肿瘤侵袭和转移.ppt

第八章肿瘤的侵袭和转移 本文由医学百事通高端医生网志愿者医师制作 肿瘤转移的基本过程肿瘤转移的分子生物学阻止肿瘤转移存在问题及发展方向 第一节肿瘤转移的基本过程 一 肿瘤侵袭 tumorinvasion 指恶性肿瘤细胞从其起源部位沿组织间隙向周围正常组织扩张性增生的过程 其标志是肿瘤细胞突破基底膜肿瘤侵袭生长行为有以下特点 侵袭的肿瘤细胞能侵占和排挤周围正常组织 但瘤细胞并未与原瘤灶分离对周围正常组织的功能有干扰或破坏 二 肿瘤转移 tumormetastasis 个别瘤细胞能脱离原发肿瘤 通过侵润在周围间质中生长 通过淋巴管或血管迁移至其他部位继续增殖生长 形成与原发肿瘤相同性质的继发肿瘤的全过程 继发灶可再增殖 继发侵袭生长和形成新的肿瘤 并进一步发生转移 产生继续扩散和转移 侵袭生长是癌组织扩张的先行活动 转移是瘤体达到一定数量和体积后才会出现的现象 转移时伴有侵袭生长 但侵袭生长并不一定发生转移 两者相辅相成 三 肿瘤的侵袭生长和转移过程 早期原发癌的生长肿瘤血管形成肿瘤细胞脱落并侵入基质进入脉管系统癌栓的形成继发组织器官定位生长转移癌继续扩散 一 逃脱局部控制和侵润转移的第一步就是破坏与邻近细胞的联系 摆脱邻近细胞的控制 穿过基质进入血管和淋巴管 1 肿瘤细胞的增殖和扩张2 肿瘤细胞的分离与脱落 细胞粘附性状发生改变 正常细胞间的相互作用细胞粘附 细胞 细胞 细胞 细胞外基质粘附关系 同质粘附 相同细胞间粘合异质粘附 不同细胞或与细胞外基质的粘合粘附分子 同嗜粘合 粘合分子相同异嗜粘合 粘合分子不同癌细胞 同型识别的破坏和异型识别的变化是侵润和转移癌的特点 细胞外基质降解酶系统 降解细胞外基质 形成一条侵润和转移通路 丝氨酸蛋白酶 胰蛋白酶 凝血酶 纤溶酶 尿激酶型和组织型纤溶酶原激活因子 弹性蛋白酶半胱氨酸蛋白酶天冬酰氨蛋白酶糖苷酶基质金属蛋白酶 3 恶性肿瘤细胞的运动性和趋化性 癌细胞向邻近周围细胞移动 贴近受侵细胞表面 表现为癌细胞表面伸出许多伪足贴附于受侵细胞癌细胞伸出伪足 阿米巴样运动 向受侵组织细胞间隙生长侵入 二 内侵指肿瘤细胞从癌组织脱落侵入到血管中 1 转移途径 1 血路转移 2 淋巴路转移 3 体腔 血流转移一些肿瘤细胞可从原发部位分离脱落 浸透组织基底膜 穿透间质内血管壁瘤细胞自血管壁游离 或形成细胞聚集体 脱落进入血循环 在循环中的肿瘤细胞大部分被迅速清除存活的瘤细胞则随血循环运行 到达靶器官 在该器官小血管内与内皮细胞粘附 滞留肿瘤细胞聚集体可在血管腔内增殖 或再穿过血管壁 先与细胞外基质粘附 进入靶器官实质 同实质细胞发生粘附 在该处生长 形成微小转移灶微小转移灶长至一定体积时 瘤组织血管新生 获得营养 进一步长大 形成转移瘤 特点 动脉壁较厚 不易被侵犯 静脉和毛细血管壁薄 易侵犯 毛细血管内皮细胞周期性脱落更新 暴露基底膜需蛋白酶消化基底膜血流是一个恶劣环境 进入血流的癌细胞99 以上会因机械压力 蛋白水解酶 宿主免疫系统监控而破坏肿瘤细胞在血液中是以单个细胞或若干个癌细胞与淋巴细胞和附着的血小板形成复合物的方式运输癌细胞与靶器官血管内皮细胞发生黏附 内皮细胞收缩 受损 暴露其下的基底膜 瘤细胞附着于基底IV型胶原上 转移出血管 2 淋巴路转移 淋巴管特点 淋巴管壁薄 无完整的基底膜 易被癌细胞附着和穿入内皮细胞间有暂时裂隙 利瘤细胞进入淋巴液流动缓慢 在有外力作用下 易促进管内瘤细胞运动 转移路径 癌细胞穿透上皮基底膜 侵入结缔组织间隙癌细胞开始向淋巴管靠近 并接触管壁癌细胞穿过淋巴管内皮基底膜屏障 进入管腔内癌细胞在淋巴管内移动癌细胞通过输入淋巴管到达汇流区淋巴结 在淋巴结内滞留癌细胞在淋巴结内继续生长 可破坏窦壁内皮 穿出淋巴窦 然后在淋巴结实质内增埴 破坏淋巴结的正常结构 终至全部为癌组织所取代 进入淋巴管内或淋巴结内癌细胞有2种命运被血流中免疫T cell NK等杀死极少数逃脱免疫杀伤并能快速生长 3 体腔腹膜和肺部的胸膜腔是转移的主要部位腹膜腔内器官的癌症易在腹膜中扩散腹腔内癌细胞外侵到达器官表面 挣脱并被腹膜液携带或直接与腔内其它位点接触肺部肿瘤或其它位点转移来的转移灶 都能植入肺周围和胸膜之间的腔隙 产生胸膜渗出液 2 肿瘤转移的器官选择性 1889Reget提出 种子 土壤 学说 认为肿瘤的转移是特殊的肿瘤细胞 种子 在适宜的环境 土壤 中生长发展的结果1929Ewing以器官的血液 淋巴的行流方向来解释转移的发生乳腺癌的淋巴转移至腋窝淋巴结肠胃道恶性肿瘤血行转移多经门静脉首先转移至肝脏下肢皮肤癌及恶性黑色素瘤转移至腹股沟淋巴结 1 血液循环的结构特征能部分决定转移生长的位点来自内脏的血液汇集于肝门静脉 通过肝 由心脏经肺重新分布因此 肝和肺是癌转移的常见位点 2 首先经过的器官从原发位点通过血管最先遇到的器官经常是癌细胞继发生长的位点肝是常见的转移位点肺是头颈部癌症的转移位点 肿瘤细胞转移能力的影响因素肿瘤细胞表面差异性组织器官微环境差异影响肿瘤转移器官选择性的相关因素 三 外侵逃避血管内的破坏 逃离并侵入新的环境 1 肿瘤细胞血管内锚定黏附当癌细胞聚集体 淋巴细胞和血小板复合物黏附到毛细血管内皮细胞上时 锚定在内皮细胞表面血小板与内皮细胞表面的纤维蛋白原相互作用 并通过P 选择素与内皮聚糖蛋白相互作用内皮E 选择素结合到癌细胞的聚糖蛋白上肿瘤细胞和淋巴细胞上的 4 1整合素 有利于癌细胞聚集体运动的停止 及与内皮的连接 2 从血管逃逸内皮细胞回缩 暴露基底膜上的糖蛋白 癌细胞黏附其上 然后利用蛋白酶和糖苷酶将其消化癌细胞前导边缘交替黏附到基质蛋白上 同时滞后的边缘交替脱离基质来完成迁移过程基质蛋白质水解过程中释放的肽段也可作为趋化因子 吸引其它癌细胞到这个区域 3 定位生长肿瘤细胞进入继发脏器的基质后 并不意味转移一定形成 只有当侵入继发脏器的肿瘤细胞增殖并长大 才真正完成转移癌细胞在新的位点上增殖最初局限于直径1mm 要扩大生长 必须形成新血管 来提供氧和营养4 转移的休眠 第二节肿瘤转移的分子生物学 一 基因调控下的肿瘤转移肿瘤转移促进基因Bcl 2 Myc ras raf erbB 2肿瘤转移抑制基因Nm23 TIMP 1 Thenm23genefamilyThefirstmetastasissuppressorgeneidentifiedwasnm23Eightmembersofthehumannm23familyhavebeenreportedandarefoundinmultiplesubcellularcompartments 2 Biochemicalfunctionsnm23proteinspossesmultiplebiochemicalfunctionsInteractionwithnumerousproteinsANDPKinaseactivityDNAnucleaseSerineorhistidineproteinkinase 3 NucleosidediphosphatekinaseactivityThenm23 H1geneproducthasbeenidentifiedastheNDPKAisoformThenm23 H2geneproducthasbeenidentifiedastheNDPKBisoformNDPKs catalyzethephosphorylationofnucleosidediphosphatestothecorrespondingnucleosidetriphosphates mainlyattheexpenseoftheATPsynthesizedthroughoxidativephosphorylation Thepingpongmechanisminvolvesaconservedhistidine namelyhistidene118inhumanenzymes asaphosphorylatedintermediate AlltheeucaryoticNDPKsarehexamers trimersofparalleldimers 4 Theroleofnm23intumormetastasisInteractionsofNDPKs withotherproteinsmaybeimportantintheregulationoftheunderlyingbiochemicalmechanismbywhichNDPKsdeterminethemetastaticfateofatumorcell InteractionwithnumerousproteinTiam1 aspecificGEFforRac1 NDPKAisabletoregulatetheactivityofRac1NDPKAsuppressestheactivityofTiam1V SrcinteractswiththeN terminalregionofTiam1 NDPKAcouldinterferewiththisbinding modulatingtheGEFactingofTiam1bycontrolofitsbindingtotheplasmamembrane InteractionsregulatingtheactivityofsmallGTPaseNDPKregulatestheMAPKpathwaybymodulatingthephosphorylationsiteofthekinasesuppressorofRas KSR NDPKAfunctionsasaGAPofRad Interactionwithtranscriptionfactors 2 InteractionwithcytoskeletalproteinNDPKmodulatescellshape dependentprocessesinvolvedindevelopment cellproliferation differentiationandinvasionandmetastasisoftumorcellspreventingRac RhoactivationbyblockingtheGDP exchangefunctionofTiam1 bypreventingSrctobindtoTiam1byregulationthelocalGTP GDP blanceinproteincomplexesmodulatingthephosphorylationofaminoacidofIFs 3 DNAnucleaseAmodel thetranscriptionalregulationwasexplainedbyanintrinsicnuclease likeactivityofNDPK NDPKBcouldcleavebothlinearandsupercoileddouble strandedDNAatasequencespecificsite resultinginacovalentlyboundenzyme DNAcomplexenergyofthiscovalentbondcouldbeusedtoreligatetheDNA 4 serine histedineproteinkinase HistidinephosphorylationPhosphohistidineisformedbyaN Pphosphoramidatebond Phosphorylationofthe1and3nitrogenshasbeendetected Histidinekinasesformaphospho histidineintermediate whichthentransfersthephosphatetothesubstrate nm23 H1phosphorylationonKsrserine392 a14 3 3bindingsite andonserine434inconjunctionwiththeserine392mutation KsristhoughttobeascaffoldmoleculefortheErkMapkinasesignalingpathway Histidinekinaseactivityofnm23 H1isrequiredforinhibitionoftheMapkinasepathwayandcorrelatedwithmotilitysuppression 二 黏附因子与肿瘤转移 一 celljunctionsManycellsintissuesarelinkedtooneanotherandtotheextracellularmatrixatspecializedcontactsitescalledcelljunctions Occludingjunctionssealcellstogetherinanepitheliuminawaythatpreventsevensmallmoleculesfromleakingfromonesideofthesheettotheother 2 AnchoringjunctionsMechanicallyattachcellstotheirneighborsortotheextracellularmatrix 1 Connectthecytoskeletonofacelleithertothecytoskeletonofitsneighborsortotheextracellularmatrix 2 AnchoringjunctionsoccurintwofunctionallydifferentformsAdherensjunctionsanddesmosomesholdcellstogetherandareformedbytransmembraneadhesionproteinsthatbelongtothecadherinfamilyFocaladhesionsandhemidesmosomesbindcellstotheextracellularmatrixandareformedbytransmembraneadhesionproteinsoftheintegrinfamilyAdherensjunctionsandfocaladhesionsserveasconnectionsitesforactinfilamentsDesmosomesandhemidesmosomesserveasconnectionsitesforintermediatefilaments 3 CommunicatingjunctionsMediatethepassageofchemicalorelectricalsignalsfromoneinteractingcelltoitspartnerGapjunctionsallowsmallmoleculestopassdirectlyfromcelltocell Asummaryofthevariouscelljunctions 二 cell celladhesionToformanchoringjunction cellsmustfirstadhereAnimalcellscanassembleintotissueeitherinplaceoraftertheymigrateDissociatedvertebratecellscanreassembleintoorganizedtissuesthroughselectivecell celladhesion CAMs celladhesionmoleculescell celladhesionmoleculescell matrixadhesionmoleculesCa2 dependentCa2 independent 1 CadherinsmediateCa2 dependentcell celladhesion StructureTheCa2 ionsarepositionedbetweeneachpairofcadherinrepeats lockingtherepeatstogethertoformastiff rodlikestructure themoreCa2 ionsthatarebound themorerigidthestructureis IfCa2 isremoved theextracellularpartoftheproteinbecomesfloppyandisrapidlydegradedbyproteolytiocenzyme b Cadherinsmediatecell celladhesionbyahomophilicmechanism c Cadherinsarelinkedtotheactincytoskeletonbycatenins 2 Selectinsmediatetransientcell celladhesioninthebloodstreamSelectinsarecell surfacecarbohydrate bindingprotein lectins thatmediateavarietyoftransient ca2 dependent cell celladhesioninteractionsinthebloodstream L selectinE selectinP selectin 3 MembersoftheIgsuperfamilyofproteinsmediateCa2 independentcell celladhesionN CAM neuralcelladhesionmolecule I CAM intercellularadhesionmolecule 4 IntegrinsBindingmostECMproteinsIntegrinsaretransmembraneheterodimers Integrinsmustinteractwiththecytoskeletontobindcellstotheextracellularmatrix Summary 三 theextracellularmatrixofanimalsThematrixhasafarmoreactiveandcomplexroleinregulatingthebehaviorofthecellsthatcontactit influencingthesurvival development migration proliferation shape andfunction 1 TheextracelluarmatrixismadeandorientedbythecellswithinitGlycosaminoglycans GAGS proteoglycansFibrousproteins collagen elastin fibronectin laminin 1 Glycosaminoglycans proteoglycansGlycosaminoglycan GAG chainsoccupylargeamountsofspaceandformhydratedgels Structure fourgroups hyaluronanchondroitinanddermatansulfateheparansulfatekeratansulfatefunction formporoushydratedgelsfillmostofextracellularspaceprovidemechanicalsupporttothetissueCo receptors hyluronanisthoughttofacilitatecellmigrationduringtissuemorphogenesisandrepair proteoglycansarecomposedofGAGchainscovalentlylinkedtoacoreprotein GAGchainsmaybehighlyorganizedintheextracellularmatrix 2 FibrousproteinscollagensarethemajorproteinsofthexetracellularmatrixSecretedbyconnectivetissuecellsandavarietyofothercelltypesMajorcomponentofskinandboneThemostabundantproteininmammals Structure classification TheformationofacollagenfibrilCollagensaresecretedwithanonhelicalextensionateachendAftersecretion fibrillarprocollagenmoleculesarecleavedtocollagenmolecules whichassembleintofibrilsFibril associatedcollagenshelporganizethefibrils elastingivestissuestheirelasticity fibronectinisanextracellularproteinthathelpscellsattachtothematrix laminin 3 BasallaminaearecomposemainlyoftypeIVcollagen laminin nidogen andaheparansulfateproteoglycan Function separatecelltocellandtissuetotissuefilteringrolesdeterminecellpolarityinfluencecellmetabolismorganizetheproteinsinadjacentplasmamembranepromotecellsurvival proliferation differentiationserveasspecifichighwayforcellmigrationThebasallaminaissynthesizedlargelybythecellsthatonitIstetheredtotheunderlyingconnectivetissuebyspecializedanchoringfibrilsmadeoftypeVIIcollagenmolecules Amodelofthemolecularstructureofabasallamina 4 ThecontrolleddegradationofmatrixcomponentshelpscellmigrateCellsmigratethroughabasallamina requiredegradationofmatrixcomponentsmatrixcomponentsaredegradedbyextracellularproteolyticenzymes proteases thataresecretedlocallybycellsTheproteolysisofmatrixproteinscancontributetocellmigrationinseveralwaysItcansimplyclearapaththroughthematrixItcanexposecrypticsitesonthecleavedproteinsthatpromotecellbinding cellmigrationorbothItcanpromotecelldetachmentsothatacellcanmoveonwardItcanreleaseextracellularsignalproteinsthatstimulatecellmigration 四 cadherins Cadherincompriseanimportantgroupofcell celladhesionmoleculesthatmediateintercellularadhesionbyCa2 dependenthomophilicinteractions Byforminghomedimers cadherincanclusterthroughazipper likemechanism whiletheirintracellulardomainisanchoredtotheactincytoskeletonthrough and catenin 1 cadherins 1 Classificationmorethan80membersofthecadherinsuperfamilyhavebeenidentifiedinthehumangenome Including classiccadherins fat likecadheins seven passtransmembranecadherinsClassiccadherins E N P cadherinAsubfamilyofcadherinsthatshareacommonprimarystructureandbindtocateinsthroughconservedcytoplasmicdomains Fat likecadherins FAT 1andFAT 2Asubfamilyofcadherinsthatcontainlargetandemarrays 19 34 ofextracellularcadherindomainandanEGFdomain Seven passtransmembranecadherins AsubfamilyofcadherinsthatshowsomesimilaritytothesecretinfamilyofG protein linkedreceptorsandcontaineighttonineextracellularcadherindomains twoglobindomainsandfourEGFdomains AlsopresentisadomaincalledtheFlamingobox whichislocatedbetweenthelastextracellularcadherindomainandthefirstEGFdomainandishighlyconservedacrossspeciesinthissubfamily Cadherinsaretraditionallycalssifiedaccordingtothetissuedistributionortotheoriginfromwhichtheydiscovered thecadherinseeninepithelialcellsisnamedasE CDInheartasH CDInneuraltissuesasN CDMostofthecadherinsarefoundinavarietyoftissues Thesecadherinsarethereforereclassifiedaccordingtothestructuralandfunctionalsimilaritieswhichtheyshare ascadherin1 12 2 StructureExtracellularCDdomain 5tandemrepeats mediateCa2 dependenthomophilicinteractions fromdisorderedcadherinstructuretoarigidrod likestructure cisdimer andthenatransdimerofmultiplecisdimers thetransdimersforming zipper structureTransmembranedomain 35aaCytoplasmicdomainofclassicCDs twoportions 3 E CDThehumanE CDgene CDH1 issituatedonchromosome16q22 1E CDformsfroma135KDprecursorthatundergoescytoplasmictrimmingofwhatwillbecometheextracellularN terminalendofthematuremoleculeThematureE CD weightingapproximately120KD ThefirstcatenintointeractwithE CDis cateninFollowedbybindingof catenintoashortregionclosetoNH2 terminalof cateninAtlast formingstablebondsbetweenthecomplexandtheactincytoskeletonP120ctnisresponsibleformodulationofCDclusteringandthusthestabilizationofadhesion 2 cateninsCateninsareagroupofcytoplasmicproteinswhichinteractwiththeintracellulardomainofthecadherinmolecule providinganchoragetothemicrofilamentcytoskeleton catenin102KD catenin88KD catenin plakoglobin 82KDP120ctn120KD 3 TwodistinctE CD catenincomplexE CD cateninand cateninE CD cateninand catenin 4 therelationshipbetweenregulationofE CD catenincomplexandtumormetastasis 1 ExternalfactorsregulateE CD catenincomplexTheinterferencewithcomplexassemblyseemstobemediatedbyamitogenicsignaltransmittedbyEGFRthroughitstyrosinekinaseresultingintyrosinephosphorylationof cateninandE CDitself Theendresultisdissociationof cateninfromE CD catenincomplexandtranslocationoffree catenintothecytosolicpool 2 MembersofthesmallGTPasefamilyregulateE CD catenincomplex RegulationofRho familyGTPasesThesmallGTPasefamily theRastheRhosubfamily Rho Rac1 cdc42 PossiblemodesofactionofRhoGTPaseintheregulationofE cadherin mediatedcell celladhesionRac1 Cdc42andIQGAP1canregulateE CDactivityIQGAP1islocalizedtositesofcell cellcontactanditnegativelyregulatesE CD mediatedcell celladhesionbyinteractingwith catenin withcauses catenintodissociatefromthecadherin catenincomplexActivatedRac1andCdc42positivelyregulatecadherin mediatedcell celladhesionbyinhibitingtheinteractionofIQGAP1with catenin E CDexistsindynamicequilibriumbetweentheE CD catenin catenincomplexandtheE CD catenin IQGAP1complexatsitesofcell cellcntactWhentheamountsofactivatedRac1andCdc42increasebingingtoIQGAP1inhibitingtheinteractionofIQGAP1with catenintheE CD catenin catenincomplexishighStrongadhesionactivityWhentheamountsofinactivatedRac1andCdc42increaseIQGAP1isfreeIntercatingwith catenintodissociate cateninfromthecadherin catenincomplextheE CD catenin IQGAP1complexishighResultinginweakadhesionabdcell celldissociation CadherinrecyclingE CDcleavagebymetalloproteinases 3 Wnt 1signalingpathwayTheincreasedpoolof catenin haveaneffectoncelladhesionwiththe catenininthecytosolicpooleitherlinkingwithE CDoractingintheWnt 1pathwaythe catenincombinewithLEF TCF causingtranscriptionofthecyclinD1geneanddownregulationoftheCDH1gene ThenetresultofalltheseinteractionisareductioninE CD mediatedcelladhesionandproliferationofcells 4 summary 5 TherolehypoxiainE CDregulationandmetastasis 5 changesofcadherincomplexincancer ReductionincelladhesionisofmajorimportanceintumormetastasisandappearstobeachievedbyavarietyofmechanismsaffectingtheE CD catenincomplexIncluding ReducedlevelofCDAbnormallocationofE CDMutationofE CDSheddingofE CDMutationandabnormallevelof cateninAbnormalitiesof cateninChangeof cateninbindingpartnersChangesofproteinphosphorylationE CDcomplexisdirectlyinvolvedinthebenigntomalignenttransition 五 integrins Integrinsareheterodimeric subunits cellsurfaceglycoproteinsthatbindtoECMproteinsoutsideofthecell andconnect viatheircytoplasmicdomains tocomponentsoftheactincytoskeletonwithinthecell Membersoftheintegrinfamilyofcelladhesionreceptorsinfluenceseveralimportantacceptsofcancercellbehavior includingmotilityandinvasiveness cellgrowthandcellsurvival 1 structureandfunction 1 StructureThreeareatleast18 subunitsand8 subunits givingrisetomorethentwodozendistinctintegrinsinmammaliancellsIntegrinisaheterodimer Alargeextracellularligand bindingdomainAsingletransmembranedomainAsmallcytoplasmicdomain 2 functionIntegrinsactasthebridgebetweenECMcomponentsandthecytoskeletonandotherproteins regulatingcellsurvival proliferation differentiationandmigration 2 integrinandcancer 1 integrinconnectionstoRas andRho familyGTPaseIntegrinsactivateRho GTPaseThestateofintegrinactivationisregulatedbyRas familyGTPaseRacandCdc42induceinvasivenessthroughcollagenviathe 2 1integrininaPI3K dependentmannerRasinducesinvasionthroughcollagenthroughacombinationofPI3KandproteinkinaseCRasappearstoincreasetheexpressionofbothMMP2andMMp9inacell specificmanner 2 IntegrinandWnt 1pathwayILK integrin linkedkinase phosphorylationofGSK 3onSer9InhibitionofGSK 3ActivetheWnt 1signalingpathway 3 integrinandPI3K AktpathwayILKmayactivatethePI3K Akt PKBpathway ILKphosphorylationofPKBonSer437ispositivelyregulatedbytheactingofPI3KandnegativelyregulatedbythetumorsuppressorgenePTEN 4 IntegrinmodulationofapoptosisThebalancebetweencellproliferationandcelldeathcontrolstherateoftumorgrowth thusdysregulationofapoptosis programmedcelldeath canbeakeydeterminantofmalignancy 5 Schematicrepresentationoftumorinvasionbyintegrin mediatedremodelingofbasementmembraneCompressionorremodelingofbasementmembraneindiscreteregion aprocessstimulatedbythe 6 4integrinDepletingbasementmembranecomponentsfromsurroundingregionsCreating gaps throughwhichcarcinomacellscouldescape 整合素对肿瘤细胞的侵袭和迁移作用 直接介导黏附于细胞外基质 影响细胞外环境作为细胞表面受体 将接收的信号传递到细胞核内 控制细胞骨架变形和能量代谢 改变细胞的形态 移行 增殖和寿命诱导活化蛋白溶解酶 促进细胞外基质和基底膜的降解 进一步促进肿瘤转移启动某些细胞逃逸机制 抑制细胞凋亡 三 纤维蛋白溶解酶及其调节因子 纤维蛋白溶解酶激活因子 PA 组织型PA t PA 尿激酶型PA u PA 纤维蛋白溶解酶抑制因子 PAI PAI 1PAI 2PAI 3 四 MMP matrixmetalloproteinases MMPsareatightregulatedfamilyofproteolyticenzymesthatdegradecomponentsoftheextracellularmatrixandbasementmembrane MMPsplayaroleinawiderangeoftumorigenesis includingearlycarcinogenesisevents tumorgrowthandtumorinvasionandmetastasis TheMMPfamily atleast23members Classification Soluble secreted typeMMPBasedonsubstratespecificity collagenases gelatinases stromelysins matrilysins theothersMostsoluble typeMMPsaresecretedfromthecellasinactivezymogenwiththeprodomainActivationrequiresthedisruptionofthecysteine zincinteractionpossiblybytissueorplasmaproteinases andthisprocessoftenconsistsofatwo stepsreaction membrane anchoredMMPsBasedonthemembrane anchoringmechanisms theseMT MMPscanbefurtherdividedinto TypeItransmembraneMMP MT1 3andMT5 MMPTheglycosylphophatidylinositol GPI anchoredMMP MT4 andMT 6 MMPtypeIItransmembraneMMP MMP 23orCA MMP