肿瘤的细胞微环境和肿瘤转移.ppt

,BasicClinicalOncologyTheCellularMicroenviromentandMetastases,FudanUniversityCancerCenterProf.Dr.WentaoYANG,OriginandHistory,TheoldestandoneofthemostprestigiouscancercentersinChinaFoundedin1931asSino-BelgiumRadiumInstitutebyKingdomofBelgiumFormerlyaffiliatedtoShanghaiMedicalUniversity(1954-2000),Sino-BelgiumRadiumInstitutein1950,Today,1205-bedCancerCenterOutpatients/year:932,000Inpatients/year:40600Operation/year:23219Numberofemployees:1300AffiliatedtoFudanUniversitysince2000,BasicClinicOncology,CourseObjectives:Toknowtheetiologyandbiologyofcancerandthesituationofcancerprevention.Tolearnthebasicsofcancerdiagnosis,includingtheclinical,imaging,pathologyandthelabsToknowtheprinciplesofcancertherapy,especiallythemultidisciplinarymodalitiesforacomprehensivecancerpatientcareToknowthefrontiersofbasicandclinicalresearchesbriefly,DefinitionofMetastasis,Theprocesswherebymalignanttumorsspreadfromtheirsiteoforigin(theprimarytumor)toformtumorsatsecondarysites(secondarytumor).Acquisitionofthecapabilityforinvasionandmetastasisisthehallmarksofcancer.Metastasisremainsthemajordriverofmortalityinpatientswithcancer.,BoneMetastasis,LungMetastasis,BrainMetastasis,Softtissuesarcomainleftleg,alveolarsoftpartsarcomainleftleg,Lungalveolarsoftpartsarcoma,MalignantPhyllodesTumoroftheBreast,MalignantPhyllodesTumormetastasizetothelung,Metastaticcarcinomaoftheovaryfromthestomach,ClassicType,TubularType,SclerosingType,ClassicType,Pulmonaryblastomametastasizetorightovary,Metastaticcarcinomaoftheovaryfromthecolon,FromBlausteinsPathologyoftheFemaleGenitalTract,Metastaticcarcinomaoftheovaryfromtheappendix,TheessentialcomponentinprovidingqualitycancercareThestagingofcancersisbasedonthesizeoftheprimarylesion,itsextentofspreadtoregionallymphnodes,andmetastases.Widelyusedisaso-calledTNMsystem.,T:PrimaryTumorT1,T2,T3,orT4,withincreasingsizeofprimarylesionN:regionallymphnodeinvolvementNo,N1,N2,N3toindicateprogressivelyadvancingnodaldiseaseM:metastasesMoorM,accordingtowhethertherearedistantmetastases.,Metastaticcancerisresponsibleforabout90%ofcancermortality.,-understandinghowcellsdisseminatefromtheprimarytumortoinvadeandsuccessfullycolonizedistanttissuesrepresentstheLEASTunderstoodandthemostdeadlyareaofcancerbiology.,MultistepProcessofMetastasis,MetastasisisinfluencedbytheinteractionsbetweenTumorcellsandhostcellsImmediateandextendedtumormicroenviroments,MandiMurph,ResearchonMelanoma,Multistepprocessedaccomplishedbymetastasizingcancer,MotilityandtissueinvasionIntravasation(Alternatively,canenterlymphaticvessels)Survivalinthebloodstream(trauma,immunecells,oxygenlevels,growthfactoravailabilityetc.)ArrestatnewlocationExtravasationAttraction/inductionofnewstromalcells(mayoccurBEFOREmetastasisoccurs).GrowthandProliferation.Angiogenesis,Figure14.4TheBiologyofCancer(GarlandScience2007)p.591,Tumormetastasisisacomplex,multistepprocessconsistingofaseriesofdiscretebiologicalprocesses.,InvasionandMetastasis,cancercellsproliferateandspread(metastasize)tootherpartsofthebodyInvasion-directmigrationandpenetrationintoneighboringtissuesMetastasis-cancercellspenetrateintolymphaticsystemandbloodvessels,AcquiringInvasiveness,Primarycarcinomacell(s)must:DisengagefromtheirneighboringepithelialcellsBecomemotileDegradethesurroundingextracellularmatrix,InvasionandCellMotility,Thefirststepofmetastasis.Normaltissuerequiresproperadhesionswithbasementmembraneand/orneighboringcells.Cellsmustundergochangesintheircell-cellandcell-matrixadhesioninteractionstodissociatethemselvesfromthetumor.Tumorcellsdisplaydiminishedcellularadhesion,allowingthemtobecomemotile.Tumorcellsusetheirmigratoryandinvasivepropertiesinordertoburrowthroughsurroundingextracellularstromaandtogainentryintobloodvesselsandlymphatics.Cellmotilityisacriticalcomponentoftheinvasivephenotype.,DisruptionoftheBasementMembrane,Adensemeshworkunderlyingtheepithelialcellsconsistingofcollagen,glycoproteins,andproteoglycans.Physicalbarrierbetweenepithelialcellsandthestroma.Degradationofbasementmembranecollagenisanearlyandcriticalinvasioneventforepithelialcellinvasion.,DuctalCarcinomainsitu,Earlyinvasivebreastcancer,FromBryson,FromBryson,Intravasation,Intravasation:theentryoftumorcellsintothecirculationExtravasation:theexitoftumorcellsfromthecirculationtohosttissue,JournalofCarcinogenesis2012,11:4,AbnormalVasculatureintumor,MalformedandirregularPossessingbreaksintheirthinliningthatpermittheeasyaccessoftumorcellsintothecirculationdilated,hyperpermeableThevasculatureofnormaltissuedonothavethesesamefeatures.,SurvivalintheCirculatorySystem,Outofmanythousandsofcancercellsthatreachthebloodcirculation,onlyonesurvivetoformasecondarycancerormetastasis.Immuneattack,circulatoryforces,apoptosisinducedbylossofadhesionBindtocoagulationfactorscreatingemboli,whicharemoreresilienttobothcirculatoryforcesandimmuneattack.,ArrestandExtravasation,Extracellularmatrix(ECM)componentssuchasfibronectinandlamininenhancetumorcellarrest,Extravasationoftumorcellsismorechallengingthanintravasationsinceintravasationoccursattheprimarytumorsitewherethevasculatureisalreadyquiteleakyandthereforeeasytotraverse.Extravasationisfacilitatedbycirculatingfactorsreleasedbytheprimarytumoritselfe.gTGF-andTNFreleasedfromprimarytumorsleadstoincreasedexpressionofMMPsresultinginhyperpermeabilityandextravasation.,Proliferation,CellproliferationatthesecondsiteInductionofangiogenesistosupplyoxygenandnutrients,Angiogenesis-thegrowthofnewcapillarybloodvessels,Tumorsrequirethecontinuingformationofnewbloodvessels,SupplyoxygenandnutrientsSupplyendocrineandparacrinegrowth-enablingfactors,Theprocessofangiogenesisintumor,AngiogenicfacoractivateendothelialcellsDegradationofthewallofthevesselSprout,proliferationandmigrationoftheendothelialcellsFormationofnewvessel,andanastomosis,血管检测标记：CD34,CD31,VIII,微血管密度（MVD),Figure14.42TheBiologyofCancer(GarlandScience2007),Metastaticseedingpatternsofvariouscancers,Colonizationofdistantsitebymetastatictumorcells,Colonizationisanextremelyinefficientprocessthatisheavilydependentontheinteractionsbetween“seeding”tumorcellsandthe“soil”microenvironmentofthesecondarysite.Manyfactorsincludingformationofapremetastaticnicheandorganspecificitydeterminethesepatternsofcolonization.,OrganTropismApropensityforcertaintumorstoseedinparticularorgans.,Reasonfororganselectivity,Mechanistictheory:determinedbythepatternofbloodflow.“Seedandsoil”theory:theprovisionofafertileenvironmentinwhichcompatibletumorcellscouldgrow.,50,1889:StephenPagetsSeedandSoilHypothesisTumorCells=Seedenvironment=SoilTumorcellslikeseeds“arecarriedinalldirections;buttheycanonlyliveandgrowiftheyfalloncongenialsoil”,Figure20-44MolecularBiologyoftheCell(GarlandScience2008),Metastasisisaveryinefficientprocess.Themajorityoftumorcellsfailtosurviveandestablishmetastaticcascade.,DefinitionofMicroenvironment,Anetworkofscaffoldingmadeoutofcollagens,glycoproteins,growthfactors,andglycanscoupledwiththecellularcomponentcomprisingthenormalstromalelements:includingfribroblasts,endothelialcells,andimmunecellsintowhichthetumorcellsinvadeandgrow.,WhatisinaTumor?,Cancercellsmakeuponlyaportionofatumor.Otherpartsarecomposedofstromalcells.Largeamountofextracellularmatrixmaterial(ECM).,Whatothercellsarepresent?,FibroblastmakeandsecreteECMproteinsandgrowthfactors.e.gMMPs.Myofibroblast-derivedfromfibroblastsbutmakeactin.EndothelialCells-Growthfactorsformbloodlymphaticfunction.Pericytes-Nearthebloodvessels,supportbloodvesselstructureandfunctionbygivingthemgrowthfactors.Smoothmusclecells-Contractilefunction.Adiopocytes-storageoffats.ImmuneCells,Thetumormicroenvironmentisquitecomplex.,Thecellsinatumortalktoeachotherallthetime.,NormalStroma,NormalCells,Basementmembrane,ECM,ImmuneCells,Fibroblast,Tumorstroma,CancerCells,Halfofthesecretsofthecellareoutsidethecell.Dr.MinaBissell.Oct17,2007ErlangerAuditorium,ECMisthematrixlaiddownbycellsuponwhichtheyadhereandmove.Itconsistsofmanycomponentsincludinglamininandfibronectin,whichcaninfluencetumorcellbehaviour.ECMisalsoarichsourceofgrowthfactorsthatcanbereleaseduponproteolyticdegradationandwhichinmanycasesincreasemetastasis.,Whatisextracellularmatrix(ECM)?,TypesofECMComponents,Basementmembrane(basallamina)Epithelia,endothelia,muscle,fat,nervesElasticfibersSkin,lung,largebloodvesselsStromalorinterstitialmatrixBone,tooth,andcartilageTendonandligament,DEFINITIONofEpithelial-MesenchymalTransition(EMT),Anorchestratedseriesofeventsinwhichcell-cellandcell-extracellularmatrix(ECM)interactionsarealteredtoreleaseepithelialcellsfromthesurroundingtissue.Thecytoskeletonisreorganizedtoallowmovementin3dimensionsintheECMandanewtranscriptionalprogramisinducedtomaintainthemesenchymalphenotype,Mesenchymegivestheimpressionofmuchmorerelaxedorganization,andthissuggestsflexibility,individualism,andmotilepropensities.Mesenchymecellsformarelativelydiffusetissuenetwork:Thereisnocompletecellularlayer,andthecellstypicallyhaveonlypointsontheirsurfaceengagedinadhesiontotheirneighbors.,DiscoveryofEMT,FirstobservedanddefinedbyElizabethHayinlate1960satHarvardFirstassociatedwithearlystagesofembryonicdevelopment.Processisreversiblew/unstableintermediateEMTMetastableMET,EpithelialMesenchymalTransition(EMT),/dmontell/research/,Epithelial-MesenchymalTransition(EMT),ThenumberofpublishedreportsonEMTandcancergrew12-foldbetween2002and2007.EMT“isoneofthethingsthateverybodysdoingnowadays,”TheEMT,whichismarkedbycomplexandcoordinatedsetofmolecularchangesleadingtocellbehavioralchanges,isaportmanteauconceptthatcanbeappliedtothemetastaticbehaviorofcarcinomacellsatanumberofjunctures.,EMTMarkers,ProteinsthatincreaseinabundanceN-cadherinVimentinFibronectinSnail1(Snail)Snail2(Slug)TwistGoosecoidFOXC2Sox10MMP-2MMP-3MMP9Integrinv6,ProteinsthatdecreaseinabundanceE-cadherenDesmoplakinCytokeratinOccludinProteinswhoseactivityincreasesILKGSK-3RhoProteinsthataccumulateinthenucleus-cateninSmad-2/3NF-Snail1(Snail)Snail2(Slug)Twist,EMTandCancer,OccurrenceofEMTduringtumorprogressionallowstumorstoinfiltratesurroundingtissueandultimatelymetastasizetodistantsitesWeseeEMTstagesinpathologicalstagingoftumors,RouteofMetastasis,HematogenousMetastasisLymphaticMetastasisImplantationmetastasisMetastasisthroughthebodywallintopleural,pericardialandperitonealcavities,LymphaticMetastasis,Thisisthemostcommonpathwayforinitialdisseminationofcarcinoma.Insolidtumors,thestatusofthelymphnodeisthemostimportantprognosticindicatorfortheclinicaloutcomeofpatients.,Cancercellsmayspreadtolymphnodesneartheprimarytumor,knownastheregionallymphnodes.Throughtheefferentlymphaticchannelstumormaystillbecarriedtodistancedlymphrode,andenterthebloodstreambythewayofthethoracicductfinally.,Inlymphnodes,initiallytumorcellareconfinedtothesubcapsularsinus;withthetime,thearchitectureofthenodesmaybeentirelydestroyedandreplacedbytumor.Destructionofthecapsuleorinfiltrationtoneighboringlymphnodeseventuallycausesthesenodestobecomefirm,enlargedandmattedtogether.,Tumorcellsformsecondarytumorsthroughthecirculatory(blood)systemwhichhasdrainedfromatumor.Bone,lung,liverandbrainfrequentlymultiple,circle,scatterAngiogenesisplaysanimportantrole,HematogenousMetastasis,Tumorcellsseedthesurfaceofbodycavities,Mostofteninvolvedistheperitonealcavity.Butalsomayaffectpleural,pericardial,subarachnoid,andjointspace.,Implantationmetastasis,Metastaticcarcinomaoftheovaryfromthestomach（KrukenbergTumor）,Metastasisthroughthebodywallintopleural,pericardialandperitonealcavities,Resultsinaneoplasticeffusion(transcoelomic).Thefluidcontainstheneoplasticcellscausingtheeffusion,andcytologicalexaminationoftheaspiratedfluidisveryimportantindiagnosingthecauseofeffusionsintobodycavities.Thetumorcellsoftengrowasnodulesonthemesothelialsurfaceofthecavity.,Anti-metastatictherapy,MetastasisPromotingGenes-I,MetastasisPromotingGenes-II,MetastasisSuppressorGenes-I,MetastasisSuppressorGenes-II,正常血管agiogenesis抗血管治疗,Anti-angiogenesisTherapy,Normalvesselangiogenesisanti-angiogenesistherapy,Usingangiogenesisinhibitorstoblocktheproteincarryingtheg