Emerging Concepts of Tumor Exosome–Mediated Cell-Cell Communication PDF
Preview Emerging Concepts of Tumor Exosome–Mediated Cell-Cell Communication
Emerging Concepts of Tumor Exosome–Mediated Cell–Cell Communication Huang-Ge Zhang Editor Emerging Concepts of Tumor Exosome–Mediated Cell–Cell Communication 2123 Editor Huang-GeZhang UniversityofLouisville Louisville,KY USA ISBN978-1-4614-3696-6 ISBN978-1-4614-3697-3 (eBook) DOI10.1007/978-1-4614-3697-3 SpringerNewYorkDordrechtHeidelbergLondon LibraryofCongressControlNumber:2012948293 © SpringerScience+BusinessMediaNewYork2013 Thisworkissubjecttocopyright.AllrightsarereservedbythePublisher,whetherthewholeorpartofthe materialisconcerned,specificallytherightsoftranslation,reprinting,reuseofillustrations,recitation, broadcasting,reproductiononmicrofilmsorinanyotherphysicalway,andtransmissionorinformation storageandretrieval,electronicadaptation,computersoftware,orbysimilarordissimilarmethodology nowknownorhereafterdeveloped.Exemptedfromthislegalreservationarebriefexcerptsinconnection withreviewsorscholarlyanalysisormaterialsuppliedspecificallyforthepurposeofbeingenteredand executed on a computer system, for exclusive use by the purchaser of the work. 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Printedonacid-freepaper SpringerispartofSpringerScience+BusinessMedia(www.springer.com) Preface Over the past decades, secretion of proteins that bind to receptors on neighboring cells was considered a primary mode for communication between cells. Recently, the release of membrane vesicles including exosomes/microvesicles has become recognized as an important mode of intercellular communication. Unlike a single solublefactorsecretedbycells,exosomescancarryagroupoffunctionalmolecules enrichedwithparticularproteins,lipids,andmicroRNAs(miRNAs)andprovidean increasedstabilityofthetransportedmolecules. Therefore, exosomescanserveas intercellular communicators not only locally but also systemically. Exosomes are released by many different cell types, and their biological effects on the recipient cellsaredependentonthecompositionoftheexosomesandthemicroenvironment wheretherecipientcellsareresidents. Thisbookwillfocusonexosomesastheyrelatetotumorcellsandcancer.Thefirst fourchapterswillcoverthebasicbiologyofexosomesandtherolesofspecificcom- ponentsofexosomes,primarilyfocusingonproteins,mRNAs/miRNA,andlipids.In thefirstchapter,Dr.GraçaRaposoprovidesanintroductiontoexosomes,describes thecomposition,biogenesis,functionofexosomesingeneral,andthemethodology forisolationandcharacterizationofexosomes/microvesicles. Chapter2writtenby Dr. Jan Lötvall further elucidates the role of exosomal shuttle RNA in cell-to-cell communication. Dr. Lötvall’s group discovered that miRNAs are encapsulated in exosomesandthattheyplayacriticalroleincell-cellcommunicationandalsoaspo- tentialmarkersforprodiagnosisofdiseases.Dr.MichelRecordwroteChapter3and hefocusesontheeffectsofexosomallipidsincell-cellcommunication.Development ofcutting-edgelipidomictechnologyhasprovidedameanstorecognizethebiolog- icalandpathobiologicaleffectsoflipidsonmanydifferentcelltypesanddiseases. Exosomescarryinglipidscanfunctioninexosomallipidmediatedtargetingaswell ascarryinglipidstorecipientcells.ThefinalchapterinthissectionbyDr. Margot Zöllerwillcoverthemechanismsunderlyingtheselectiverecruitmentofmolecules intoexosomes. Dr. Zöllerusestetraspaninasanexcellentexampletodemonstrate howtetraspaninsregulateproteinassemblyofexosomesandthepossiblerecruitment ofmiRNA. BookChapters5–9focusontheeffectsofexosomesatthecellularandmolec- ularlevels, ontumorcellproliferation, onmetastasis, andonimmunosuppression. Topicsinthesechaptersdealwiththeroleoftumorexosomesintheprogressionof tumordevelopment(Drs.Huang-GeZhang,WilliamGrizzle,andDouglasTaylor); v vi Preface the mechanisms underlying tumor exosome-mediated immunosuppression includ- inginductionofregulatoryTcellsandmyeloidcells,immunemodulationofTcells, andnaturalkillercellsbytumor-derivedexosomes(Dr.TheresaWhiteside),tumor- stroma interactions (Dr. Johan K. O. Skog), and microenvironment regulation of metastasisbyexosomes(Dr.DavidLyden). Thefinalchapterdealswiththefutureofexosomebiologyandmorespecifically theinductionofstemcellsinregenerativemedicine(Dr.MariuszRatajczak). TherearemanyindividualsIwishtothank,withoutwhoseeffortsthisbookwould nothavebecomeareality.Firstandforemost,mythanksgotoalltheauthorswho contributed material for publication in this book. Their expertise and scientifically informedviewpoints,coupledwithacollaborativespiritundertighttimeconstrains, hasmadeworkingwiththemapleasure.Ialsowishtothankouracquisitionseditor, FionaSarneforherpatience,encouragement,andsupport.Thisbookmarkedalot offirstsforme, sointheprocessoflearningtheinsandoutsofpublishingabook ofthisnature,Ialsodevelopedaverystrongfriendshipwithher.Ilookforwardto workingwithheragaininthefuture. Last, but not least, I thank my wife Lifeng Zhang, and my twin daughters ShuangqinZhangandShuangyinZhangfortheirsupportandunderstandingduring themanytimesthatbook-writingtookprecedenceoverfamilymatters. Contents 1 TheCellBiologyofExosomes:HistoricalandPerspectives.......... 1 AlessandraLoCiceroandGraçaRaposo 2 The Role of Exosomal Shuttle RNA (esRNA) in Cell-to-Cell Communication................................................ 33 CeciliaLässer,MariaEldhandJanLötvall 3 ExosomalLipidsinCell–CellCommunication..................... 47 MichelRecord 4 TheFunctionalImportanceofTetraspaninsinExosomes ........... 69 SanyuktaRanaandMargotZöller 5 TheEffectsofExosomesandRelatedVesiclesonCancer Development,Progression,andDissemination..................... 107 Huang-GeZhangandWilliamE.Grizzle 6 CirculatingCell-derivedVesiclesMediateTumorProgression ....... 131 DouglasD.TaylorandCicekGercel-Taylor 7 ImmuneModulationofTCellsandNaturalKillerCells byTumor-DerivedExosomes .................................... 149 TheresaL.Whiteside 8 TheRoleofTumorExosomesinTumorigenicity ................... 169 JohanK.O.Skog 9 MicroenvironmentalRegulationofMetastasisbyExosomes......... 181 HaiyingZhang,GuillermoGarcia-Santos,HéctorPeinado andDavidC.Lyden 10 MicrovesiclesandTheirEmergingRoleinCellularTherapies forOrganandTissueRegeneration .............................. 203 Mariusz Z. Ratajczak, Kasia Mierzejewska, Magda Kucia, NickGrecoandJaninaRatajczak Index ............................................................ 217 vii Chapter 1 The Cell Biology of Exosomes: Historical and Perspectives AlessandraLoCiceroandGraçaRaposo Abstract Cells release into the environment not only soluble but also membrane- associated factors. Whereas membranous microvesicles up to 1 μ m are generated by outward budding of portions of the plasma membrane, membrane vesicles of 30–100nm,calledexosomesaresecretedduringfusionofendosomalmultivesicular bodieswiththecellsurface.Exosomescontainmembraneandcytosoliccomponents thatincludeproteins,lipidsandRNAs.Exosomesfromdifferentcelltypesnotonly harboracommonsetofcomponentsbutuniquesubsetsofproteinsarealsoassociated withcelltype-associatedfunctions.Thecompositionofexosomesisrelatedtotheir biogenesis within the endosome, a process that requires the inward invagination of the endosomal membrane to form small membrane vesicles. The mechanisms involvedintheirformationandsecretiononlybegintobeelucidated.Interventionon theirfunctionrepresentscertainlywaystounderstandtheirinvolvementinessential cellularprocessesthatextendfromimmuneregulationtoneuronalcommunication but also pathogen transmission. Exosomes are present in biological fluids and are potentialcandidatebiomarkersfordiseasethatcouldalsopossiblybeexploitedfor therapeuticaldeliveryofdrugs. Abbreviations ILV Intraluminalvesicle MVE Multivesicularendosomes G.Raposo((cid:2)) InstitutCurie,CNRS-UMR144,26Rued’Ulm, 75248ParisCedex,France e-mail:[email protected] A.Lo.Cicero InstitutCurie,CentredeRecherche,75248ParisCedex,France H.-G.Zhang(ed.),EmergingConceptsofTumorExosome–Mediated 1 Cell–CellCommunication,DOI10.1007/978-1-4614-3697-3_1, ©SpringerScience+BusinessMediaNewYork2013 2 A.Lo.CiceroandG.Raposo 1.1 OntheDiscoveryofExosomes 1.1.1 TheReticulocyteUnravelsaNovelPathwayofSecretion Differentiationofthereticulocyteintoamatureerythrocyterequiresthatone-thirdof thesurfaceareaislostaccompaniedbytheeradicationofmanymembrane-associated proteins[1].Oneofthemainmechanismsforthelossofplasmamembraneproteins appearedtobethroughtheselectiveintracellularbuddingofvesiclesintoaso-called multivesicular endosome (MVE) [2]. The groups of R. Johnstone in Montreal and P.StahlinSaintLouisreportedinthemid-1980sthatimmaturesheepreticulocytes released the bulk of their transferrin receptor in association with small membrane vesiclesreleaseduponfusionofMVEswiththecellsurfaceofthereticulocytedur- ingitsmaturationprocess[2–5](Fig.1.1). Reticulocytesculturedwithradioactive transferrin, with radioactive antibody bound to the cell surface exposed transfer- rin receptor or with gold-labeled antibodies released rapidly the majority of their transferrinreceptor.Electronmicroscopicalobservationshavebeenfundamentalto uncoverexocyticprofilesofMVEsfusingwiththecellsurfaceandtocharacterize the secreted membrane vesicles [2]. The exocytosed vesicles were recovered after ultracentrifugationat100.000×gfor90minandwerenamedexosomes(exocytosed endosomalcontents)[6].Redbloodcellsofdifferentspeciessecreteexosomesand the Johnstone’s group further showed that, in addition to the transferrin receptor otherproteinssuchasacetylcholinesterase, cytochalasinB-binding(glucosetrans- + porter) nucleoside binding (i.e., nucleoside transporter), Na -independent amino acid transport, can be lost from the reticulocyte by such unconventional secretory process [6, 7]. Dr Rose Johnstone was a scientist with an incredible strength and enthusiasmandwhobelievedthattheprocessofexosomesecretionthathergroup described in reticulocytes would be a key in additional cellular processes. As she commentedwithhumorafterthefirstworkshoponexosomesinMontrealin2005: An “Alice in Blunderland” approach led to the discovery of exosomes and their involvementinproteinextrusionfrommaturingreticulocytes.Currentstudieshave shownthattheprocessofexosomeformationextendstomanymammaliancells.Full knowledgeofthecontributionofexosomestointercellularinformationtransmission andthepotentialmedicalapplicationofthisknowledgewilldependontheingenuity offutureinvestigatorsandtheirinsightintobiologicalprocesses(Citationfrom[8]). 1.1.2 ExosomesintheImmuneSystem Whilestudiesonreticulocytesuncoveredexosomesecretionasaprocessoferadi- cationofunwantedmoleculesrequiredforcelldifferentiation,only10yearslatera similarprocesshasbeendescribedforimmunecellsgrantingexosomesextracellular functions[9].ImmunoelectronmicroscopyofBlymphoblastoidcellsdemonstrated that the limiting membrane of major histocompatibility complex (MHC) class II compartmentsthathaveallthehallmarksofMVEscanfusedirectlywiththeplasma 1 TheCellBiologyofExosomes:HistoricalandPerspectives 3 Fig.1.1 Releaseofexosomesbyreticulocytes.IntracellularlocalizationofMVEsandtheirfusion withtheplasmamembrane.aIntheMVEs,thegoldlabelforthetransferrinreceptorisassociated withthesmalldensebodiesof∼50nm,whicharepresentinsidelargervesiclesof300–500nm. Notetheabsenceofsurfacelabel.Colloidalgoldof20nmwasused.Incubationwasfor60minat 37◦C.bFusionofMVEswiththeplasmamembraneandreleaseoftheso-calledroundbodies: exosomes.Note,exocytosisintothemediumofsmalldensebodieslabeledwithgoldaftera3-h incubationat37◦C.Thegoldlabelisonlypresentonthe50-nmbodies,whichareinsidevesicles of300–800nmindiameter.ThelimitingmembraneoftheMVEisdevoidoflabel.Magnification × 61,500.(Copyrightpermission1985RockefellerUniversityPress.Originallypublishedin[2]) membrane.Similartotheprocessdescribedforreticulocytes,fusionresultedinre- lease from the cells of internal MHC class II-containing vesicles [9]. By analogy, thesesecretedvesicleswerealsonamedexosomes.Theywereisolatedfromthecell culturemediabydifferentialcentrifugationfollowedbyflotationonsucrosedensity gradientsinwhichexosomesandthemajorityofMHCclassIIfloatedtoameanden- sityof1.13revealingtheirvesicularnature.Importantly,theoverallsurfaceprotein compositionofexosomesdifferedsignificantlyfromthatoftheplasmamembrane. Exosome-boundMHCclassIIwereinacompact,peptide-boundconformationand metabolicallylabeledMHCclassIIwerereleasedintotheextracellularmediumwith relativelyslowkinetics,10±4%in24h,indicatingthatdirectfusionofMIICswith theplasmamembraneisnotthemajorpathwaybywhichMHCclassIIreachesthe plasmamembranebutbywhichitisreleasedextracellularly.Importantlyanddespite theinitialhypothesisthatexosomescouldserveforeradicatingnonfunctionalMHC class II exosomes derived from both human and murine B lymphocytes- induced antigen-specificMHCclassII-restrictedTcellresponses[9].Thesedatasuggested aroleforexosomesinantigenpresentationinvivo.Fromthesestudiesitwasspec- ulatedthatinvivo,inthecirculation,exosomesmightfunctionastransportvehicles forMHCclassIIpeptidecomplexesresponsibleforthemaintenanceoflong-term T cell memory orT cell tolerance [9]. Moreover, they certainly opened a new av- enuetoexploretheusefulnessofexosomes, inparticularasbiologicalvehicles, in immunotherapy. 4 A.Lo.CiceroandG.Raposo 1.1.3 Exosomes Stimulate Antitumoral Immune ResponsesInVivo Only2yearsafterthefindingsthatBlymphocytessecreteexosomeswithantigen- presenting capacities, a first breakthrough on the way to transfer from the bench to the bedside has been the demonstration, in vivo, in mice bearing tumors, that exosomes can eradicate and/or suppress tumor growth [10]. Firstly, it was shown thatthedendriticcell(DC),aprofessionalantigen-presentingcell(APC)alsohasthe capacitytosecreteexosomes.Secondly,tumorpeptide-pulsedDC-derivedexosomes onceinjectedintomice,primespecificcytotoxicTlymphocytesinvivoanderadicate orsuppressgrowthofestablishedmurinetumorsinaTcell-dependentmanner[10]. Theseresultsprovidedthebasisforthehypothesisthatexosomescouldplayanactive roleinintercellularcommunication,atleastintheimmunesystem,andpromptedthe veryfirstattemptatusingthemintheclinic,asanewtypeofexosome-basedcell-free vaccinesrepresentinganalternativetoDC-adoptivetherapyforsuppressingtumor growth [11, 12]. Phase I trials using the Dex strategy in melanoma and nonsmall- cell lung cancer patients have been held (1999–2002) [13, 14] and a phase II trial iscurrentlyongoingattheGustaveRoussyInstitute(withparticipationoftheCurie Institute) in France [15]. Despite the accumulating evidence for the bioactivity of exosomes and their involvement in intercellular communication, however, and as detailedinthefollowingsectionsofthischapter,thereisstilllimitedunderstanding onthemechanismsinvolvedintheirbiogenesisandtheirsecretion.Thishaslargely precludedunderstandingtheirphysiologicalrelevanceinvivo. 1.2 DefinitionofExosomes 1.2.1 Exosomes,Microvesicles,andOtherSecretedVesicles Indifferentconditions,cellsreleasedifferenttypesofmembranevesicles.Notonly endosome-derivedexosomesbutalsovesiclesgeneratedbysheddingorexfoliationof theplasmamembrane[16,17](seealsoFig.1.2).Onemajorongoingchallengeisto definemethodsthatwillallowseparatingbothtypesofvesiclesandcomparingtheir respectiveproperties.Severalstudiesreportingonthecompositionandfunctionsof secretedvesiclesdonotmakeacleardistinctionbetweenthedifferenttypes,certainly becausethepurificationandcharacterizationofeachtypeofvesicleisnotaneasytask andrequiresamultiplicityofcomplementarymethods.Theprocessof“ectocytosis“ isproposedtodescribetriggeredsheddingofright-side-outmembranevesiclesfrom the surface of eukaryotic cells but the term ectosome is more generally related to vesicle shedding by neutrophiles [18, 19]. Other vesicles are generally called mi- crovesicles(MVs),orexosome-likeifincompletelycharacterized.Interestingly,the release of bioactive membrane vesicles from the cell surface is not only a feature ofmammaliancellsbutisalsoconservedacrossmicrobiallife,inbacteria,archaea,
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