Studying hallmarks of cancer | Abcam

Studying hallmarks of cancer · Genome instability · ​ Enabling replicative immortality · Evading growth suppressors · Cell death · Reprogramming energy metabolism. ForthebestexperienceontheAbcamwebsitepleaseupgradetoamodernbrowsersuchasGoogleChrome Hello.We'reimprovingabcam.comandwe'dwelcomeyourfeedback. Takealook Maybelater Hello.We'reimprovingabcam.comandwe'dwelcomeyourfeedback. Takealook Wehaven'taddedthistotheBETAyet NewBETAwebsite NewBETAwebsite Hello.We'reimprovingabcam.comandwe'dwelcomeyourfeedback. TakealookatourBETAsiteandseewhatwe’vedonesofar. SwitchonournewBETAsite Nowavailable Searchandbrowseselectedproducts Aselectionofprimaryantibodies Purchasethesethroughyourusualdistributor Inthecomingmonths Additionalproducttypes Supportingcontent Signintoyouraccount Purchaseonline Studyinghallmarksofcancer Related Cancerresources Cancerbiomarkerpanels CancerimmunotherapyandPD-L1 Cellbiologyresources Thecellproliferationguide Cellviabilityassayguide Primaryantibodyresources Knockout-validatedantibodies Multipleximmunoassays OptimizingICCandIFexperiments ​Findthekeymarkersandtoolsyouneedtostudythehallmarksofcancer ReviewedDecember142020Inearly2000,Professors Hanahan andWeinbergproposedthatwhencellsprogresstowardsaneoplasticstate,theyacquiredistinctive capabilities1.Theseweretermedhallmarksofcancerandformedausefulframeworkinwhichtounderstandtumorpathogenesis.Theyincludesustainingproliferativesignaling,evadinggrowth,suppressors,resistingcelldeath,enablingreplicativeimmortality,inducing angiogenesis,andactivatinginvasionandmetastasis.Therewereallunderpinnedbygenomeinstabilityandmutation.Laterin2011,theypublishedanupdatetoreflectadvancesinunderstanding,andtoincludereprogrammingofenergymetabolism,avoidingimmunedestruction,tumor-promotinginflammation,andevadingimmune destruction2.Hereweprovidetherelevantmarkersandtoolstostudytheseimportanthallmarksofcancer.Genomeinstability andmutationEnablingreplicativeimmortalityEvadinggrowthsuppressorsCelldeathReprogrammingenergymetabolismAngiogenesisAvoidingimmunedestructionTumor-promotinginflammationSustainingproliferativesignalingActivationofinvasionandmetastasis GenomeinstabilityCancercellsarehighlyproliferative.Thisfeaturemeansthatthereisanincreasedtendencyforgenomicchangesandmutationsinthesecellsthataffectscelldivisionandtumorsuppressiongenes.Thisinstabilitypromotesfurthercancerousadaptationsincells.ChangesmayarisethroughdirectDNAmutationsorthroughepigeneticmodificationsthatcanchangeproteinexpressionlevelsandaffectgenomicintegrity.Precisioncancertherapieshavebeentargetedtocheckpointkinasesofthecellcycle,suchasChk1andChk2proteins,andDNAdamagerepairenzymes,suchasBRCAand53BP1.Mechanism            KeymarkersFunctionNucleotideexcisionrepairERCC1-XPFERCC1 – XPF isanessential endonuclease forDNAdamagerepair.ItisalsoinvolvedinDNA interstrand crosslink anddouble-strandbreakrepair.XPAXPA isaZincfingerproteinresponsibleofDNAdamagerepair.TFIIDTFIID isacomplexthatbindstotheTATAboxinthecorepromoterofthegene.BaseexcisionrepairAPEX1/APEX2APEXarenucleasesinvolvedinDNArepair.PNKPPNKP catalyzes5’- kinase and3’– phosphatases activityFEN1FEN1 isan endonuclease thatremoves5’overhangingflapsinDNArepair.Double-strandbreak(DSB)repairGamma H2AXGammaH2AXisacomponentofhistoneoctamerinthenucleosome.ItisphosphorylatedinDNAdamage.XRCC4                  XRCC4functionstogetherwithDNAligaseIVandDNAdependentproteinkinasetorepairDNADSB.BRCA1                              BRCAgenesareoneofthewidelystudiestumorsuppressorproteinsthatregulateDNArepairandcellcycle53bp153bp1bindstodamagedchromatinandpromotesDNArepair.Kap1Kap1isakeyregulatorofnormaldevelopmentanddifferentiation.DNAmismatchrepairMsh2/Msh6Msh2andMsh6formMutSαwhichbindstothesiteofmismatchbase.Msh2/Msh3Msh2andMsh3formMutSβwhichparticipatesininsertion/deletionlooprepair.PMS2FormsheterodimerswithMLH1toformMutLα.​EnablingreplicativeimmortalityTumorcellscanachieveunlimitedreplicativepotentialeitherbysynthesizinghighlevelsoftelomeraseenzymeorviaarecombination-basedmechanism.Thispreventstelomereshorteningwhichleadstosenescenceandapoptosis.However,manycancercellshavebeenshowntopossessshorttelomeres.KeytargetsincludethetelomeremaintenancemachineryalongwithsignalingpathwayssuchasWntandHIPPO.​MechanismKeymarkersFunctionTelomeremaintenanceandregulationhTERThTRETisthemajorcomponentoftelomeraseactivity.Telomerasehasbeenidentifiedasadiagnosticmarkerforvarioustypesofcancer.TRF1/TRF2/POT1/​TIN2/RAP1/TPP1TheShelterincomplexisacoreofsixproteinsintegralfortelomerefunction.p53signalingTP53 (p53)p53iscalledthe“guardianofthegenome”isthekeyregulatorofgeneexpression.MDM2MDM2isaproto-oncogeneandplaysanimportantp53regulation.Itistheprimaryinhibitorofp53transcriptionalactivation.MDM2activityistightlycontrolledbypost-translationalmodifications. p14ARF/p19ARFp14ARFisatumorsuppressorgenethatbindstotheMDM2-p53complexandpreventsdegradationofp53.E2F-1E2F-1isthetranscriptionfactorofthep53pathwaythatregulatesbyinitiatingtranscriptionofp14ARF.EvadinggrowthsuppressorsToovercomegrowthinhibitionfromnormalhomeostaticsignals,cancercellslackresponsetoexternalgrowth-inhibitorysignals.Autophagyandapoptoticcontrolareresistedbycancercells.Bothoftheseprocessesallowtightcontrolovercelldeathandproliferativecellgrowth.Apoptosisallowstheremovalofcellsundergoingexcessiveproliferationtolimitcellnumberandremovediseasedcells,whileautophagyisacellularrecyclingsystemthatremovesabnormalproteinsandcytoplasmiccontentsandpromotesregeneration.Cancercellsresistapoptoticsignalingtopreventcelldeathandpromoteautophagytoincreasegrowthandovercomenutrient-limitingconditions.KeytargetsforthesepathwaysincludeBcl-2andCaspasesinapoptosisandproteasomalandlysosomalpathways,suchasMAPK,ATG,andp62,inautophagy.MechanismKeymarkersFunctionTumorsuppressorsRb1Retinoblastomaregulatesthecellcycleandplaysimportantroleincellulardifferentiation.TP53 (p53)p53iscalledthe“guardianofthegenome”isthekeyregulatorofgeneexpression.Itisalsoanestablishedmarkerforcancerdiagnosis.APCAPCregulatestumorgrowthbysuppressingWntsignaling.Italsoplaysanimportantroleincelladhesionandmigration.BRCA1,  BRCA2BRCAisoneofthewidelystudiestumorsuppressorproteinsthatregulateDNArepairandcellcyclePTENPTENisakeyregulatorofcellularactivities.ItregulatesPI3K-AKT-mTORsignalingthroughitslipidphosphataseactivity.WT1,WT2Wilmstumorproteinisatranscriptionfactorimportantfornormalcellulardevelopmentandsurvival.WT1playsbothoncogenicroleandtumorsuppressor.NF1, NF2NeurofibrominisatumorsuppressorthatnegativelyregulatestheRaspathway.CelldeathThishallmarkreferstocancercellspreventing apoptosis throughintrinsicmechanisms,ratherthanalackofresponsetoexternalstimuli.Cancercellsmaycontainmutationsthatpreventdamagedetectionorpreventapoptoticsignalingwithinthecell.Apoptosis ischaracterizedbyseveralfeatures,includingcellshrinkage,membraneblebbing,chromosomecondensation(pyknosis),nuclearfragmentation(karyorrhexis),DNAladderingandtheeventualengulfmentofthecellbyphagosomes.SeeourguidetoapoptosisAutophagy hasanimportantroleinallowingcellstosurviveinresponsetomultiplestressconditions.Tumorcellsexploitthisautophagicmechanismasawaytoovercomenutrient-limitingconditionsandfacilitatetumorgrowth.Autophagycanmodulatethetumormicroenvironmentbypromotingangiogenesis,supplynutrients,andmodulatetheinflammatoryresponse. SeeourguidetoautophagyCaspase-8,Bcl-2and,p53areamongkeyapoptoticsignalingproteinsthatareknowntobemutatedinmanycancers.​ReprogrammingenergymetabolismDuetotheirexcessivegrowth,cancercellsrequirehighlevelsofenergyandnutrients withtheabilitytosurviveinhypoxicenvironments,astheyarenotcompletelyvascularized.Tomeettheseneeds,manyofthecellularmetabolicpathwaysarealteredincancer.TheWarburgeffectconcernsthealteredglycolyticmetabolismthatoccursincancercells,wherepyruvateisdivertedfromtheKrebscycletolactateproductionunderoxygenconditions.Cancercellsarealsoknowntoincreaseglutaminemetabolismtopromotecellproliferation.KeytargetsforthecontrolofthehypoxictumorenvironmentincludeHIF-1αandAMPKthatswitchestoatumorpromoteractingtoprotectagainstmetabolic,oxidative,andgenotoxicstress. MechanismKeymarkerFunctionHypoxiaHIF1α/ HIF2a / HIF1βHIFisaheterodimericDNAbindingtranscriptionfactorthatregulatesabroadrangeofcellularsystemstohypoxia.CAIXCAIXisamediatorofhypoxia-inducedstressresponseinacancercell.AP-1/c-junTheAP-1transcriptionfactorfamilyisknowntoplayanimportantroleintumorprogressionanddevelopment.GLUT-1GLUT1levelscanbeelevatedinhypoxiaandcanbeusedtoindicatethedegreeofhypoxia.GlycolysisTomm20TOMM20andGAPDHhavebeenshowntobeupregulatedinvarioustypesofcanceranditisnecessarytometabolizeglutamine.V-ATPaseV-ATPaseexpressionisshowntobeupregulatedincancercells.GAPDHGAPDHandTom20havebeenshowntobeupregulatedinvarioustypesofcancerandcanbeusedasamarker.MitochondrialmetabolismCOXIVCOXIVisusedasamarkerfortheinnermitochondrialmarker.VDAC1/PorinVDAC1/Porinisusedasamarkerfortheoutermitochondrialmarker.ATPaseBetaBetasubunithasacrucialroleinthestructuralandfunctionalmaturationofNa+/K+-ATPase.AngiogenesisGrowthofthevascularnetworkisimportantformetastasisascancercellsrequireasufficientsupplyofnutrientsandoxygen,aswellasameansofwasteremoval.Thisisachievedbyangiogenesisandlymphangiogenesis,respectively.Aberrantgrowthfactorsignaling,suchasVEGF,fibroblastgrowthfactor(bFGF),andplatelet-derivedgrowthfactor(PDGF),isknowntoplayasignificantroleinpromotingangiogenesisofthetumor.LearnmoreabouttheroleofVEGFinangiogenesisAvoidingimmunedetectionThehumanimmunesystem protectsagainstforeignpathogensanddiseases,butitalsoplaysaveryimportantroleinclearingthebody’sownunhealthyandailingcells.Assuch,theimmunesystemisalsocapableofrecognizingandeliminatingcancercells.Tcellshavethecapacitytoselectivelyrecognizeandkillpathogensorunhealthycellsbyorchestratingacoordinatedimmuneresponsethatencompassesbuttheinnateandadaptiveresponses.ImmunecheckpointtargetssuchasPD1/PD-L1,TIM3,andLAG3areallcriticalcheckpointmoleculesthathaverevolutionizedcancerimmunotherapy.HereweoutlinevariousstrategiesusedinimmunotherapySeeourpathwaythatoutlinestheimmunecheckpointpathway​Tumor-promotinginflammationSignalingwithinthetumormicroenvironment(TME)operatestohijacktheimmunecellstopromotetumorsurvival.TheimmunecellsintheTMEsecretefactorsthatallowgrowthandmetastasis,ratherthanrecognizinganddestroyingthecancerouscells.ImportantinflammatorymechanismsthatarecorruptedbythetumorincludeNF-κB,immunecheckpointsignaling,andinflammasomesignaling.Theinflammasomepromotesthecleavageofcaspase-1andsubsequentcleavageofpro-inflammatorycytokinesIL-1βandIL-18.MechanismKeymarkerFunctionNF-κBsignalingNF-κBNF-κBisatranscriptionfactorthatplaysanimportantroleintheregulationofcytokines.DysregulationofNF-κBislinkedtoinflammatory,autoimmunediseases,andcancer.IKKBetaIKKbetaispartoftheIKKcomplexwhichisanegativeregulatoroftranscriptionfactorNF-κB.Tumor-associatedmacrophagesCD68CD68isakeymarkertorecognizebothM1andM2macrophagesintumortissue.CD163CD163isascavengerreceptorupregulatedinmacrophagesinananti-inflammatoryenvironment.iNOSiNOSisoneofthemajormarkersofM1tumor-associatedmacrophages.SustainingproliferativesignalingNormalcellsdependonthegrowthsignalingofatightly-regulated cellcycletoproliferate andmaintaintissuehomeostasis.Thiscycleisdisruptedincancer.Cancercellsreleaseandrespondtotheirowngrowthfactorstostimulategrowth,overcomingtherequirementforexternalgrowthfactors,suchasepidermalgrowthfactor(EGF/EGFR).Thisself-sufficiencyincellproliferationisdrivenviathreemainsignalingpathways:Akt,MAPK/ERK,andmTOR. Cellproliferationcanbeusedtoassessnormalcellhealth,tomeasureresponsestotoxicinsult,orasaprognosticanddiagnostictoolinseveralcancers. TheavailablemarkerstypicallylookatDNAlevelsorsynthesis,cellularmetabolism,orproliferation-specificproteins.​Foralookatthemostcommonmethodstomarkandscorecellproliferation seeourguide.​ActivationofinvasionandmetastasisTissueinvasionistheprocessthatallowstumorcellstoexpandintonearbytissues.Metastasisistheprocessoftumorcellsmigratingfromtheprimarytumorsitetoanewdistantlocationandestablishingsecondarytumors.Thewelldocumented epithelial-to-mesenchymaltransition isakeyprocessinthesemechanisms,allowinguninhibitedcelldivisionandmetabolicadaptationsthatenablecellsurvivalundernutrient-limitingandstressconditions.Bothofthesecancermechanismsinvolveextensivechangestocell-cellandcell-matrixinteractionsandcellulartransformationtoallowinvasionandmigration,includingtargetssuchasCollagenandCEACAM1.MechanismKeymarkerFunctionECMHyaluronanHyaluronanisaglycosaminoglycanfoundintheextracellularmatrix(ECM).HAisdramaticallyincreasedinmostmalignancies.VersicanVersicaniseitherexpressedbycancercellsorstromalcellsandplaysawideroleininvasionandmetastasis.CollagenIVCollagenIVisessentialfortumorangiogenesisbymodulatingcellgrowthandproliferation.AdhesionmoleculesCEACAM1CEACAM1isdown-regulatedinseveralcancers.L-FormCEACAM1hastumorsuppressivefunctionanddysregulationisfoundintheearlycarcinogenicprocess.DCCDCCisatransmembranereceptorfornetrins.Itpromotesapoptosisintheabsenceofnetrinligands.E-CadherinE-Cadherinregulatesmorphogenicprocesseslikecell-cellrecognition,cytoskeletonregulation,andsurfaceadhesion.SecretedfactorsTenascinCTenascinCinteractswithECMproteoglycansitcaninterferewithtumorsuppressoractivityoffibronectin.FibrinogenFibrindepositsoccurinthestromaofmanycancertypesandaffecttheprogressionoftumorcellsPeriostinPeriostinisasecretedadhesion-relatedproteinexpressedintheperiosteumandperiodontalligamentsandplaysaroleintumorigenesis. References1. Hanahan,D.&Weinberg,R.A.TheHallmarksofCancer. Cell 100, 57–70(2000).​2. Hanahan,D.&Weinberg,R.A.Hallmarksofcancer:Thenextgeneration. Cell 144, 646–674(2011). Getresourcesandoffersdirecttoyourinbox Signup