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NATURE | NEWS&VIEWS

Cancer:Organseekingvesicles
JanuszRak
Nature 527, 312314 (19November2015) doi:10.1038/nature15642
Publishedonline 28October2015
Ananalysisrevealsthatcancercellsremotelypreparedistantsitesfortumourspreadinanorganspecificmanner,by
deployingorganseekingextracellularvesicles.SeeArticlep.329
Subjectterms: Cancer

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Cellbiology

Themetastaticdisseminationofcancercellsfromtheirsiteoforiginthroughthebloodstreamtodistantorgansisamajorcauseof
cancerrelateddeaths.Thisprocessisnotrandom1instead,certainpopulationsofcancercellspreferentiallyseekoutandcolonize
specificorgans2,underthecontrolofarangeofmolecularprograms3.Suchhomingimplicitlyinvolvesinteractionsbetweencancercells
thatescapetheprimarytumour,sometimesknownasseeds,andthemicroenvironment,or'soil',oftargetsites1.Butlessintuitiveisthe
discoverybyHoshinoetal. 4,describedonpage329ofthisissue,thatseedscaninfluencethesoilbeforetheirarrival,sendingout
extracellularvesiclescalledexosomesthatpreconditionspecificorgansformetastaticinvasion.
Thereisgrowingsupportfortheprovocativenotionthatabuildupofsystemicresponsestoaprimarytumourmightprecede,andeven
enable,theeruptionofmetastaticcancer.Theseresponsesmightinvolvecomplexalterationsinthebody'svascular,coagulationand
inflammatorysystemsforexample,cancerrelatedchangesinthecompositionofsolubleproteins,incellpopulations3orinthe
characteristicsofexosomes5intheblood.
Hoshinoetal.defineexosomesassmallextracellularvesicles 6membraneboundedcompartmentsthattransportproteins,lipidsand
nucleicacids7fromonecelltoanother,andwhichcantravelconsiderabledistancesinbodilyfluidsorthebloodstream.Thisinformation
transferprocesshasattractedconsiderableinterestincancerresearch,becausesomeextracellularvesiclescarrycancercausinggenes
calledoncogenes,oroncogenicproteinsthatpromotecancerformationanddiseaseprogression8.
Theinvolvementofextracellularvesicles,includingexosomes,inmetastasishasbeenstudiedforsometime9,10,andcontributesto
severalkeyeventsthatprepareadistantsiteforcolonizationaprocesscalledpremetastaticnicheformation11.Forexample,ina
mousemodelofmelanoma,contactbetweenexosomesandthecapillarywalltriggersvascularpermeability,whichenablescancercells
toescapefromthebloodvesselintoanewsite5.Inaddition,theseexosomescantransfertheoncogenicMETreceptorproteinto
circulatingbloodcellscalledmyeloidcells,alteringthecells'behavioursuchthattheyconditionpremetastaticsitesforsubsequent
colonizationbycancercells5.Inpancreaticcancer,circulatingexosomestransfermigrationinhibitoryfactorproteintoimmunecellscalled
Kupffercellsintheliver,triggeringacascadeofeventsthatresultsinpremetastaticnicheformation12.
Althoughtheseresultsindicatethatexosomescanpromotemetastasisingeneral,whetherandhowexosomesareinvolvedinorgan
specificmetastasishasnotbeenextensivelyinvestigated.Toexplorethisquestion,Hoshinoetal.askedwhethercancercelltypesknown
topreferentiallyhometothelung,liver,brainorbonemightproduceexosomesthatselectivelyinteractwiththesameorgan.Remarkably,
thisispreciselywhattheyobserved.Whenexosomesfromcancercellswereinjectedintomice,theybecamelodgedintheorganto
whichthosecancercellsarepronetometastasize.Furthermore,theorganseekingexosomesinteractedwithdifferentcelltypes.For
instance,exosomesthattargetedthelungbecamelodgedintheepithelialcellsthatlinetheorgan'sinterior,whereaslivertargeting
exosomesenteredKupffercells.
Hoshinoetal.injectedmicewithexosomesfollowedbycancercellsfromthesamecellline,anddemonstratedthattheexosomes
promotedorganspecificmetastaticgrowth.Theythenmadeatantalizingobservationexosomestakenfrombreastcancercellsthat
metastasizetothelungcouldredirectanothercancercellpopulationtodisseminateinthelung,whenitwouldnormallyhometothe
bone.Thisdiscoverystrengthensthenotionthatthemetastaticcharacteristicsofcancercellsarenotautonomous,butcaninsteadbe
influencedbyexternalfactors.

Theauthorsprovideseveralcluestohowexosomesorchestrateorganspecificmetastasis.Theyfoundthatexosomestargetingdifferent
sitesdisplayeddifferentcelladhesionreceptorproteinscalledintegrinsontheirsurface.Theintegrinprofileofeachexosomesubtype
facilitateditsuptakeintoorgansinwhichanabundanceofligandforthatintegrinwasproduced.Forinstance,v5integrindirected
exosomestotheliver,whereas64promotedhomingtothelung(Fig.1).Furthermore,inhibitingtheexosomalexpressionorbindingof
integrinslimitedorganspecificmetastasis.Finally,theauthorsfoundevidencethatinvasionoftargetorgansbyexosomestriggeredthe
productionofS100proteins,whichpromoteinflammationandcellmigration,andactivationoftheproteinSrcresponsesthat
preconditionhostcellsformetastasis.
Figure1:Pavingthewayfororganspecificmetastasis.

a,Smallextracellularvesiclescalledexosomesbudofffromcancercellsinaprimarytumourandenterthebloodstream,transportingproteins,
lipidsandnucleicacidstodistantcellsinthebody.Hoshinoetal. 4reportthatexosomesderivedfromdifferentcelltypeswithinamixedpopulation
ofcancercellscandisplaydifferentintegrinproteinsontheirsurface.Thisintegrinprofilepromotesadhesionwithcellsatspecifictargetsites
exosomesdisplayingtheintegrin64preferentiallyinteractwithcellsinthelung,whereasv5directsexosomestotheliver.b,Thecontentsof
theexosometriggercellularchangesinthetargetorganthatconditionthesiteformetastasis.Thus,exosomespromoteorganspecificinvasionand
metastaticgrowthofthecancercelltypefromwhichtheyoriginated.

Thesefascinatingobservationsexpandourunderstandingoforganspecificmetastasis.However,furtherinvestigationisrequiredto
establishwhetherandhowthisknowledgecanbeputtopracticaluse.Theauthorsdemonstratethatintegrinexpressionmightpredict
metastaticspread,pointingtothepossibilitythatexosomalintegrinprofilescouldbeusedincancerdiagnostics.Theirdataalsoindicate
thatintegrininhibitorsmightcurtailmetastaticspreadtospecificorgans.Butinmanycases,advancedcancersdisseminatetoseveral
sites3,limitingthepotentialoftherapeuticsthatworkinanorganspecificmanner.
Itisalsoworthconsideringthatthemolecularpathwaysthatinducemetastasis,bothexosomedependentandindependent,are
probablyextremelydiverse.Assuch,theymightbetriggeredbymanycontextspecificfactors:theactivationofdifferentiationpathwaysin
cancercellstheemergenceofaparticularmolecularsubtypewithinatumourtherapeuticinterventionsandmore.Forexample,the
incidenceofbrainmetastasisdiffersbetweenmolecularsubtypesofbreastcancer,andtendstobehigherinthosedrivenbythe
oncogenicproteinERBB2,evenaftereffectivetreatmentwithERBB2inhibitors13.Whether,andhow,ERBB2,itsantagonistsandthe
therapiesusedtotreatERBB2drivencancersmightinfluencetheemissionoforganseekingexosomesisunknown,andisofgreat
interest.Similarly,inflammation,abnormalclottingandothercancerassociatedchangesinphysiologymightinterferewiththeorgan
seekingmechanismofexosomesandcellsandmustbetakenintoaccountwhenanalysingroutesofmetastasis.Thus,muchremains
tobeunderstoodaboutthefascinatingpartthatorganspecificexosomesmightplayinfertilizingthemetastaticsoilindifferenthuman
cancers.

Notes
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References
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Authorinformation
Affiliations
JanuszRakisintheDepartmentofPediatrics,McGillUniversity,Montreal,QuebecH4A3J1,Canada,andattheResearch
InstituteofMcGillUniversityHealthCentre,MontrealChildren'sHospital.
Correspondingauthor
Correspondenceto:JanuszRak

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