病理生理學第11章 細胞增殖和凋亡異常與疾病(英文)

CellProliferation,Differentiation,Apoptosisand

theRelatedDiseasesWhatisCellDifferentiation?WhatisCellDeath?WhatisCellProliferation?22023/2/18Theincreaseincellnumbersasaresultofcellgrowthanddivision.Cellproliferation細胞增殖32023/2/18CelldifferentiationDifferentiationistheprocessbywhichalessspecializedcellbecomesamorespecializedcelltype.Differentiationdramaticallychangesacell'ssize,shape,membranepotential,metabolicactivity,andresponsivenesstosignals.

細胞分化42023/2/18CelldeathApoptosis 凋亡

Autophagy 自噬

Pyroptosis 細胞焦亡

Pyronecrosis “焦櫚酚壞死”Necrosis 壞死

Oncosis 細胞腫脹死亡（脹亡）

細胞死亡52023/2/18CelldeathApoptosis 凋亡

Autophagy 自噬

Pyroptosis 細胞焦亡

Pyronecrosis “焦櫚酚壞死”Necrosis 壞死

Oncosis 細胞腫脹死亡（脹亡）

細胞死亡Programmedcelldeath(PCD)62023/2/18Celldeath

Programmednecrosis（necroptosis)Apoptosis 凋亡

Autophagy 自噬

Pyroptosis 細胞焦亡

Pyronecrosis “焦櫚酚壞死”Necrosis 壞死

Oncosis 細胞腫脹死亡（脹亡）

細胞死亡Programmedcelldeath(PCD)72023/2/181.CellProliferationandDiseases2.CellApoptosisandDiseases3.CellDifferentiationandDiseases細胞增殖與疾病細胞凋亡與疾病細胞分化與疾病82023/2/181.CellProliferationandDiseases2.CellApoptosisandDiseases3.CellDifferentiationandDiseases細胞增殖與疾病細胞凋亡與疾病細胞分化與疾病92023/2/181.CellProliferationandDiseasesWhatistheCellCycle?

(什么是細胞周期？)(2)HowistheCellCycleRegulated?(細胞周期的調控)(3)WhatWillHappenifCellProliferationisDysregulated?(細胞增殖調控異常與疾病)102023/2/181.CellProliferationandDiseasesWhatistheCellCycle?

(什么是細胞周期？)(2)HowistheCellCycleRegulated?(細胞周期的調控)(3)WhatWillHappenifCellProliferationisDysregulated?(細胞增殖調控異常與疾病)112023/2/18CellCycleInterphaseCelldivision122023/2/18CellCycle

Gap1(G1)phase(postmitotic/presynthesisgapphase)

（DNA合成前期）FromtheendofthepreviousMphaseuntilthebeginningofDNAsynthesis.ThisphaseismarkedbysynthesisofvariousenzymesthatarerequiredinSphase,mainlythoseneededforDNAreplication.

132023/2/18CellCycle

Sphase(DNAsynthesisphase)

（DNA合成期）SphasestartswhenDNAsynthesiscommences;whenitiscomplete,allofthechromosomeshavebeenreplicated,i.e.,eachchromosome（染色體）hastwo(sister)chromatids

（染色單體）.Thus,theamountofDNAinthecellhaseffectivelydoubled.142023/2/18CellCycle

Gap2(G2)phase(postsynthesis/premitoticgapphase)

（DNA合成后期）Significantbiosynthesisoccursduringthisphase,mainlyinvolvingtheproductionofmicrotubules,whicharerequiredduringtheprocessofmitosis（有絲分裂）.

152023/2/18CellCycle

Mitotic(M)phase（有絲分裂期）

Mitosisandcytokinesis（胞質分裂）occurinthisphase.Thedivisionofthemothercellintotwodaughtercells.Furtherdividedintoseveralsubphases:Prophase（早期）,Prometaphase（早中期）,Metaphase（中期）,

Anaphase（后期）,Telophase（末期）,andCytokinesis（胞質分裂期）.162023/2/18CellCycle

G0phase

（休眠期）CellsthatarenotactivelydividingmaybetemporarilyremovedfromthecyclebyenteringarestingstatedefinedasG0Phase.172023/2/181.CellProliferationandDiseasesWhatistheCellCycle?

(什么是細胞周期？)(2)HowistheCellCycleRegulated?(細胞周期的調控)(3)WhatWillHappenifCellProliferationisDysregulated?(細胞增殖調控異常與疾病)182023/2/18CellcyclecontrolsystemCyclinsandCyclin-DependentKinases(CDK)

周期蛋白和周期素依賴性蛋白激酶192023/2/18CellcyclecontrolsystemCyclins

andCyclin-DependentKinases(CDK)

周期蛋白和周期素依賴性蛋白激酶CyclinsareafamilyofproteinsthatcontrolthecellcyclebyactivatingCDK.

CyclinN-terminaldomainC-terminaldomain

Cyclinstructure:202023/2/18CellcyclecontrolsystemCDKareafamilyofproteinkinasesfirstdiscoveredfortheirroleinregulatingthecellcycle.

ThediscoveryofthecyclinsandCDKwasawarded2001NobelPrizeinPhysiologyorMedicine.

Cyclins

andCyclin-DependentKinases(CDK)

周期蛋白和周期素依賴性蛋白激酶212023/2/18Cyclins(15families29members)CyclinACyclinBCyclinCCyclinDCyclinECyclinFCyclinGCyclinHCyclinICyclinJCyclinKCyclinLCyclinOCyclinTCyclinYCDKs(13CDKs)CDK1CDK2CDK3CDK4CDK5CDK6CDK7CDK8CDK9CDK10CDK11CDK12CDK13Activatesalargenumberofvariousproteinsandleadstodifferentgenesexpressionaswellasinitiatesdifferentphaseofcellcycle.222023/2/18CellCycleCyclinD–CDK4CyclinD–CDK6CyclinE–CDK2CyclinA–CDK2CyclinA–CDK1CyclinB–CDK1232023/2/18CDKsCDKinhibitors(CKIs)CDK抑制物CellcycleprogressionCyclins+-CKIslnk4familyP15P16P18P19Kip/CipfamilyP21P27P57242023/2/18CDKinhibitors(CKIs)lnk4familyP15P16P18P19Kip/CipfamilyP21P27P57InhibitcyclinD/CDK4andcylcinD/CDK6Universalinhibitors252023/2/18RetinoblastomaE2FDPCyclinCDKHowdoesCKIwork?CKICKIDNApolymeraseThymidinekinase262023/2/18Cellcyclecheckpointsarecontrolmechanismsthatensuretheaccuracyofcelldivision.Thesecheckpointsverifywhethertheprocessesateachphaseofthecellcyclehavebeenaccuratelycompletedbeforeprogressionintothenextphase.MultiplecheckpointshavebeenidentifiedCellcyclecheckpoints

細胞周期檢查點272023/2/18MitoticspindlecheckpointG1/Scheckpoint(RestrictionPoint)G2/McheckpointCellcyclecheckpoints

AnimportantfunctionofcheckpointsistoassessDNAdamage,whichisdetectedbysensor（探測器）mechanisms.Whendamageisfound,thecheckpointusesasignal

（信號）mechanismeithertostallthecellcycleuntilrepairsaremadeor,ifrepairscannotbemade,totargetthecellfordestructionviaapoptosis(effector

（效應器）mechanism).AllthecheckpointsthatassessDNAdamageappeartoutilizethesamesensor-signal-effectormechanism.282023/2/18MitoticspindlecheckpointG1/Scheckpoint(RestrictionPoint)G2/McheckpointCellcyclecheckpoints

292023/2/18HowcellcyclecheckpointworksAtaxia-telangiectasiamutated(ATM)(SensesDNAdouble-strandbreaks)P53proteinactivation(sequence-specifictranscriptionalfactor)Kip/Cipproteinsexpression(P21,P27,P57)ArrestcellcycleatG1/StransitionAllowDNArepairpriortoDNAreplicationEffectorSensorTransducerG1SX探測器傳感器效應器302023/2/18Regulationofcellproliferationbyextracellularsignal細胞外信號對細胞增殖的調控Manyexogenousagentsandstimuliareabletoregulatecellproliferation:

growthfactors（生長因子）：epidermalgrowthfactor,EGF；

mitogens（促細胞分裂劑）

/antimitogens；

adhesionmolecules（粘附分子）-mediatecell-cellinteractions,nutrients,etc.312023/2/18FedwithgrowthagentFedwithnogrowthagentGrowthfactorinducescellproliferation322023/2/18RegulationofcellproliferationbyextracellularsignalManyexogenousagentsandstimuliareabletoregulatecellproliferation:

growthfactors(epidermalgrowthfactor,EGF),mitogens/antimitogens,adhesionmolecules-mediatedcell-cellinteractions,nutrients,etc.332023/2/18Cell-celladhesioninducescellproliferation342023/2/18RegulationofcellproliferationbyextracellularsignalManyexogenousagentsandstimuliareabletoregulatecellproliferation:

growthfactors(epidermalgrowthfactor,EGF),mitogens/antimitogens,adhesionmolecules-mediatedcell-cellinteractions,nutrients,etc.352023/2/18Howtheextracellularsignalregulatecellproliferation?ExtracellularagentsSignalingpathwaysCyclin/CDKCellproliferationCKIInhibitionofproliferation362023/2/18Howtheextracellularsignalregulatecellproliferation?TransformingGrowthFactor-b(TGF-b，轉化生長因子)SignalingpathwaysCDKCKI(P15,P16,P21,P27)InhibitionofproliferationRetinoblastomaE2FDPP(Exampleofnegativeregulation)Cellproliferation372023/2/181.CellProliferationandDiseasesWhatistheCellCycle?

(什么是細胞周期？)(2)HowistheCellCycleRegulated?(細胞周期的調控)(3)WhatWillHappenifCellProliferationisDysregulated?(細胞增殖調控異常與疾病)382023/2/18DysregulationofcellproliferationandrelateddiseasesDysregulationofcellproliferationisassociatedwithmanydiseases:

TumorInflammatorydiseases(Rheumatoidarthritis)CardiachypertrophyVascularproliferativedisorders(atherosclerosis)392023/2/18TumorProto-oncogene（原癌基因）:Aproto-oncogeneisanormalgenethatcanbecomeanoncogeneduetomutationsorincreasedexpression.Theresultantproteinistermedasoncoprotein（癌蛋白）.

Oncogene（癌基因）:Anoncogeneisagenethathasthepotentialtocausecancer.Intumorcells,oncogenesareoftenmutatedorexpressedathighlevels.

Tumor-suppressorgene（腫瘤抑制基因）:Atumorsuppressorgene,oranti-oncogene,isagenethatprotectsacellfromonesteponthepathtocancer.Whenthisgeneismutatedtocausealossorreductioninitsfunction,thecellcanprogresstocancer.

402023/2/18Activationofproto-oncogeneTheproto-oncogenecanbecomeanoncogenebyarelativelysmallmodificationofitsoriginalfunction.Therearethreebasicactivationtypes:

Amutationwithinaproto-oncogenecancauseachangeintheproteinstructure,causing 1)increaseinprotein(enzyme)activity, 2)lossofregulation(outofcontrol).2.Anincreaseinproteinconcentration,causedbyproteinormRNAexpression.3.Achromosomaltranslocation,causinganincreasedgeneexpressioninthewrongcelltypeoratwrongtimes.

412023/2/18Chromosomaltranslocation422023/2/18Activationofproto-oncogeneTheproto-oncogenecanbecomeanoncogenebyarelativelysmallmodificationofitsoriginalfunction.Therearethreebasicactivationtypes:

Amutationwithinaproto-oncogenecancauseachangeintheproteinstructure,causing 1)increaseinprotein(enzyme)activity, 2)lossofregulation(outofcontrol).2.Anincreaseinproteinconcentration,causedbyproteinormRNAexpression.3.Achromosomaltranslocation,causinganincreasedgeneexpressioninthewrongcelltypeoratwrongtimes.

432023/2/18DysregulationofcellproliferationcausestumorGrowthfactors,Signaltransductionproteins,Transcriptionalfactors,CyclinsCDKsTumor-suppressorgeneslose-of-functionmutationDecreaseintumorsuppressiveproteins(TGF-b,CDKinhibitors)TumorformationProto-oncogeneOncogeneActivation(gain-of-functionMutation)Oncoproteinsover-expression442023/2/18CellProliferationandDiseasesWhatistheCellCycle?G1-S-G2-M(2)

HowistheCellCycleRegulated?1)Cyclins,Cyclin-dependentkinases(CDK)and

CDKinhibitors(CKIs)2)Checkpoints3)Regulationofcellproliferationbyextracellularsignal.(3)WhatWillHappenifCellProliferation

isDysregulated?TumorSummary452023/2/181.CellProliferationandDiseases2.CellApoptosisandDiseases3.CellDifferentiationandDiseases462023/2/181.CellProliferationandDiseases2.CellApoptosisandDiseases3.CellDifferentiationandDiseases472023/2/18Apoptosis

Aprogrammedcelldeathprocessregulatedbycaspases(半胱氨酸天冬氨酸蛋白酶cysteine-asparticproteases

）.Morphologicalcharacteristics:DNAandnuclearfragmentationLossofcellvolumeFormationofcytoplasmicandmembraneblebs(apoptoticbody凋亡小體）.482023/2/18Apoptosis

Aprogrammedcelldeathprocessregulatedbycaspases.Morphologicalcharacteristics:DNAandnuclearfragmentationLossofcellvolumeFormationofcytoplasmicandmembraneblebsApoptoticcellsarerapidlyremovedbyneighboringphagocyteswithoutcausinginflammation492023/2/18NecrosisApassiveunprogrammedcelldeathprocess.Morphologicalcharacteristics:PersistenceofDNAcontent(nonuclearfragmentation),Increaseofcellvolume(cellswelling),Rapidlossofplasmaandmitochondrialmembrane.

NecrosiscausesinflammationDisruptionofplasmamembraneandorganelles.Numerouslesionsappearonthecellsurface.

502023/2/18AComparisonofApoptosisandNecrosisApoptosis(programmed)Necrosis(accidental)Caspase-dependent

BlebbingofplasmamembraneChromatincondensationRecyclingofcellularcontentsCaspase-independentReleaseofcellularcontentsLossofplasmamembraneNochromatincondensationNon-inflammatoryInflammatory512023/2/18WebbedfingersWebbedtoesApoptosisisanessentialprocessinembryonicdevelopment522023/2/18RegulationofcellapoptosisInducersRegulatorsEffectors532023/2/18EffectorsofApoptosis

（細胞凋亡的執(zhí)行因子）Caspases（半胱氨酸天冬氨酸蛋白酶）(cysteine-asparticproteases

)Endonucleases（內源性核酸內切酶）Transglutaminase（轉谷氨酰胺酶）542023/2/18EffectorsofApoptosis

（細胞凋亡的執(zhí)行因子）Caspases（半胱氨酸天冬氨酸蛋白酶）(cysteine-asparticproteases

)Endonucleases（內源性核酸內切酶）Transglutaminase（轉谷氨酰胺酶）552023/2/18CaspasesThecaspasefamilyisagroupofpolymorphicproteasesandthecentralexecutionersresponsibleforapoptosis.Elevenhumancaspaseshavebeendiscovered.Only7oftheseareinvolvedinapoptosis.Caspasesaresynthesizedinthecellinaninactiveform,whichcanbeactivatedthroughdifferentpathways.Caspasescanbedividedintotwogroups: initiatorcaspases–caspases2,8,9,10. effectorcaspases–caspases3,6,7.562023/2/18RegulationofcellapoptosisInducersRegulatorsEffectors572023/2/18RegulatorsofApoptosisApoptosisistightlyregulatedbyavarietyoffactorsthatmainlyregulatecaspasecascade.Mitochondria-derivedregulators2.Bcl-2familyproteins3.Inhibitorofapoptosis(IAP)family582023/2/18RegulatorsofApoptosisApoptosisistightlyregulatedbyavarietyoffactorsthatmainlyregulatecaspasecascade.Mitochondria-derivedregulators2.Bcl-2familyproteins3.Inhibitorofapoptosis(IAP)family592023/2/18RegulatorsofApoptosisMitochondria-derivedregulators2.Bcl-2familyproteins3.Inhibitorofapoptosis(IAP)family602023/2/18Bcl-2familyproteinsBcl-2isafamilyofevolutionarilyconservedproteins.Theseproteinscontrolmitochondrialoutermembranepermeability.

Bcl-2familyproteinsconsistofbothanti-apoptotic

(antideath)andpro-apoptotic

(prodeath)proteins.Thereareatotalof25genesintheBcl-2familyknowntodate.612023/2/18Bcl-2familyproteinsBH3-onlymoleculesBax,BakBcl2622023/2/18TheBH3-onlyfamilymembersplayakeyroleinpromotingapoptosis.VariousapoptoticstimuliinduceexpressionandactivationofspecificBH3-onlyfamilymembers,whichtranslocatetothemitochondriaandinitiateBax/Bak-dependentapoptosis.

RoleofBH3-onlyproteins632023/2/18BH3-onlypro-apoptoticproteins(Bad,Bid,Bim)Anti-apoptoticproteins(Bcl-2,Bclx,Mcl-1,A1)Multi-domainpro-apoptoticproteins(Bax,Bak)Bcl-2familyproteininteractionsApoptosisApoptosis642023/2/18RegulatorsofApoptosisMitochondria-derivedregulators2.Bcl-2familyproteins3.Inhibitorofapoptosis(IAP)family652023/2/18IAPareafamilyofproteinsthatserveasendogenousinhibitorsofapoptosis.ThehumanIAPfamilyconsistsof8members.IAPinhibitapoptosismainlythroughpreventingcaspasesactivation.TheInhibitorsofApoptosis(IAP)662023/2/18ApoptosomeMitochondria-derivedregulatorsInnermembraneOutermembraneCristaeCytochromeC(cytC)Apoptosis-inducingfactor(AIF)stressdATPCaspase-9Apaf-1Caspase-3ApoptosisIAPX672023/2/18RegulatorsofApoptosisMitochondria-derivedregulators2.Bcl-2familyproteins3.Inhibitorofapoptosis(IAP)family682023/2/18RegulationofcellapoptosisInducersRegulatorsEffectors692023/2/18InducersofcellapoptosisAwidevarietyofpathologicalcellularinsultsaswellasinternalandexternalphysiologicalstimulicouldtriggerapoptosis.ApoptosisinducedbydeathsignalApoptosisinducedbyDNAdamage702023/2/18InducersofcellapoptosisAwidevarietyofpathologicalcellularinsultsaswellasinternalandexternalphysiologicalstimulicouldtriggerapoptosis.ApoptosisinducedbydeathsignalApoptosisinducedbyDNAdamage712023/2/18Deathsignalismediatedthroughdeathreceptors(DR).Deathreceptorsaremembersofthetumornecrosisfactor(TNF)receptor(TNFR)superfamily.TNFRsuperfamilyischaracterizedbyacytoplasmicregionknownasthe“deathdomain”thatenablesthereceptorstoinitiatecytotoxicsignalswhenboundwithcognateligands.Bindingtotheligandresultsinreceptoraggregationandrecruitmentofadaptorproteins,which,inturn,initiatesaproteolyticcascadebyrecruitingandactivatinginitiatorcaspases,i.e.caspases8.DeathSignal722023/2/181.TNFR2.Fas:alsoknownasapoptosisantigen1(APO-1),

CD95orTNFRsuperfamilymember6(TNFRSF6).3.DR3,DR4,DR5,…TNFRSuperfamily732023/2/18InducersofcellapoptosisApoptosisinducedbydeathsignalApoptosisinducedbyDNAdamage742023/2/18HowcellcyclecheckpointworksAtaxia-telangiectasiamutated(ATM)(SensesDNAdouble-strandbreaks)P53proteinactivation(sequence-specifictranscriptionalfactor)Kip/Cipproteinsexpression(P21,P27,P57)ArrestcellcycleatG1/StransitionAllowDNArepairpriortoDNAreplicationEffectorSensorTransducerG1SX752023/2/18ApoptosisinducedbyDNAdamageP53proteinAnti-apoptoticproteinBcl-2Pro-apoptoticproteinBaxDeathreceptorFasMitochondriaCytCleakageCaspase-3ApoptosisCaspase-9Caspase-8/10DISCformation-++X762023/2/18ApoptosisinducedbyDNAdamageP53proteinAnti-apoptoticproteinBcl-2Pro-apoptoticproteinBaxDeathreceptorFasMitochondriaCytCleakageCaspase-3ApoptosisCaspase-9Caspase-8/10DISCformation-++X772023/2/18DISCDeathligandDeathreceptorActivecaspase-8/10ExtrinsicpathwayApoptosomeRegulationofcellapoptosisCytCstressdATPCaspase-9Apaf-1Caspase-3ApoptosisIntrinsicpathwayIAP(DNAdamage,ROS,etc.)782023/2/18Abnormalcellapoptosisanddiseases1.Tumor2.Autoimmunediseases3.HeartFailure792023/2/18AbnormalcellapoptosisanddiseasesTumor802023/2/18TumorCellsTumordisappearedApoptosisDefectsinApoptosisTumorcellssurvivedTumorcellsGrowthMetastasisChemotherapyRadiationApoptosisTumordisappearedDefectsinApoptosisTumorcellssurvived812023/2/18Mechanismsofapoptosisdefects1.Anti-apoptoticproteinBcl-2over-expressionBcl-2over-expressionwasfoundinB-celllymphomasandothertumors.Bcl-2geneisconsideredasaproto-oncogene2.ChromosometranslocationPhiladelphiachromosome,ashortchromosome22,resultsfromtranslocationbetweenchromosome9and22.ThechimericgeneencodingthefusionproteinBCR-ABLsuppressesapoptosisinchronicmyeloidleukemia(CML)patients.3.P53genemutationP53mutationwasfoundincolorectalcarcinomapatients.822023/2/18DysregulationofcellproliferationDysregulationofcellapoptosisTumorSummary832023/2/18DysregulationofcellproliferationcausestumorGrowthfactorsSignaltransductionproteinsTranscriptionalfactorsCyclinsCDKsProto-oncogeneOncogeneActivation(gain-of-functionMutation)Oncoproteinsover-expressionTumor-suppressorgeneslose-of-functionmutationDecreaseintumorsuppressiveproteins(TGF-b,CDKinhibitors)Tumorformation842023/2/18TumorCellsTumordisappearedApoptosisDefectsinApoptosisTumorcellssurvivedTumorcellsGrowthMetastasisChemotherapyRadiationApoptosisTumordisappearedDefectsinApoptosisTumorcellssurvivedDysregulationofcellapoptosiscausestumor852023/2/18CellDifferentiationDefinitionCellDifferentiationisthenormalprocessbywhichalessspecializedcelldevelopsormaturestopossessamoredistinctform(structure)andfunction.

StemcellsStemcellshavetheremarkablepotentialtodevelopintomanydifferentcelltypesinthebodyduringearlylifeandgrowth.

Inmanytissuesstemcellsserveasainternalrepairsystem,dividingessentiallywithoutlimittoreplenishothercellsaslongasthepersonoranimalisstillalive.862023/2/18StemcellsProliferation(Self-renewal)DifferentiationLineage(Asinglecelltype)MultipotentavarietyofcelltypesSymmetricdivisionAsymmetricdivision872023/2/18RegulationofCellDifferentiation1.Intracellularregulators2.DNAmethylation3.Extracellularfactors882023/2/18RegulationofCellDifferentiation1.Intracellularregulators2.DNAmethylation3.Extracellularfactors892023/2/18Homeoticgenesaregenesthatdeterminewhichpartsofthebodyformwhatbodyparts;andwhere,when,andhowbodysegmentsdevelop.Alterationsinthesegenes

causechangesinpatternsofbodyparts.Homeoticgenes902023/2/18IntracellularregulatorsHomeoticgenes(asmallnumberofmasterregulatorygenes)ExtracellularfactorsTranscriptionalfactorsGeneproductsCellreceptorParticulargenesexpressionDifferentiation912023/2/18RegulationofCellDifferentiation1.Intracellularregulators2.DNAmethylation3.Extracellularfactors922023/2/18TFParticulargenesexpressionandcelldifferentiationmmTFParticulargenesexpressionisblockedandnodifferentiationoccurs.DNAmethylation932023/2/18RegulationofCellDifferentiation1.Intracellularregulators2.DNAmethylation3.Extracellularfactors942023/2/18ExtracellularfactorsCell-cellinteractionCell-ECM(extracellularmatrix)interactionGrowthfactors:1)EGFs(epidermalgrowthfactor)2)TGFb(transforminggrowthfactor-b)3)IGF-1(Insulin-likegrowthfactor-1)4.Hematopoieticfactors:G-CSF(granulocytecolony-stimulatingfactor)5.Interleukins6.Steroidhormones7.Nuclearreceptorligands:1)VitaminD2)RA(Retinoicacid,ametaboliteofvitaminA)952023/2/18DifferentiationandTumorAlltumorsshowabnormalitiesindifferentiation.Immaturedifferentiationisthehallmarkofcancercells.Tumorcellscanreleaseglycoproteinsandotherproductssimilartothoseinfetaltissues.Examples:Prostate-specificantigen(PSA)issecretedbytheepithelialcellsoftheprostategland.SerumlevelofPSAislowinnormalmen,butisoftenelevatedinthepresenceofprostatecancer.2.Alpha-fetoprotein(AFP,α-fetoprotein)isamajorplasmaproteinproducedbytheliverduringfetaldevelopment.IncreasedserumlevelofAFPinadultssuggestshepatocellularcarcinoma.962023/2/18Howtumoroccurswhencelldifferentiationisdysregulated?1.Intracellularregulators2.DNAmethylation3.ExtracellularfactorsRegulationofCellDifferentiation972023/2/1