The Hallmarks of Cancer - Wikipedia

In an update published in 2011 ("Hallmarks of cancer: the next generation"), Weinberg and Hanahan proposed two new hallmarks: (1) abnormal metabolic pathways ... TheHallmarksofCancer FromWikipedia,thefreeencyclopedia Jumptonavigation Jumptosearch 2000paperbyHanahanandWeinberg Theabilitytoinvadesurroundingtissueandmetastasiseisahallmarkofcancer. Thehallmarksofcancerwereoriginallysixbiologicalcapabilitiesacquiredduringthemultistepdevelopmentofhumantumorsandhavesincebeenincreasedtoeightcapabilitiesandtwoenablingcapabilities.TheideawascoinedbyDouglasHanahanandRobertWeinbergintheirpaperTheHallmarksofCancerpublishedJanuary2000inCell.[1] Thesehallmarksconstituteanorganizingprincipleforrationalizingthecomplexitiesofneoplasticdisease.Theyincludesustainingproliferativesignaling,evadinggrowthsuppressors,resistingcelldeath,enablingreplicativeimmortality,inducingangiogenesis,andactivatinginvasionandmetastasis.Underlyingthesehallmarksaregenomeinstability,whichgeneratesthegeneticdiversitythatexpeditestheiracquisition,andinflammation,whichfostersmultiplehallmarkfunctions.Inadditiontocancercells,tumorsexhibitanotherdimensionofcomplexity:theyincorporateacommunityofrecruited,ostensiblynormalcellsthatcontributetotheacquisitionofhallmarktraitsbycreatingthe“tumormicroenvironment.”Recognitionofthewidespreadapplicabilityoftheseconceptswillincreasinglyaffectthedevelopmentofnewmeanstotreathumancancer.[1] Inanupdatepublishedin2011("Hallmarksofcancer:thenextgeneration"),WeinbergandHanahanproposedtwonewhallmarks:(1)abnormalmetabolicpathwaysand(2)evasionoftheimmunesystem,andtwoenablingcharacteristics:(1)genomeinstability,and(2)inflammation.[2] Contents 1Listofhallmarks 1.1Self-sufficiencyingrowthsignals 1.2Insensitivitytoanti-growthsignals 1.3Evadingprogrammedcelldeath 1.4Limitlessreplicativepotential 1.5Sustainedangiogenesis 1.6Tissueinvasionandmetastasis 2Updates 2.1EmergingHallmarks 2.1.1Deregulatedmetabolism 2.1.2Evadingtheimmunesystem 2.2EnablingCharacteristics 2.2.1Genomeinstability 2.2.2Inflammation 3Criticisms 4Notesandreferences Listofhallmarks[edit] Signallingpathwaysarederegulatedincancer.HanahanandWeinbergcomparedthesignallingpathwaystoelectroniccircuitswheretransistorsarereplacedbyproteins.TheprototypicalRaspathwaystartswithanextracellularsignalfromgrowthfactors(suchasTGF-α).Othermajorextracellularsignalsareanti-growthfactors(suchasTGF-β),deathfactors(suchasFASL),cytokines(suchasIL-3/6)andsurvivalfactors(suchasIGF1).Proteinsinsidethecellcontrolthecellcycle,monitorforDNAdamageandotherabnormalities,andtriggercellsuicide(apoptosis).HanahanandWeinberg'ssignalpathwayillustrationisatCell100:59[3] Cancercellshavedefectsinthecontrolmechanismsthatgovernhowoftentheydivide,andinthefeedbacksystemsthatregulatethesecontrolmechanisms(i.e.defectsinhomeostasis). Normalcellsgrowanddivide,buthavemanycontrolsonthatgrowth.Theyonlygrowwhenstimulatedbygrowthfactors.Iftheyaredamaged,amolecularbrakestopsthemfromdividinguntiltheyarerepaired.Iftheycan'tberepaired,theycommitprogrammedcelldeath(apoptosis).Theycanonlydividealimitednumberoftimes.Theyarepartofatissuestructure,andremainwheretheybelong.Theyneedabloodsupplytogrow. Allthesemechanismsmustbeovercomeinorderforacelltodevelopintoacancer.Eachmechanismiscontrolledbyseveralproteins.Acriticalproteinmustmalfunctionineachofthosemechanisms.Theseproteinsbecomenon-functionalormalfunctioningwhentheDNAsequenceoftheirgenesisdamagedthroughacquiredorsomaticmutations(mutationsthatarenotinheritedbutoccurafterconception).Thisoccursinaseriesofsteps,whichHanahanandWeinbergrefertoashallmarks. Summary Capability Simpleanalogy Self-sufficiencyingrowthsignals "acceleratorpedalstuckon" Insensitivitytoanti-growthsignals "brakesdon'twork" Evadingapoptosis won'tdiewhenthebodynormallywouldkillthedefectivecell Limitlessreplicativepotential infinitegenerationsofdescendants Sustainedangiogenesis tellingthebodytogiveitabloodsupply Tissueinvasionandmetastasis migratingandspreadingtootherorgansandtissues Self-sufficiencyingrowthsignals[edit] Cancercellsdonotneedstimulationfromexternalsignals(intheformofgrowthfactors)tomultiply. Typically,cellsofthebodyrequirehormonesandothermoleculesthatactassignalsforthemtogrowanddivide.Cancercells,however,havetheabilitytogrowwithouttheseexternalsignals.Therearemultiplewaysinwhichcancercellscandothis:byproducingthesesignalsthemselves,knownasautocrinesignalling;bypermanentlyactivatingthesignallingpathwaysthatrespondtothesesignals;orbydestroying'offswitches'thatpreventsexcessivegrowthfromthesesignals(negativefeedback).Inaddition,celldivisioninnormal,non-cancerouscellsistightlycontrolled.Incancercells,theseprocessesarederegulatedbecausetheproteinsthatcontrolthemarealtered,leadingtoincreasedgrowthandcelldivisionwithinthetumor.[4][5] Insensitivitytoanti-growthsignals[edit] Cancercellsaregenerallyresistanttogrowth-preventingsignalsfromtheirneighbours. Thecellcycleclock.CellsdonotdivideinG0andarequiescent.Afterreceivinggrowthfactorsignals,theypreparefordivisionbyenteringG1,whereeverythingwithinthecellexceptDNAisdoubled.Thisdoublingincludesthesizeofthecell.ThenextphaseofthecellcycleisS(synthesis)phase.Itisthecellcyclephasewherethechromosomes(DNA)areduplicatedinpreparationforcellulardivision.ThetransitionfromG1toSisacheckpoint.IfthecellhasdamagedDNAorisexpressingoncogenesorotherinappropriateproteins,specializedcheckpointproteins,tumorsuppressorssuchasp53orpRB,willinterruptthetransitiontoSphaseuntilthedamageisrepaired.Ifthedamagecannotberepaired,thecellwillinitiateapoptosis,oftenreferredtoascellularsuicide,whichisprogrammedcelldeath.Ifthetumorsuppressorgenesincurloss-of-functionmutationsorareknockedout,thedamagedcellcancontinuetodivideunchecked–oneofthehallmarksofcancer. Thehallmarksofcancer. Totightlycontrolcelldivision,cellshaveprocesseswithinthemthatpreventcellgrowthanddivision.Theseprocessesareorchestratedbyproteinsknownastumorsuppressorgenes.Thesegenestakeinformationfromthecelltoensurethatitisreadytodivide,andwillhaltdivisionifnot(whentheDNAisdamaged,forexample).Incancer,thesetumoursuppressorproteinsarealteredsothattheydon'teffectivelypreventcelldivision,evenwhenthecellhassevereabnormalities.Anotherwaycellspreventover-divisionisthatnormalcellswillalsostopdividingwhenthecellsfillupthespacetheyareinandtouchothercells;knownascontactinhibition.Cancercellsdonothavecontactinhibition,andsowillcontinuetogrowanddivide,regardlessoftheirsurroundings.[4][6] Evadingprogrammedcelldeath[edit] Apoptosisisaformofprogrammedcelldeath(cellsuicide),themechanismbywhichcellsareprogrammedtodieintheeventtheybecomedamaged.Cancercellsarecharacteristicallyabletobypassthismechanism. Cellshavetheabilityto'self-destruct';aprocessknownasapoptosis.Thisisrequiredfororganismstogrowanddevelopproperly,formaintainingtissuesofthebody,andisalsoinitiatedwhenacellisdamagedorinfected.Cancercells,however,losethisability;eventhoughcellsmaybecomegrosslyabnormal,theydonotundergoapoptosis.Thecancercellsmaydothisbyalteringthemechanismsthatdetectthedamageorabnormalities.Thismeansthatpropersignalingcannotoccur,thusapoptosiscannotactivate.Theymayalsohavedefectsinthedownstreamsignalingitself,ortheproteinsinvolvedinapoptosis,eachofwhichwillalsopreventproperapoptosis.[4][7] Limitlessreplicativepotential[edit] Non-cancercellsdieafteracertainnumberofdivisions.Cancercellsescapethislimitandareapparentlycapableofindefinitegrowthanddivision(immortality).Butthoseimmortalcellshavedamagedchromosomes,whichcanbecomecancerous. Cellsofthebodydon'tnormallyhavetheabilitytodivideindefinitely.Theyhavealimitednumberofdivisionsbeforethecellsbecomeunabletodivide(senescence),ordie(crisis).ThecauseofthesebarriersisprimarilyduetotheDNAattheendofchromosomes,knownastelomeres.TelomericDNAshortenswitheverycelldivision,untilitbecomessoshortitactivatessenescence,sothecellstopsdividing.Cancercellsbypassthisbarrierbymanipulatingenzymes(telomerase)toincreasethelengthoftelomeres.Thus,theycandivideindefinitely,withoutinitiatingsenescence.[4][8] Mammaliancellshaveanintrinsicprogram,theHayflicklimit,thatlimitstheirmultiplicationtoabout60–70doublings,atwhichpointtheyreachastageofsenescence. ThislimitcanbeovercomebydisablingtheirpRBandp53tumorsuppressorproteins,whichallowsthemtocontinuedoublinguntiltheyreachastagecalledcrisis,withapoptosis,karyotypicdisarray,andtheoccasional(10−7)emergenceofanimmortalizedcellthatcandoublewithoutlimit.Mosttumorcellsareimmortalized. Thecountingdeviceforcelldoublingsisthetelomere,whichdecreasesinsize(losesnucleotidesattheendsofchromosomes)duringeachcellcycle.About85%ofcancersupregulatetelomerasetoextendtheirtelomeresandtheremaining15%useamethodcalledtheAlternativeLengtheningofTelomeres.[9] Sustainedangiogenesis[edit] Angiogenesisistheprocessbywhichnewbloodvesselsareformed.Cancercellsappeartobeabletokickstartthisprocess,ensuringthatsuchcellsreceiveacontinualsupplyofoxygenandothernutrients. Normaltissuesofthebodyhavebloodvesselsrunningthroughthemthatdeliveroxygenfromthelungs.Cellsmustbeclosetothebloodvesselstogetenoughoxygenforthemtosurvive.Newbloodvesselsareformedduringthedevelopmentofembryos,duringwoundrepairandduringthefemalereproductivecycle.Anexpandingtumourrequiresnewbloodvesselstodeliveradequateoxygentothecancercells,andthusexploitsthesenormalphysiologicalprocessesforitsbenefit.Todothis,thecancercellsacquiretheabilitytoorchestrateproductionofnewvasculaturebyactivatingthe'angiogenicswitch'.Indoingso,theycontrolnon-cancerouscellsthatarepresentinthetumorthatcanformbloodvesselsbyreducingtheproductionoffactorsthatinhibitbloodvesselproduction,andincreasingtheproductionoffactorsthatpromotebloodvesselformation.[4][10] Tissueinvasionandmetastasis[edit] Cancercellscanbreakawayfromtheirsiteororganoforigintoinvadesurroundingtissueandspread(metastasize)todistantbodyparts. Oneofthemostwellknownpropertiesofcancercellsistheirabilitytoinvadeneighboringtissues.Itiswhatdictateswhetherthetumorisbenignormalignant,andisthepropertywhichenablestheirdisseminationaroundthebody.Thecancercellshavetoundergoamultitudeofchangesinorderforthemtoacquiretheabilitytometastasize,inamultistepprocessthatstartswithlocalinvasionofthecellsintothesurroundingtissues.Theythenhavetoinvadebloodvessels,surviveintheharshenvironmentofthecirculatorysystem,exitthissystemandthenstartdividinginthenewtissue.[4][11] Updates[edit] Inhis2010NCRIconferencetalk,Hanahanproposedtwonewemerginghallmarksandtwoenablingcharacteristics.Thesewerelatercodifiedinanupdatedreviewarticleentitled"Hallmarksofcancer:thenextgeneration."[2] EmergingHallmarks[edit] Deregulatedmetabolism[edit] Mostcancercellsusealternativemetabolicpathwaystogenerateenergy,afactappreciatedsincetheearlytwentiethcenturywiththepostulationoftheWarburghypothesis,[12][13]butonlynowgainingrenewedresearchinterest.[14]CancercellsexhibitingtheWarburgeffectupregulateglycolysisandlacticacidfermentationinthecytosolandpreventmitochondriafromcompletingnormalaerobicrespiration(oxidationofpyruvate,thecitricacidcycle,andtheelectrontransportchain).InsteadofcompletelyoxidizingglucosetoproduceasmuchATPaspossible,cancercellswouldratherconvertpyruvateintothebuildingblocksformorecells.Infact,thelowATP:ADPratiocausedbythiseffectlikelycontributestothedeactivationofmitochondria.Mitochondrialmembranepotentialishyperpolarizedtopreventvoltage-sensitivepermeabilitytransitionpores(PTP)fromtriggeringofapoptosis.[15][16] Theketogenicdietisbeinginvestigatedasanadjuvanttherapyforsomecancers,[17][18][19]includingglioma,[20][21]becauseofcancer'sinefficiencyinmetabolizingketonebodies. Evadingtheimmunesystem[edit] Despitecancercellscausingincreasedinflammationandangiogenesis,theyalsoappeartobeabletoavoidinteractionwiththebody'simmunesystemviaalossofinterleukin-33.(Seecancerimmunology) EnablingCharacteristics[edit] Theupdatedpaperalsoidentifiedtwoemergingcharacteristics.Thesearelabeledassuchsincetheiracquisitionleadstothedevelopmentofthehypothesized"hallmarks" Genomeinstability[edit] Cancercellsgenerallyhaveseverechromosomalabnormalitieswhichworsenasthediseaseprogresses.HeLacells,forexample,areextremelyprolificandhavetetraploidy12,trisomy6,8,and17,andamodalchromosomenumberof82(ratherthanthenormaldiploidnumberof46).[22]Smallgeneticmutationsaremostlikelywhatbegintumorigenesis,butoncecellsbeginthebreakage-fusion-bridge(BFB)cycle,theyareabletomutateatmuchfasterrates.(Seegenomeinstability) Inflammation[edit] Recentdiscoverieshavehighlightedtheroleoflocalchronicinflammationininducingmanytypesofcancer.Inflammationleadstoangiogenesisandmoreofanimmuneresponse.Thedegradationofextracellularmatrixnecessarytoformnewbloodvesselsincreasestheoddsofmetastasis.(Seeinflammationincancer) Criticisms[edit] AnarticleinNatureReviewsCancerin2010pointedoutthatfiveofthe'hallmarks'werealsocharacteristicofbenigntumours.[23]Theonlyhallmarkofmalignantdiseasewasitsabilitytoinvadeandmetastasize.[23] AnarticleintheJournalofBiosciencesin2013arguedthatoriginaldataformostofthesehallmarksislacking.[24]Itarguedthatcancerisatissue-leveldiseaseandthesecellular-levelhallmarksaremisleading. Notesandreferences[edit] ^abHanahanD,WeinbergRA(January2000)."TheHallmarksofCancer".Cell.100(1):57–70.doi:10.1016/S0092-8674(00)81683-9.PMID 10647931. ^abHanahan,D.;Weinberg,R.A.(2011)."HallmarksofCancer:TheNextGeneration".Cell.144(5):646–674.doi:10.1016/j.cell.2011.02.013.PMID 21376230. ^Cell100:59 ^abcdefHanahan,D;Weinberg,RA(4March2011)."Hallmarksofcancer:thenextgeneration".Cell.144(5):646–74.doi:10.1016/j.cell.2011.02.013.PMID 21376230. ^Evan,GI;Vousden,KH(17May2001)."Proliferation,cellcycleandapoptosisincancer".Nature.411(6835):342–8.Bibcode:2001Natur.411..342E.doi:10.1038/35077213.PMID 11357141.S2CID 4414024. ^McClatchey,AI;Yap,AS(October2012)."Contactinhibition(ofproliferation)redux".CurrentOpinioninCellBiology.24(5):685–94.doi:10.1016/j.ceb.2012.06.009.PMID 22835462. ^Elmore,S(June2007)."Apoptosis:areviewofprogrammedcelldeath".ToxicologicPathology.35(4):495–516.doi:10.1080/01926230701320337.PMC 2117903.PMID 17562483. ^Greenberg,RA(March2005)."Telomeres,crisisandcancer".CurrentMolecularMedicine.5(2):213–8.doi:10.2174/1566524053586590.PMID 15974875. ^Cesare,AnthonyJ.;Reddel,RogerR.(2010)."Alternativelengtheningoftelomeres:Models,mechanismsandimplications".NatureReviewsGenetics.11(5):319–330.doi:10.1038/nrg2763.PMID 20351727.S2CID 19224032. ^Bergers,G;Benjamin,LE(June2003)."Tumorigenesisandtheangiogenicswitch".NatureReviews.Cancer.3(6):401–10.doi:10.1038/nrc1093.PMID 12778130.S2CID 11096398. ^vanZijl,F;Krupitza,G;Mikulits,W(2011)."Initialstepsofmetastasis:cellinvasionandendothelialtransmigration".MutationResearch.728(1–2):23–34.doi:10.1016/j.mrrev.2011.05.002.PMC 4028085.PMID 21605699. ^Alfarouk,KO;Verduzco,D;Rauch,C;Muddathir,AK;Adil,HH;Elhassan,GO;Ibrahim,ME;DavidPoloOrozco,J;Cardone,RA;Reshkin,SJ;Harguindey,S(2014)."Glycolysis,tumormetabolism,cancergrowthanddissemination.AnewpH-basedetiopathogenicperspectiveandtherapeuticapproachtoanoldcancerquestion".Oncoscience.1(12):777–802.doi:10.18632/oncoscience.109.PMC 4303887.PMID 25621294. ^O.Warburg,K.Posener,E.Negelein:"UeberdenStoffwechselderTumoren"BiochemischeZeitschrift,152,pp.319–344,1924.(German).ReprintedinEnglishinthebookOnmetabolismoftumorsbyO.Warburg,Publisher:Constable,London,1930. ^"Targetingtumourmetabolism".NatureReviewsDrugDiscovery.9(7):503–504.2010.doi:10.1038/nrd3215.ISSN 1474-1776.PMID 20592733.S2CID 7521218. ^ForrestMD."Whycancercellshaveamorehyperpolarisedmitochondrialmembranepotentialandemergentprospectsfortherapy".bioRxiv 10.1101/025197. ^GottliebE,ArmourSM,HarrisMH,ThompsonCB(2003)."Mitochondrialmembranepotentialregulatesmatrixconfigurationandcytochromecreleaseduringapoptosis".CellDeathDiffer.10(6):709–717.doi:10.1038/sj.cdd.4401231.PMID 12761579. ^Schwartz,L;Supuran,CT;Alfarouk,KO(2017)."TheWarburgEffectandtheHallmarksofCancer".Anti-CancerAgentsinMedicinalChemistry.17(2):164–170.doi:10.2174/1871520616666161031143301.PMID 27804847. ^BarañanoKW,HartmanAL(2008)."Theketogenicdiet:usesinepilepsyandotherneurologicillnesses".CurrTreatOptionsNeurol.10(6):410–9.doi:10.1007/s11940-008-0043-8.PMC 2898565.PMID 18990309. ^AllenBG,BhatiaSK,AndersonCM,et al.(October2011)."Ketogenicdietsasanadjuvantcancertherapy:Historyandpotentialmechanism".RedoxBiol.2C(3):327–337.doi:10.1016/j.eplepsyres.2011.09.022.PMID 22019313.S2CID 20445641. ^Schwartz,L;Seyfried,T;Alfarouk,KO;DaVeigaMoreira,J;Fais,S(April2017)."OutofWarburgeffect:AneffectivecancertreatmenttargetingthetumorspecificmetabolismanddysregulatedpH".SeminarsinCancerBiology.43:134–138.doi:10.1016/j.semcancer.2017.01.005.PMID 28122260. ^ScheckAC,AbdelwahabMG,FentonKE,StaffordP(October2011)."Theketogenicdietforthetreatmentofglioma:insightsfromgeneticprofiling".EpilepsyRes.100(3):327–37.doi:10.1016/j.eplepsyres.2011.09.022.PMID 22019313.S2CID 20445641. ^"HeLanuclearextractlysate(ab14655)".abcam. ^abLazebnikY(April2010)."Whatarethehallmarksofcancer?".Nat.Rev.Cancer.10(4):232–3.doi:10.1038/nrc2827.PMID 20355252.S2CID 8862667. ^SonnenscheinC,SotoAM(September2013)."Theagingofthe2000and2011HallmarksofCancerreviews:Acritique"(PDF).J.Biosci.38(3):651–63.doi:10.1007/s12038-013-9335-6.PMC 3882065.PMID 23938395. 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