Vol5,Supplement2(August2016):TranslationalCancerResearch/Exosomesas“translational”cancerpromoterorganelles
EditorialExosomesas“translational”cancerpromoterorganelles

IsabellaPanfoli

UniversityofGenova,SchoolofMedicalandPharmaceuticalSciences,DIFAR-BiochemistryLab.,VialeBenedettoXV,316132Genova,Italy

Correspondenceto:IsabellaPanfoli,MD.UniversityofGenova,DIFAR-BiochemistryLab.,ValeBenedettoXV,316132Genova,Italy.Email:Isabella.Panfoli@unige.it.

SubmittedJun18,2016.AcceptedforpublicationJun29,2016.

doi:10.21037/tcr.2016.08.08

ThetermExosomehascomeintousetodefinenano-vesiclescontainedinmultivesicularendosomes(MVE),secretedbyfusionofMVEwiththeplasmamembrane(1-3).Exosomesaresecretedinvivobyalmostanycelltypeandcanbeisolatedfrombodyfluids(4-6).Indeed,circulatingvesiclesaccountforbothexosomesandmicrovesicles(MVs),whichcanbepurifiedbyvariouspurificationmethodsandfullydiscriminatedaccordingtotheirshape,sizeandCD-Markers(7,8).DuetotheirproteinandRNAcontent,onceinternalized,exosomeshavethepotentialtoactas“translational”organelles,alteringtheexpressionpatternofrecipientcells,theirgrowth,andfate.Infact,exosomesareinvolvedinmanyofphysio-pathologicalprocesses,therebyincludingcancer(9).

TheworkrecentlypublishedbyFranzenetal.inTheJournalofUrology(10)examinedtheroleofexosomesinintercellularcommunicationandtheirpotentialasnoninvasivecancerbiomarkersourcetoassessdiseaseanditsprogression,orvehiclesfortherapeuticdeliveryinurologiccancer(11).Theneedforapredictorofmalignancyisuniversallyrecognized.Thisisparticularlytrueinthecaseofearlytumors.Thereisevidencethatcancer-derivedexosomescontributetotumorprogressionandmetastasis(12).Tumorcellsproduceexosomes,emergingasapotentialfortheearlydetectionortherapyofhumancancer(13).

Humanurinaryexosomalproteomehasbeenextensivelystudied(7).Urinaryexosomescomefromeverycelltypeoftheurinarytract,kidneyandprostate(14-16).Thereisincreasinginterestinurinaryexosomes,duetotheirabilitytocarryinformationspecificofthetissueoforigin.Iampositiveabouttheideathatexosomes,whichcanbeeasilyisolatedfromhumanurinebyminimallyinvasivetechniques,canallowtodetectbiomarkersinpatientswithurogenitalcancer,withawealthofapplicationsintherapyanddiagnosis,aswehavealreadyobserved(17).Bladdercancerisoneexample,asitrepresentsaserioushealthproblem,(about8%ofallhumanmalignancies),stillburdenedbyahighpercentageofrelapse(18).

However,IamsceptictotheideathatexosomescanbeusedintherapeuticsasRNAortherapydeliveryvectortotargetcancercells.Surely,RNAwouldbeprotectedbythemembranefromdegradation.Nevertheless,itseemsthatwestillknowtoolittleaboutthesurfaceproteinsofexosomes.WehaveshownthatamongtheexosomalsurfaceproteinstherearetherespiratorychainsandF1Fo-ATPsynthase,conductinganoxidativephosphorylation(19,20).Beforeseeingthecontentsofapackage,itsenvelopemustbeopened.Similarly,beforetheRNAcontentofanexosomecomplexisshed,anditcanaffectthecellexpressionpattern,itssurfaceproteinswillhaveinteractedwiththecytosol.Wehavereportedtheproteomeanalysisofurinaryexosomes,studiedbyOrbitrapmassspectrometry,comparedtourinoma(20).Cytoscapesoftwareanalysisofthedataelucidatedtheenrichedpresenceinurinaryexosomesofproteinsclusteredtoaerobicmetabolism.Moreover,functionalexperimentsshowedthaturinaryexosomescarryoutoxidativephosphorylation.Thesameappliestoexosomesderivedfromhumanumbilicalcordmesenchymalcells(MSC),whichareabletoconductanaerobicmetabolism(19).SuchemergingmetabolicfunctionforbothhumanMSCandurinaryexosomesshouldnotbeignored.Itappearsconsistentwiththereportthatexosomescantransfertheaerobicmetabolismcapacitytoprofoundlyhypo-metaboliccellsinlessthanonehour(21).Thisdramaticeffectoverturnedthefateofdoomedcellslongbeforeanytranscriptionaleventcanhaveoccurred.Incaseoftumorcells,thismaynotbedesirable.ForexampleitwasfoundthatvariousconcentrationsofexosomespurifiedfromthesupernatantsofhumanbladdercancerT24cellculturesinducetheproliferationanddecreasetheratesofapoptosis(22).Havingtheobservationsbeenlimitedtolateevents,posingATPavailabilityasaprerequisite(viabilityassayofat72hr,AnnexinVandtranscriptionfactorsactivity),aninvolvementofearlymetaboliceffectcannotbeexcluded.Infact,itwasalsofoundthatbladdercancerexosomescancauseurothelialcellstoundergoepithelial-mesenchymaltransition(EMT).AuthorstreatedprimaryurothelialcellswiththeexosomesisolatedmRNAandevaluatedtheexpressionofseveralmesenchymalgenesnecessarilyaftera4-and6-htimetorevealnewlytranscribedmRNAs(23).WhileitisknownthattheEMTinducesinvasivepropertiesinepithelialtumors,verylittleisknownaboutEMT-inducedmetabolicchanges.AstudyonHER2-positiveBT-474breastcancercellsshowedenhancedaerobicmetabolism,alongwiththeoverexpressionofspecificglucosetransporters(24).

Amethodtobeusedclinicallyshouldbesimple,cost-effectiveandminimallyinvasive,whichexosomecollectionfromurineappearstobe.Inconclusion,Iamoptimisticthatfurtherstudiesaboutthepotentialforexosomeswillhelpindiagnosis,treatmentandprognosisassessmentofurinarytractcancer.However,severalunansweredquestionsregardingthemetabolicpotentialofexosomesremain.Inthiscontext,improvedknowledgeaboutthemetabolismofexosomesareneeded.

Acknowledgements

None.

Footnote

Provenance:ThisisaGuestEditorialcommissionedbySectionEditorPengZhang(DepartmentofUrology,UnionHospital,TongjiMedicalCollege,HuazhongUniversityofScienceandTechnology,Wuhan,China).

ConflictsofInterest:Theauthorhasnoconflictsofinteresttodeclare.

Commenton:FranzenCA,BlackwellRH,ForemanKE,etal.UrinaryExosomes:ThePotentialforBiomarkerUtility,IntercellularSignalingandTherapeuticsinUrologicalMalignancy.JUrol2016;195:1331-9.

ReferencesVlassovAV,MagdalenoS,SetterquistR,etal.Exosomes:currentknowledgeoftheircomposition,biologicalfunctions,anddiagnosticandtherapeuticpotentials.BiochimBiophysActa2012;1820:940-8.MathivananS,JiH,SimpsonRJ.Exosomes:extracellularorganellesimportantinintercellularcommunication.JProteomics2010;73:1907-20.[Crossref][PubMed]PantS,HiltonH,BurczynskiME.Themultifacetedexosome:biogenesis,roleinnormalandaberrantcellularfunction,andfrontiersforpharmacologicalandbiomarkeropportunities.BiochemPharmacol2012;83:1484-94.[Crossref][PubMed]WangD,SunW.Urinaryextracellularmicrovesicles:isolationmethodsandprospectsforurinaryproteome.Proteomics2014;14:1922-32.[Crossref][PubMed]LässerC,AlikhaniVS,EkströmK,etal.Humansaliva,plasmaandbreastmilkexosomescontainRNA:uptakebymacrophages.JTranslMed2011;9:9.[Crossref][PubMed]PisitkunT,ShenRF,KnepperMA.Identificationandproteomicprofilingofexosomesinhumanurine.ProcNatlAcadSciUSA2004;101:13368-73.[Crossref][PubMed]Conde-VancellsJ,Rodriguez-SuarezE,EmbadeN,etal.Characterizationandcomprehensiveproteomeprofilingofexosomessecretedbyhepatocytes.JProteomeRes2008;7:5157-66.[Crossref][PubMed]PanBT,TengK,WuC,etal.Electronmicroscopicevidenceforexternalizationofthetransferrinreceptorinvesicularforminsheepreticulocytes.JCellBiol1985;101:942-8.[Crossref][PubMed]HendersonMC,AzorsaDO.Thegenomicandproteomiccontentofcancercell-derivedexosomes.FrontOncol2012;2:38.[Crossref][PubMed]FranzenCA,BlackwellRH,ForemanKE,etal.UrinaryExosomes:ThePotentialforBiomarkerUtility,IntercellularSignalingandTherapeuticsinUrologicalMalignancy.JUrol2016;195:1331-9.[Crossref][PubMed]RabinowitsG,Gerçel-TaylorC,DayJM,etal.ExosomalmicroRNA:adiagnosticmarkerforlungcancer.ClinLungCancer2009;10:42-6.[Crossref][PubMed]KharazihaP,CederS,LiQ,etal.Tumorcell-derivedexosomes:amessageinabottle.BiochimBiophysActa2012;1826:103-11.SimpsonRJ,LimJW,MoritzRL,etal.Exosomes:proteomicinsightsanddiagnosticpotential.ExpertRevProteomics2009;6:267-83.[Crossref][PubMed]DearJW,StreetJM,BaileyMA.Urinaryexosomes:areservoirforbiomarkerdiscoveryandpotentialmediatorsofintrarenalsignalling.Proteomics2013;13:1572-80.[Crossref][PubMed]Gámez-ValeroA,Lozano-RamosSI,BancuI,etal.Urinaryextracellularvesiclesassourceofbiomarkersinkidneydiseases.FrontImmunol2015;6:6.[Crossref][PubMed]BourderiouxM,Nguyen-KhoaT,ChhuonC,etal.Anewworkflowforproteomicanalysisofurinaryexosomesandassessmentincystinuriapatients.JProteomeRes2015;14:567-77.[Crossref][PubMed]BruschiM,RaveraS,SantucciL,etal.Thehumanurinaryexosomeasapotentialmetaboliceffectorcargo.ExpertRevProteomics2015;12:425-32.[Crossref][PubMed]HurstRE.Doesthebiomarkersearchparadigmneedre-booting?BMCUrol2009;9:1.[Crossref][PubMed]PanfoliI,RaveraS,PodestàM,etal.Exosomesfromhumanmesenchymalstemcellsconductaerobicmetabolismintermandpretermnewborninfants.FASEBJ2016;30:1416-24.[Crossref][PubMed]BruschiM,SantucciL,RaveraS,etal.Humanurinaryexosomeproteomeunveilsitsaerobicrespiratoryability.JProteomics2016;136:25-34.[Crossref][PubMed]ArslanF,LaiRC,SmeetsMB,etal.Mesenchymalstemcell-derivedexosomesincreaseATPlevels,decreaseoxidativestressandactivatePI3K/Aktpathwaytoenhancemyocardialviabilityandpreventadverseremodelingaftermyocardialischemia/reperfusioninjury.StemCellRes2013;10:301-12.[Crossref][PubMed]YangL,WuXH,WangD,etal.Bladdercancercell-derivedexosomesinhibittumorcellapoptosisandinducecellproliferationinvitro.MolMedRep2013;8:1272-8.[PubMed]FranzenCA,BlackwellRH,TodorovicV,etal.Urothelialcellsundergoepithelial-to-mesenchymaltransitionafterexposuretomuscleinvasivebladdercancerexosomes.Oncogenesis2015;4:e163.[Crossref][PubMed]KondaveetiY,GuttillaReedIK,WhiteBA,etal.Epithelial-mesenchymaltransitioninducessimilarmetabolicalterationsintwoindependentbreastcancercelllines.CancerLett2015;364:44-58.[Crossref][PubMed]Citethisarticleas:PanfoliI.Exosomesas“translational”cancerpromoterorganelles.TranslCancerRes2016;5(Suppl2):S205-S207.doi:10.21037/tcr.2016.08.08