exosome 外泌体在肿瘤转移中的作用

Theroleofexosomesincancermetastasis外泌体在肿瘤转移中的作用Exosome•1986年,绵羊红细胞上清液中发现了一种有膜结构的小囊泡,命名为外泌体。•1996年,B细胞分泌外泌体，可通过MHC激活T细胞；其他APC细胞也可。•2013年诺贝尔生物/医学奖Morphology•40-100nm•圆形•双脂质层•来源广泛，几乎所有细胞都可分泌•分布广泛，血液、尿液、胸水、唾液•作用广泛，包含信息丰富biogenesisExosomalcontentBiologicalfunctionsandeffects•antigenpresentation•immuneregulation•tissuedevelopment•cell-to-cellspreadofinfectious•discardsmembraneproteins•cancerdevelopment外泌体的临床应用•Biomarker•Drugdelivery肿瘤转移•1.EMT•2.Detachment•3.circulation•4.Adhesion•5.Migration•6.invasion•7.MET•8.Engraftment•9.Proliferation•10.cancerstroma/immunescape1.exosomesasmediatorsinEMTSnail(zincfingerproteinsSnailandSlug),Zeb(zincfingerandhomeodomainproteinsZeb1and2)andTwist(basichelix-loop-helixproteinsE12,E47,Twist1,Twist2andId)pathwaysEMTandmigration•TDEsfromtumorcellswhohaveundergoneEMTcaninturnstimulateneighbouringcellstoacquireEMTlikefeatures,creatingasynergisticeffect•EBVinfection-nasopharyngealcarcinomacells-exosme-HIF1a-SnailandTwistpathway-moreinvasivephenotypeinrecipientcells•muscle-invasivebladdercancercells-exosome-urothelialcells-EMTincrease(exosomefromembryonickidneycellsfailed)•ExosomalmiR-23a,MiR-191andlet7a2.ExosomeandinvasionHighlights•miR-105isuniquelyexpressedandsecretedbymetastaticbreastcancercells•miR-105directlytargetsthetightjunctionproteinZO-1•Cancer-secretedmiR-105destroysendothelialbarriersinthehost•CirculatingmiR-105predictsmetastasisinearly-stagebreastcancerpatients•Blockingofastrocyte-exosomesinhibitsbrainmetastasisExosomesDerivedfromHypoxicOralSquamousCellCarcinomaCellsDelivermiR-21toNormoxicCellstoElicitaPrometastaticPhenotype3.ExosomesandCAFs•Wefoundthatsomecancer-derivedexosomescouldtriggerelevatedα-smoothmuscleactinexpressionandotherchangesconsistentwiththeprocessoffibroblastdifferentiationintomyofibroblasts.•WeshowthatTGF-βisexpressedattheexosomesurfaceinassociationwiththetransmembraneproteoglycanbetaglycan.Althoughexistinginalatentstate,thiscomplexwasfullyfunctionalinelicitingSMAD-dependentsignaling.•SolubleTGF-b1aloneisnotabletodrivestromadifferentiationtoacancer-associatedphenotype.•Exosome-depletedcancercellsfailtogainastroma-mediatedgrowthadvantageinvivoandtheTGF-b1effectonstromadifferentiationisabrogatedbyblockingofexosomesCAFsproduceexosomes,whichstimulatetheWnt-pathwayinbreastcancercellsandenhancetheirmigratorycapabilities4.Engraftmentofmetastaticcells1.CAFsstimulateneoangiogenesisviasecretionofexosomalSDF-1(stromalcellderivedfactor-1)2.TDEsstimulateendothelialprogenitorcellstoformtube-likestructures.•Inductionofneoangiogenesisisnotonlyduetotheexosome’stransportofparacrinesignalingfactorsbutalsoduetodirecttransportofrelevantmRNAtothesurroundingstroma.5.Exosomesinorganotropicmetastaticgrowth1.Apre-metastaticnicheformationisrequiredfortumorcellstoengraftadistantorgan•Ourdatashowthatexosomeproduction,transferandeducationofbonemarrowcellssupportstumorgrowthandmetastasis,hasprognosticvalueandofferspromisefornewtherapeuticdirectionsinthemetastaticprocess.•Inaddition,weidentifiedanexosome-specificmelanomasignaturewithprognosticandtherapeuticpotentialcomprisedofTYRP2,VLA-4,HSP70,anHSP90isoformandtheMEToncoprotein.2.M.Y.Fong,W.Zhou,L.Liu,A.Y.Alontaga,M.Chandra,J.Ashby,etal.,Breast-cancer-secretedmiR-122reprogramsglucosemetabolisminpremetastaticnichetopromotemetastasis,Nat.CellBiol.17(2)(2015)183–194.•Hereweshowthatcancercellscansuppressglucoseuptakebynon-tumourcellsinthepremetastaticniche,bysecretingvesiclesthatcarryhighlevelsofthemiR-122microRNA.•HighmiR-122levelsinthecirculationhavebeenassociatedwithmetastasisinbreastcancerpatients,andweshowthatcancer-cell-secretedmiR-122facilitatesmetastasisbyincreasingnutrientavailabilityinthepremetastaticniche.•Mechanistically,cancer-cell-derivedmiR-122suppressesglucoseuptakebynichecellsinvitroandinvivobydownregulatingtheglycolyticenzymepyruvatekinase.•InvivoinhibitionofmiR-122restoresglucoseuptakeindistantorgans,includingbrainandlungs,anddecreasestheincidenceofmetastasis.7.Immune-modulatingeffectsofexosomesTDEsandcellularimmuneresponse•1.InaninvitroculturemodelofAML,TDEsdecreasedthecountofCD8+-T-cellsbyactivationofFas/FasL-mediatedapoptosis•2.TheyfurtherpromotedCD4+-T-cellproliferationandconversionintoregulatoryT-cellswithincreasedexpressionofIL-10(interleukin-10),TGF-b1,CTLA-4(cytotoxiclymphocyteantigen-4)andGrB(granzymeB).ThesemediatorsreducecytotoxicactivityofNKcells[3.Inaninvitromodelofnasopharyngealcancer,immunosuppressivemiRNAs(hsa-miR-24-3p,hsa-miR-891a,hsa-miR-106a-5p,hsa-miR-20a-5p,andhsa-miR-1908)werefoundinTDEs4.TDEsactivatehumanmyeloidderivedsuppressorcellsthroughHSP72/TLR-2(toll-likereceptor2)viatheSTAT3pathwayandIL-6expressionTDEsandhumoralimmuneresponse1.neutralizeantitumor-antibodies•InbreastcancercellsitwasdemonstratedthatTDEsexpressHer2andEpCAMantigens,whichbindandneutralizeanti-bodiesinterferingwithADCCoftumorcellsexpressingtheseantigens.Asaconsequence,theseTDEsmayreducethetherapeuticeffectofTrastuzumab•Accordingly,B-celllymphomacellssecreteexosomes,whichcarryCD20,neutralizingthetherapeuticeffectofRituximab