Hallmarks of Cancer-The Next Generation

LeadingEdgeReviewHallmarksofCancer:TheNextGenerationDouglasHanahan1,2,*andRobertA.Weinberg3,*1TheSwissInstituteforExperimentalCancerResearch(ISREC),SchoolofLifeSciences,EPFL,LausanneCH-1015,Switzerland2TheDepartmentofBiochemistry&Biophysics,UCSF,SanFrancisco,CA94158,USA3WhiteheadInstituteforBiomedicalResearch,Ludwig/MITCenterforMolecularOncology,andMITDepartmentofBiology,Cambridge,MA02142,USA*Correspondence:dh@epfl.ch(D.H.),[e-mail](R.A.W.)DOI10.1016/j.cell.2011.02.013Thehallmarksofcancercomprisesixbiologicalcapabilitiesacquiredduringthemultistepdevelop-mentofhumantumors.Thehallmarksconstituteanorganizingprincipleforrationalizingthecomplexitiesofneoplasticdisease.Theyincludesustainingproliferativesignaling,evadinggrowthsuppressors,resistingcelldeath,enablingreplicativeimmortality,inducingangiogenesis,andacti-vatinginvasionandmetastasis.Underlyingthesehallmarksaregenomeinstability,whichgeneratesthegeneticdiversitythatexpeditestheiracquisition,andinflammation,whichfostersmultiplehall-markfunctions.Conceptualprogressinthelastdecadehasaddedtwoemerginghallmarksofpotentialgeneralitytothislist—reprogrammingofenergymetabolismandevadingimmunedestruction.Inadditiontocancercells,tumorsexhibitanotherdimensionofcomplexity:theycontainarepertoireofrecruited,ostensiblynormalcellsthatcontributetotheacquisitionofhall-marktraitsbycreatingthe‘‘tumormicroenvironment.’’Recognitionofthewidespreadapplicabilityoftheseconceptswillincreasinglyaffectthedevelopmentofnewmeanstotreathumancancer.INTRODUCTIONWehaveproposedthatsixhallmarksofcancertogetherconsti-tuteanorganizingprinciplethatprovidesalogicalframeworkforunderstandingtheremarkablediversityofneoplasticdiseases(HanahanandWeinberg,2000).Implicitinourdiscussionwasthenotionthatasnormalcellsevolveprogressivelytoaneoplasticstate,theyacquireasuccessionofthesehallmarkcapabilities,andthatthemultistepprocessofhumantumorpathogenesiscouldberationalizedbytheneedofincipientcancercellstoacquirethetraitsthatenablethemtobecometumorigenicandultimatelymalignant.Wenotedasanancillarypropositionthattumorsaremorethaninsularmassesofproliferatingcancercells.Instead,theyarecomplextissuescomposedofmultipledistinctcelltypesthatparticipateinheterotypicinteractionswithoneanother.Wede-pictedtherecruitednormalcells,whichformtumor-associatedstroma,asactiveparticipantsintumorigenesisratherthanpassivebystanders;assuch,thesestromalcellscontributetothedevelopmentandexpressionofcertainhallmarkcapabilities.Duringtheensuingdecadethisnotionhasbeensolidifiedandextended,revealingthatthebiologyoftumorscannolongerbeunderstoodsimplybyenumeratingthetraitsofthecancercellsbutinsteadmustencompassthecontributionsofthe‘‘tumormicroenvironment’’totumorigenesis.Inthecourseofremarkableprogressincancerresearchsubsequenttothispublication,newobservationshaveservedbothtoclarifyandtomodifytheoriginalformulationofthehall-markcapabilities.Inaddition,yetotherobservationshaveraisedquestionsandhighlightedmechanisticconceptsthatwerenotintegraltoouroriginalelaborationofthehallmarktraits.Moti-vatedbythesedevelopments,wenowrevisittheoriginalhall-marks,considernewonesthatmightbeincludedinthisroster,andexpanduponthefunctionalrolesandcontributionsmadebyrecruitedstromalcellstotumorbiology.HALLMARKCAPABILITIES—CONCEPTUALPROGRESSThesixhallmarksofcancer—distinctiveandcomplementarycapabilitiesthatenabletumorgrowthandmetastaticdissemina-tion—continuetoprovideasolidfoundationforunderstandingthebiologyofcancer(Figure1;seetheSupplementalInforma-tionfordownloadableversionsofthefiguresforpresentations).InthefirstsectionofthisReview,wesummarizetheessenceofeachhallmarkasdescribedintheoriginalpresentationin2000,followedbyselectedillustrations(demarcatedbysub-headingsinitalics)oftheconceptualprogressmadeoverthepastdecadeinunderstandingtheirmechanisticunderpinnings.Insubsequentsectionsweaddressnewdevelopmentsthatbroadenthescopeoftheconceptualization,describinginturntwoenablingcharacteristicscrucialtotheacquisitionofthesixhallmarkcapabilities,twonewemerginghallmarkcapabilities,theconstitutionandsignalinginteractionsofthetumormicroen-vironmentcrucialtocancerphenotypes,andwefinallydiscussthenewfrontieroftherapeuticapplicationoftheseconcepts.SustainingProliferativeSignalingArguablythemostfundamentaltraitofcancercellsinvolvestheirabilitytosustainchronicproliferation.Normaltissuescarefullycontroltheproductionandreleaseofgrowth-promotingsignalsthatinstructentryintoandprogressionthroughthecellgrowth-and-divisioncycle,therebyensuringahomeostasisofcell646Cell144,March4,2011ª2011ElsevierInc.numberandthusmaintenanceofnormaltissuearchitectureandfunction.Cancercells,byderegulatingthesesignals,becomemastersoftheirowndestinies.Theenablingsignalsareconveyedinlargepartbygrowthfactorsthatbindcell-surfacereceptors,typicallycontainingintracellulartyrosinekinasedomains.Thelatterproceedtoemitsignalsviabranchedintra-cellularsignalingpathwaysthatregulateprogressionthroughthecellcycleaswellascellgrowth(thatis,increasesincellsize);oftenthesesignalsinfluenceyetothercell-biologicalprop-erti