CARCINOGENESIS - Weebly · Carcinogenesis •Carcinogenesis is a multistep processat both the...
Transcript of CARCINOGENESIS - Weebly · Carcinogenesis •Carcinogenesis is a multistep processat both the...
CARCINOGENESIS:THEMOLECULARBASISOFCANCER
• Non-lethalgeneticdamageliesattheheartofcarcinogenesis.
• Mutationmaybeacquiredbytheactionofenvironmentalagents,suchaschemicals,radiation,orviruses,oritmaybeinherited inthegermline.
• Thegenetichypothesisofcancerimpliesthatatumormassresultsfromtheclonalexpansionofasingleprogenitorcellthathasincurredgeneticdamage(i.e.,tumorsaremonoclonal).
• Fourclassesofnormalregulatorygenesareinvolved:1. Growth-promotingproto-
oncogenes. 2. Growth-inhibitingtumorsuppressor
genes.3. Genesthatregulateapoptosis.4. GenesinvolvedinDNA.
• Mutantallelesofproto-oncogenesarecalledoncogenes.
• Theyareconsidereddominantbecausemutationofasingleallelecanleadtocellulartransformation.
• Bothnormalallelesoftumorsuppressorgenesmustbedamagedfortransformationtooccur,referredtoasrecessiveoncogenes.(OK?).
• Genesthatregulateapoptosismaybedominant,asareproto-oncogenes,ortheymaybehaveastumorsuppressorgenes(recessive).
TumorSuppressorGenes
• Tumorsuppressorgenesareof2types:• 1- promotersgenes:
Ø Promotersarethetraditionaltumorsuppressorgenes,suchasRB orp53.
ØMutationofthesegenesleadstocelltransformationbyreleasingthecontroloncellularproliferation.
• 2- caretakersgenes.
TumorSuppressorGenes• 2- caretakersgenes.
ØCaretakergenesareresponsibleforprocessesthatensuretheintegrityofthegenome,suchasDNArepair.
ØMutationofcaretakergenesdoesnotdirectlytransformcellsbyaffectingproliferationorapoptosis.
ØDNArepairgenesaffectcellproliferationorsurvivalindirectly byinfluencingtheabilitytorepairnon-lethaldamageinothergenes,includingproto-oncogenes,tumorsuppressorgenes,andgenesthatregulateapoptosis.
Carcinogenesis• Carcinogenesisisamultistepprocess atboththephenotypicandthegeneticlevels,resultingfromtheaccumulationofmultiplemutations.
• Malignantneoplasmshaveseveralphenotypicattributes,suchasexcessivegrowth,localinvasiveness,andtheabilitytoformdistantmetastases.
• Tumorprogression• Overaperiodoftime,manytumorsbecomemoreaggressiveandacquiregreatermalignantpotentialwhichisnotsimplyrepresentedbyanincreaseintumorsize.
• Tumorprogressionandassociatedheterogeneityresultsfrommultiplemutationsthataccumulateindependentlyindifferenttumorcells,generatingsubcloneswithdifferentcharacteristics.
• Eventhoughmostmalignanttumorsaremonoclonalinorigin,bythetimetheybecomeclinicallyevident,theirconstituentcellsareextremelyheterogeneous.
• Duringprogression,tumorcellsaresubjectedtoimmuneandnonimmuneselectionpressures.
• E.g: cellsthatarehighlyantigenicaredestroyedbyhostdefenses,whereasthosewithreducedgrowthfactorrequirementsarepositivelyselected.
• Agrowingtumortendstobeenrichedforsubclones thatarecapableofsurvival,growth,invasion,andmetastasis.
Featuresofmalignentcells• 1-Self-sufficiencyingrowthsignals.• 2-Insensitivitytogrowth-inhibitorysignals.• 3-Evasionofapoptosis.• 4-Limitlessreplicativepotential(i.e.,overcomingcellularsenescenceandavoidingmitoticcatastrophe).
• 5-Developmentofsustainedangiogenesis.• 6-Abilitytoinvadeandmetastasize.• 7-GenomicinstabilityresultingfromdefectsinDNArepair.
Self-SufficiencyinGrowthSignals
• Genesthatpromoteautonomouscellgrowthincancercellsarecalledoncogenes.
• Theyarederivedbymutationsinproto-oncogenesandarecharacterizedbytheabilitytopromotecellgrowthintheabsenceofnormalgrowth-promotingsignals.
• Theirproducts,calledoncoproteins, resemblethenormalproductsofproto-oncogenesexceptthatoncoproteinsaredevoidofimportantregulatoryelements, andtheirproductioninthetransformedcellsdoesnotdependongrowthfactorsorotherexternalsignals.
• Thebindingofagrowthfactortoitsspecificreceptoronthecellmembranecausestransientandlimitedactivationofthegrowthfactorreceptor.
• " activatesseveralsignal-transducingproteinsontheinnerleafletoftheplasmamembrane
• "transmissionofthetransducedsignalacrossthecytosoltothenucleusviasecondmessengersoracascadeofsignaltransductionmolecules
• "inductionandactivationofnuclearregulatoryfactorsthatinitiateDNAtranscription
• "progressionofthecellintothecellcycle,resultingultimatelyincelldivision
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GrowthFactors• Allnormalcellsrequirestimulationbygrowthfactorstoundergoproliferation.
• Types:• 1- Paracrineaction:growthfactorsaremadebyonecelltypeandactonaneighboringcelltostimulateproliferation2-Autocrineaction:Manycancercellsacquiregrowthself-sufficiencybyacquiringtheabilitytosynthesizethesamegrowthfactorstowhichtheyareresponsive.
GrowthFactorReceptors
• Mutantreceptorproteinsdelivercontinuousmitogenicsignalstocells,evenintheabsenceofthegrowthfactorintheenvironment.
• Overexpressionofgrowthfactorreceptorscanrendercancercellshyper-responsivetolevelsofthegrowthfactorthatwouldnotnormallytriggerproliferation.
• E.g:• Overexpressioninvolvetheepidermalgrowthfactor(EGF)receptorfamily.ERBB1.
• theEGFreceptor,isoverexpressedin80%ofsquamouscellcarcinomasofthelung.
• In50%ormoreofglioblastomas.• In80-100%ofepithelialtumorsoftheheadandneck.
• HER2/NEU(ERBB2), isamplifiedin25-30%ofbreastcancersandadenocarcinomasofthelung,ovary,andsalivaryglands.
• Thesetumorsareexquisitelysensitivetothemitogeniceffectsofsmallamountsofgrowthfactors
• HighlevelofHER2/NEU proteininbreastcancercellsisapoorprognosis.
• ThesignificanceofHER2/NEU inthepathogenesisofbreastcancersisillustratedbytheclinicalbenefitderivedfromblockingtheextracellulardomainofthisreceptorwithanti-HER2/NEU antibodies.
• Treatmentofbreastcancerwithanti-HER2/NEUantibody(herciptin)provedtobeclinicallyeffective.
Signal-TransducingProteins• Thesesignalingmoleculescouplegrowthfactorreceptorstotheirnucleartargets.
• Manysuchsignalingproteinsareassociatedwiththeinnerleafletoftheplasmamembrane,wheretheyreceivesignalsfromactivatedgrowthfactorreceptorsandtransmitthemtothenucleus,eitherthroughsecondmessengersorthroughacascadeofphosphorylationandactivationofsignaltransductionmolecules.
• Twoimportantmembersinthiscategoryare:• 1-RAS gene.• 2-ABLgene.
• RAS isthemostcommonlymutatedproto-oncogeneinhumantumors.
• Approximately30%ofallhumantumorscontainmutatedversionsoftheRAS gene.
• Theincidenceisevenhigherinsomespecificcancers (e.g.,colonandpancreaticadenocarcinomas).
• RASisamemberofafamilyofsmallGproteinsthatbindguanosinenucleotides(guanosinetriphosphate[GTP]andguanosinediphosphate[GDP]).
• TheABL proto-oncogenehastyrosinekinaseactivitythatisdampenedbyinternalnegativeregulatorydomains.
• Inchronicmyeloidleukemia(CML)andacutelymphocyticleukemias.
• WhenABL geneistranslocatedfromitsnormalsiteonchromosome9 tochromosome22,whereitfuseswithpartofthebreakpointclusterregion(BCR) gene=Philadelphia(Ph)chromosome.
• TheBCR-ABLhybridproteinhaspotent,unregulatedtyrosinekinaseactivity,whichactivatesseveralpathways,includingtheRAS-RAFcascade.
• NormalABLproteinlocalizesinthenucleus,whereitsroleistopromoteapoptosisofcellsthatsufferDNAdamage.
• TheBCR-ABL genecannotperformthisfunction,becauseitisretainedinthecytoplasmasaresultofabnormaltyrosinekinaseactivity.
NuclearTranscriptionFactors
• GrowthautonomymayoccurasaconsequenceofmutationsaffectinggenesthatregulatetranscriptionofDNA.
• MYC,MYB,JUN,FOS,andRELoncogenes,functionastranscriptionfactorsthatregulatetheexpressionofgrowth-promotinggenes,suchascyclins.
• theMYC geneisinvolvedmostcommonlyinhumantumors.
• TheMYC proto-oncogeneisexpressedinvirtuallyallcells,theMYCproteinisinducedrapidlywhenquiescentcellsreceiveasignaltodivide.
• Innormalcells,MYClevelsdeclinetonearbasallevelwhenthecellcyclebegins.
• Incontrast,oncogenicversionsoftheMYC geneareassociatedwithpersistentexpressionoroverexpression,contributingtosustainedproliferation.
• DysregulationoftheC-MYC generesultingfromat(8;14)translocationoccursinBurkittlymphoma,aB-celltumor.
• MYC isalsoamplifiedinbreast,colon,lung,andmanyothercancers;
• N-MYC andL-MYC genesareamplifiedinneuroblastomasandsmall-cellcancersoflung.
CyclinsandCyclin-DependentKinases(CDKs)
• Cancersmaybecomeautonomous ifthegenesthatdrivethecellcyclebecomedysregulatedbymutationsoramplification.
• ProgressionofcellsthroughthevariousphasesofthecellcycleiscontrolledbyCDKs.
• CDKsareactivatedbybindingtocyclins, socalledbecauseofthecyclicnatureoftheirproductionanddegradation.
• TheCDK-cyclincomplexesphosphorylatecrucialtargetproteinsthatdrivethecellthroughthecellcycle.
• Oncompletionofthistask,cyclinlevelsdeclinerapidly.
• Morethan15cyclinshavebeenidentified;cyclinsD,E,A,andBappearsequentiallyduringthecellcycleandbindtooneormoreCDK.
• MishapsaffectingtheexpressionofcyclinDorCDK4seemtobeacommoneventinneoplastictransformation.
• ThecyclinDgenesareoverexpressedinmanycancers,includingthoseaffectingthebreast,esophagus,liver,andasubsetoflymphomas.
• AmplificationoftheCDK4 geneoccursinmelanomas,sarcomas,andglioblastomas.
• MutationsaffectingcyclinBandcyclinEandotherCDKsalsooccur,buttheyaremuchlessfrequentthanthoseaffectingcyclinD/CDK4.
CDKInhibitors• CyclinsarousetheCDKs.• CDKinhibitors(CDKIs)silencetheCDKsandexertnegativecontroloverthecellcycle.
• OnefamilyofCDKIs,composedofthreeproteins:
• 1- p21[CDKN1A],• 2-p27[CDKN1B],• 3-p57[CDKN1C],inhibitstheCDKsbroadly...
InsensitivitytoGrowth-InhibitorySignals
• Retinoblastoma(RB) gene,thefirstandprototypiccancersuppressorgenetobediscovered.
• Retinoblastomaisanuncommon childhoodtumor.• Approximately60%ofretinoblastomasaresporadic,and40%arefamilial,
• Thepredispositiontodevelopthetumorbeingtransmittedasanautosomaldominanttrait.
• Toaccountforthesporadicandfamilialoccurrenceofanidenticaltumor,Knudson,in1974,proposedhisnowfamoustwo-hit hypothesis.
• Twomutations(hits): arerequiredtoproduceretinoblastoma.
• TheseinvolvetheRB gene,locatedonchromosome13q14.
• Both ofthenormalallelesoftheRB locusmustbeinactivated(twohits)forthedevelopmentofretinoblastoma.
• Infamilialcases,childreninheritonedefectivecopyoftheRB geneinthegermline;theothercopyisnormal,retinoblastomadevelopswhenthenormalRB geneislostinretinoblasts asaresultofsomaticmutation.
• TheRBpathwayisimportantto:• 1- ControlofcellcycleprogressionatG1.• 2- Inducecelldifferentiation.• 3- Inducesenescence.
• MutationsinothergenesthatcontrolRBphosphorylationcanmimictheeffectofRB loss,suchgenesaremutatedinmanycancersthatseemtohavenormalRB genes.
• E.g : mutationalactivationofCDK4oroverexpressionofcyclinDwouldfavorcellproliferationbyfacilitatingRBphosphorylationandinactivation.
• CyclinDisoverexpressedinmanytumorsbecauseofgeneamplificationortranslocation.
• MutationalinactivationofCDKIsalsowoulddrivethecellcyclebyunregulatedactivationofcyclinsandCDKs.
TP53 Gene:GuardianoftheGenome
• Thep53 tumorsuppressorgeneisoneofthemostcommonlymutatedgenesinhumancancers.
• P53prevents(OK)neoplastictransformationbythreeinterlockingmechanisms:
• 1-activationoftemporarycellcyclearrest(termedquiescence),
• 2-inductionofpermanentcellcyclearrest(termedsenescence),
• 3-triggeringofprogrammedcelldeath(termedapoptosis).
• P53 canbeviewedasacentralmonitorofstress,directingthestressedcellstowardanappropriateresponse.
• Avarietyofstressescantriggerthep53 responsepathwaysincluding:anoxia,inappropriateoncogeneexpression(e.g.,MYC orRAS),damagetotheintegrityofDNA.
TransformingGrowthFactor-βPathway
• TGF-β isapotentinhibitorofproliferationinmostnormalepithelial,endothelial,andhematopoieticcells.
• ItregulatescellularprocessesbybindingtoacomplexcomposedofTGF-βreceptorsIandII.
• Dimerizationofthereceptoruponligandbindingleadstoacascadeofeventsthatresultin:transcriptionalactivationofCDKIsandsuppressionofgrowth-promotinggenessuchasMYC,CDK2,CDK4,andthoseencodingcyclinsAandE.
ContactInhibitionNF2andAPC
• Contactinhibitionisabolishedincancercellsallowingthemtopileontopofoneanother.
• Cell-cellcontactsinmanytissuesaremediatedbyhomodimeric interactionsbetweentransmembraneproteinscalledcadherins.
• E-cadherin mediatescell-cellcontactinepitheliallayersbymechanismnotfullyunderstood.
• OnemechanismthatsustainscontactinhibitionismediatedbythetumorsuppressorgeneNF2.
EvasionofApoptosis
• Thereare2distinctprogramsthatactivateapoptosis:
• 1- Extrinsicpathway(deathreceptorCD95/Fas).
• 2- Intrinsicpathway(DNAdamage).
• Stimulationofeitherpathwayresultsinactivationofanormallyinactiveprotease(caspase-8orcaspase-9),whichinitiatesaproteolyticcascadeinvolving"executioner"caspasesthatdisassemblethecellinorderlyfashion.
• Thecellularremainsarethenefficientlyconsumedbythecellularneighborsandprofessionalphagocyteswithoutstimulatinginflammation.
AbilitytoInvadeandMetastasize
• Themetastaticcascadecanbesubdividedintotwo phases:invasionofECMandvasculardisseminationandhomingoftumorcells.
InvasionofExtracellularMatrix(ECM)
• HumantissuesareorganizedintoaseriesofcompartmentsseparatedfromeachotherbytwotypesofECM:basementmembranesandinterstitialconnectivetissue.
• eachofthesecomponentsofECMiscomposedof:collagens,glycoproteinsandproteoglycans.
• InvasionoftheECMisanactiveprocessthatrequiresfoursteps:• 1-Detachmentoftumorcellsfromeachother.• 2-DegradationofECM.• 3-AttachmenttonovelECMcomponents.• 4-Migrationoftumorcells.
LimitlessReplicativePotential
• Mostnormalhumancellshaveacapacityof60to70doublings.
• Afterthisthecellslosethecapacitytodivideandentersenescence.
• Thisphenomenonisduetoprogressiveshorteningoftelomeres attheendsofchromosomes.
DevelopmentofSustainedAngiogenesis
• Tumorscannotenlargebeyond1-2mmindiameterunlesstheyarevascularized.
• Cancercellscanstimulateneo-angiogenesis duringwhichnewvesselssproutfrompreviouslyexistingcapillariesorinsomecasesvasculogenesis inwhichendothelialcellsarerecruitedfromthebonemarrow.
• Angiogenesis isthusanecessarybiologiccorrelateofneoplasia,bothbenignandmalignant.
• Angiogenesis isrequirednotonlyforcontinuedtumorgrowthbutalsoforaccesstothevasculatureandhenceformetastasis.
ReprogrammingEnergyMetabolism
• Reprogrammingofenergymetabolismissocommontotumorsthatitisnowconsideredahallmarkofcancer.
• Eveninthepresenceofampleoxygencancercellsshifttheirglucosemetabolismaway fromefficientmitochondrialoxidativephosphorylationtoglycolysis.
• Thisphenomenon,calledtheWarburgeffectandalsoknownasaerobicglycolysis.
GenomicInstability-EnablerofMalignancy
• TheimportanceofDNArepairinmaintainingtheintegrityofthegenomeishighlightedbyseveralinheriteddisordersinwhichgenesthatencodeproteinsinvolvedinDNArepairaredefective.
• IndividualsbornwithsuchinheriteddefectsinDNArepairproteinsareatagreatlyincreasedriskofdevelopingcancer.
• HereditaryNon-polyposisColonCancerSyndrome(HNPCCsyndrome)ischaracterizedbyfamilialcarcinomasofthecolonaffectingpredominantlythececumandproximalcolon.ItresultsfromdefectsingenesinvolvedinDNAmismatchrepair.
TUMORIMMUNITY
• Immunesurveillance torefertorecognitionanddestructionofnewlyappearingtumorcells,whichareseenasforeignbythehostimmunesystem.
TumorAntigens
• 2categoriesbasedontheirpatternsofexpression:
• 1-tumor-specificantigens.whicharepresentonlyontumorcells andnotonanynormalcells.
• 2-tumor-associatedantigens.presentontumorcells andalsoonsomenormalcells.