona,)Cancercellscanacquirethecapabilitytosustainproliferativesignalinginanumberofalternativeways:Theymayproducegrowthfactorligandsthemselves,towhichtheycanrespondviatheexpressionofcognatereceptors,resultinginautocrineproliferativestimulationAlternatively,cancercellsmaysendsignalstostimulatenormalcellswithinthesupportingtumorassociatedstroma,whichreciprocatebysupplyingthecancercellswithvariousgrowthfactors(Chengetal,Bhowmicketal,)Receptorsignalingcanalsobederegulatedbyelevatingthelevelsofreceptorproteinsdisplayedatthecancercellresultinginconstitutivactivatedprotein(MA)Similarly,mutatnositidekinase(PIanarrayoftumortypekinasesignalingcirctransducer(Jiangandadvantagestotumorversusdownstream(tdoesthefunctionalimpathwaysradiatingfroDisruptionsofNegaAttenuateProliferatRecentresultshavefeedbackloopsthatnofsignalingandtherefluxofsignalscoursinandDixit,CabMosessonetalanismsarecapableoprototypeofthistypeotheoncogeniceffectsofitssignalingpowaffectingrasgenescCellffectingthestructureoftheBRafprotein,esignalingthroughtheRaftomitogenP)kinasepathway(DaviesandSamuelsionsinthecatalyticsubunitofphosphoikinase)isoformsarebeingdetectedins,whichservetohyperactivatethePIuitry,includingitskeyAktPKBsignalLiu,YuanandCantley,)Thecellsofactivatingupstream(receptor)ransducer)signalingremainobscure,aspactofcrosstalkbetweenthemultiplemgrowthfactorreceptorstiveFeedbackMechanismsthatFigureTheHallmarksofCancerThisillustrationencompassesthesixhallmarkcapabilitiesoriginallyproposedinourperspectiveThepastdecadehaswitnessedremarkableprogresstowardunderstandingthemechanisticunderpinningsofeachhallmarksurface,renderingsuchcellshyperresponsivetootherwiselimitingamountsofgrowthfactorligandthesameoutcomecanresultfromstructuralalterationsinthereceptormoleculesthatfacilitateligandindependentfiringGrowthfactorindependencemayalsoderivefromtheconstitutiveactivationofcomponentsofsignalingpathwaysoperatingdownstreamofthesereceptors,obviatingtheneedtostimulatethesepathwaysbyligandmediatedreceptoractivationGiventhatanumberofdistinctdownstreamsignalingpathwaysradiatefromaligandstimulatedreceptor,theactivationofoneoranotherofthesedownstreampathways,forexample,theonerespondingtotheRassignaltransducer,mayonlyrecapitulateasubsetoftheregulatoryinstructionstransmittedbyanactivatedreceptorSomaticMutationsActivateAdditionalDownstreamPathwaysHighthroughputDNAsequencinganalysesofcancercellgenomeshaverevealedsomaticmutationsincertainhumantumorsthatpredictconstitutiveactivationofsignalingcircuitsusuallytriggeredbyactivatedgrowthfactorreceptorsThus,wenowknowthat�ofhumanmelanomascontainactivatingmutationsaiveSignalinghighlightedtheimportanceofnegativeormallyoperatetodampenvarioustypesbyensurehomeostaticregulationofthegthroughtheintracellularcircuitry(WertzritaandChristofori,Amitetal,,)DefectsinthesefeedbackmechfenhancingproliferativesignalingThefregulationinvolvestheRasoncoprotein:ofRasdonotresultfromahyperactivationersinstead,theoncogenicmutationsompromiseRasGTPaseactivity,which,March,ªElsevierIncoperatesasanintrinsicnegativefeedbackmechanismthatnormallyensuresthatactivesignaltransmissionistransitoryAnalogousnegativefeedbackmechanismsoperateatmultiplenodeswithintheproliferativesignalingcircuitryAprominentexampleinvolvesthePTENphosphatase,whichcounteractsPIkinasebydegradingitsproduct,phosphatidylinositol(,,)trisphosphate(PIP)LossoffunctionmutationsinPTENamplifyPIKsignalingandpromotetumorigenesisinavarietyofexperimentalmodelsofcancerinhumantumors,PTENexpressionisoftenlostbypromotermethylation(JiangandLiu,YuanandCantley,)YetanotherexampleinvolvesthemTORkinase,acoordinatorofcellgrowthandmetabolismthatliesbothupstreamanddownstreamofthePIKpathwayInthecircuitryofsomecancercells,mTORactivationresults,vianegativefeedback,intheinhibitionofPIKsignalingThus,whenmTORispharmacologicallyinhibitedinsuchcancercells(suchasbythedrugrapamycin),theassociatedlossofnegativefeedbackresultsinincreasedactivityofPIKanditseffectorAktPKB,therebybluntingtheantiproliferativeeffectsofmTORinhibition(SudarsanamandJohnson,O’Reillyetal,)ItislikelythatcompromisednegativefeedbackloopsinthisandothersignalingpathwayswillprovetobewidespreadamonghumancancercellsandserveasanimportantmeansbywhichthesecellscanachieveproliferativeindependenceMoreover,disruptionofsuchselfattenuatingsignalingmaycontributetothedevelopmentofadaptiveresistancetowarddrugstargetingmitogenicsignalingExcessiveProliferativeSignalingCanTriggerCellSenescenceEarlystudiesofoncogeneactionencouragedthenotionthateverincreasingexpressionofsuchgenesandthesignalsmanifestedintheirproteinproductswouldresultincorrespondinglyincreasedcancercellproliferationandthustumorgrowthMorerecentresearchhasunderminedthisnotion,inthatexcessivelyelevatedsignalingbyoncoproteinssuchasRAS,MYC,andRAFcanprovokecounteractingresponsesfromcells,specificallyinductionofcellsenescenceandorapoptosis(ColladoandSerrano,Evanandd’AddadiFagagna,Loweetal,)Forexample,culturedcellsexpressinghighlevelsoftheRasoncoproteinmayenterintothenonproliferativebutviablestatecalledsenescenceincontrast,cellsexpressinglowerlevelsofthisproteinmayavoidsenescenceandproliferateCellswithmorphologicalfeaturesofsenescence,includingenlargedcytoplasm,theabsenceofproliferationmarkers,andexpressionofthesenescenceinducedbgalactosidaseenzyme,areabundantinthetissuesofmiceengineeredtooverexpresscertainoncogenes(ColladoandSerrano,Evanandd’AddadiFagagna,)andareprevalentinsomecasesofhumanmelanoma(MooiandPeeper,)TheseostensiblyparadoxicalresponsesseemtoreflectintrinsiccellulardefensemechanismsdesignedtoeliminatecellsexperiencingexcessivelevelsofcertaintypesofsignalingAccordingly,therelativeintensityofoncogenicsignalingincancercellsmayrepresentcompromisesbetweenmaximalmitogenicstimulationandavoidanceoftheseantiproliferativedefensesAlternatively,somecancercellsmayadapttohighlevelsofoncogenicsignalingbydisablingtheirsenescenceorapoptosisinducingcircuitryCell,March,ªElsevierIncEvadingGrowthSuppressorsInadditiontothehallmarkcapabilityofinducingandsustainingpositivelyactinggrowthstimulatorysignals,cancercellsmustalsocircumventpowerfulprogramsthatnegativelyregulatecellproliferationmanyoftheseprogramsdependontheactionsoftumorsuppressorgenesDozensoftumorsuppressorsthatoperateinvariouswaystolimitcellgrowthandproliferationhavebeendiscoveredthroughtheircharacteristicinactivationinoneoranotherformofanimalorhumancancermanyofthesegeneshavebeenvalidatedasbonafidetumorsuppressorsthroughgainorlossoffunctionexperimentsinmiceThetwoprototypicaltumorsuppressorsencodetheRB(retinoblastomaassociated)andTPproteinstheyoperateascentralcontrolnodeswithintwokeycomplementarycellularregulatorycircuitsthatgovernthedecisionsofcellstoproliferateor,alternatively,activatesenescenceandapoptoticprogramsTheRBproteinintegratessignalsfromdiverseextracellularandintracellularsourcesand,inresponse,decideswhetherornotacellshouldproceedthroughitsgrowthanddivisioncycle(BurkhartandSage,Deshpandeetal,SherrandMcCormick,)CancercellswithdefectsinRBpathwayfunctionarethusmissingtheservicesofacriticalgatekeeperofcellcycleprogressionwhoseabsencepermitspersistentcellproliferationWhereasRBtransducesgrowthinhibitorysignalsthatoriginatelargelyoutsideofthecell,TPreceivesinputsfromstressandabnormalitysensorsthatfunctionwithinthecell’sintracellularoperatingsystems:ifthedegreeofdamagetothegenomeisexcessive,orifthelevelsofnucleotidepools,growthpromotingsignals,glucose,oroxygenationaresuboptimal,TPcancallahalttofurthercellcycleprogressionuntiltheseconditionshavebeennormalizedAlternatively,inthefaceofalarmsignalsindicatingoverwhelmingorirreparabledamagetosuchcellularsubsystems,TPcantriggerapoptosisNotably,thevariouseffectsofactivatedTParecomplexandhighlycontextdependent,varyingbycelltypeaswellasbytheseverityandpersistenceofconditionsofcellstressandgenomicdamageAlthoughthetwocanonicalsuppressorsofproliferationTPandRBhavepreeminentimportanceinregulatingcellproliferation,variouslinesofevidenceindicatethateachoperatesaspartofalargernetworkthatiswiredforfunctionalredundancyForexample,chimericmicepopulatedthroughouttheirbodieswithindividualcellslackingafunctionalRbgenearesurprisinglyfreeofproliferativeabnormalities,despitetheexpectationthatlossofRBfunctionwouldallowcontinuousfiringofthecelldivisioncycleinthesecellsandtheirlinealdescendantssomeoftheresultingclustersofRbcellsshould,byallrights,progresstoneoplasiaInstead,theRbcellsinsuchchimericmicehavebeenfoundtoparticipateinrelativelynormaltissuemorphogenesisthroughoutthebodytheonlyneoplasiaobservedwasinthedevelopmentofpituitarytumorslateinlife(LipinskiandJacks,)Similarly,TPmicedevelopnormally,showlargelypropercellandtissuehomeostasis,andagaindevelopabnormalitieslaterinlife,intheformofleukemiasandsarcomas(GhebraniousandDonehower,)BothexamplesmustreflecttheoperationsofredundantlyactingmechanismsthatservetoconstraininappropriatereplicationofcellslackingthesekeyproliferationsuppressorsMechanismsofContactInhibitionandItsEvasionFourdecadesofresearchhavedemonstratedthatthecelltocellcontactsformedbydensepopulationsofnormalcellspropagatedintwodimensionalcultureoperatetosuppressfurthercellproliferation,yieldingconfluentcellmonolayersImportantly,such‘‘contactinhibition’’isabolishedinvarioustypesofcancercellsinculture,suggestingthatcontactinhibitionisaninvitrosurrogateofamechanismthatoperatesinvivotoensurenormaltissuehomeostasis,onethatisabrogatedduringthecourseoftumorigenesisUntilrecently,themechanisticbasisforthismodeofgrowthcontrolremainedobscureNow,however,mechanismsofcontactinhibitionarebeginningtoemergeOnemechanisminvolvestheproductoftheNFgene,longimplicatedasatumorsuppressorbecauseitslosstriggersaformofhumanneurofibromatosisMerlin,thecytoplasmicNFgeneproduct,orchestratescontactinhibitionviacouplingcellsurfaceadhesionmolecules(eg,Ecadherin)totransmembranereceptortyrosinekinases(eg,theEGFreceptor)Insodoing,MerlinstrengthenstheadhesivityofcadherinmediatedcelltocellattachmentsAdditionally,bysequesteringgrowthfactorreceptors,Merlinlimitstheirabilitytoefficientlyemitmitogenicsignals(Curtoetal,Okadaetal,)AsecondmechanismofcontactinhibitioninvolvestheLKBepithelialpolarityprotein,whichorganizesepithelialstructureandhelpsmaintaintissueintegrityLKBcan,forexample,overrulethemitogeniceffectsofthepowerfulMyconcogenewhenthelatterisupregulatedinorganized,quiescentepithelialstructuresincontrast,whenLKBexpressionissuppressed,epithelialintegrityisdestabilized,andepithelialcellsbecomesusceptibletoMycinducedtransformation(Partanenetal,HezelandBardeesy,)LKBhasalsobeenidentifiedasatumorsu

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