Molecular principles of metastasis: a hallmark of cancer revisited

Communication with the tumor microenvironment allows invading cancer cells to overcome stromal challenges, settle, and colonize. These ... Skiptomaincontent Thankyouforvisitingnature.com.YouareusingabrowserversionwithlimitedsupportforCSS.Toobtain thebestexperience,werecommendyouuseamoreuptodatebrowser(orturnoffcompatibilitymodein InternetExplorer).Inthemeantime,toensurecontinuedsupport,wearedisplayingthesitewithoutstyles andJavaScript. Advertisement nature signaltransductionandtargetedtherapy reviewarticles article Molecularprinciplesofmetastasis:ahallmarkofcancerrevisited DownloadPDF DownloadPDF Subjects Metastasis AbstractMetastasisisthehallmarkofcancerthatisresponsibleforthegreatestnumberofcancer-relateddeaths.Yet,itremainspoorlyunderstood.Thecontinuousevolutionofcancerbiologyresearchandtheemergenceofnewparadigmsinthestudyofmetastasishaverevealedsomeofthemolecularunderpinningsofthisdisseminationprocess.Theinvadingtumorcell,onitswaytothetargetsite,interactswithotherproteinsandcells.Recognitionoftheseinteractionsimprovedtheunderstandingofsomeofthebiologicalprinciplesofthemetastaticcellthatgovernitsmobilityandplasticity.Communicationwiththetumormicroenvironmentallowsinvadingcancercellstoovercomestromalchallenges,settle,andcolonize.Thesecharacteristicsofcancercellsaredrivenbygeneticandepigeneticmodificationswithinthetumorcellitselfanditsmicroenvironment.Establishingthebiologicalmechanismsofthemetastaticprocessiscrucialinfindingopentherapeuticwindowsforsuccessfulinterventions.Inthisreview,theauthorsexploretherecentadvancementsinthefieldofmetastasisandhighlightthelatestinsightsthatcontributetoshapingthishallmarkofcancer. IntroductionThedevelopmentofsecondarytumorsinapartofthebodythatisfarfromtheoriginalprimarycanceristermed“metastasis.”Despitemetastasisbeingthekeycauseoffailureofcancertherapyandmortality,itremainspoorlyunderstood.Inpatientswithcancer,largenumbersofcancercellsarereleasedincirculationdaily;however,melanomastudiesinanimalmodelssuggestthat<0.1%oftumorcellsmetastasize.1Thedevelopmentofmetastasesrequirescancercellstoleavetheirprimarysite,circulateinthebloodstream,endurepressureinbloodvessels,acclimatetonewcellularsurroundingsinasecondarysite,andescapedeadlycombatwithimmunecells.2,3HanahanandWeinberg4specifythat“activatinginvasionandmetastasis”isahallmarkofcancer.Indeed,invasionofnearbytissueandseedingatdistantsitestoformmetastasesremainsacentralfeatureofcancermalignancy(Fig.1).Afterall,metastasisconstitutestheprimarycauseofdeathfor>90%ofpatientswithcancer.5Understandingthedynamicsofthisprocesswillhelpidentifytargetsformoleculartherapiesthatmayhaltorpossiblyreversecancergrowthandmetastasis.Here,theauthorsreviewtherecentadvancementsinthefieldofmetastasisandhighlightinsightsthatcontributetoshapingthishallmarkofcancer.Fig.1Overviewofthemetastaticcascade:Thefivekeystepsofmetastasisincludeinvasion,intravasation,circulation,extravasation,andcolonizationFullsizeimageDisseminationandinvasionChromosomalinstability:theinitialtriggerDisseminationofcancercellsprecedestheinitialstepsoftheinvasion-metastasiscascade.6Thecascadeistheconsequenceofchromosomalinstabilitythatiscausedbycontinuouserrorsinchromosomesegregationduringmitosis(Fig.2).FaultsinchromosomesegregationcausetheruptureofmicronucleiandthesecretionofgenomicDNAintothecytosol,whichsubsequentlyactivatescytosolicDNA-sensingpathways(cyclicGMP-AMPsynthase–stimulatorofinterferon(IFN)genes)anddownstreamnuclearfactorκ-light-chain-enhancerofactivatedB(NF-κB)signaling.7Fig.2Determinantsofmetastasis:Theactivationofinvasionandmetastasisistriggeredbyepigeneticfactorsthatareinducedbyenvironmentalstimuli,suchasagingandcircadiandisruptions;adhesivesignalsfromextracellularmatrix(ECM)components,suchascollagenandfibrin;ECMmechanicalpressures,includingtensionandcompression;cell–cellinteractions;solublesignals,suchasgrowthfactorsandcytokines;andtheintratumoralmicrobiotaFullsizeimageStudiessuggestthatthenatureoftheprimaryseedingcancercelldeterminesthedifferentmetastaticpropertieswithrespecttogrowthandresponsetotherapy.8,9Invivoandinvitrostudiesshowthatmetastaticcancercellsmigrateindividually.10Inhumans,however,itisbelievedthatseedingrequiresthejointactionofaclusteroftumorcellsmovingtogether,11whichbringsepithelial–mesenchymaltransition(EMT)intothepicture.Epithelial–mesenchymaltransition:whatisnew?EMTisthetransdifferentiationprocessthroughwhichtransformedepithelialcellsdeveloptheabilitytoinvade,resiststress,anddisseminate.4Epithelialcellsareimmotileandtightlyboundtoeachotherandtotheneighboringextracellularmatrix(ECM).12EMTgovernsthereversiblebiochemicalalterationsthatpermitaspecificepithelialcelltoattainamesenchymalphenotypeandconfersepithelial–mesenchymalplasticityuponepithelialcells,13whichiscrucialforcancerprogressionandmetastasis(Fig.3).However,notallcellsthatoriginatefromtheprimarytumorsitecontributetothedevelopmentofmetastasis.Studyingthedeterminantsofmetastaticpotentialinamousemodelofbreastcancerrevealedthatasparaginesynthetase,ametabolicenzyme,iscorrelatedwithmetastasisdevelopment.14Decreasingthelevelsofasparaginethroughʟ-asparaginasetreatmentorthroughdietaryrestrictiondecreasedmetastaticspread.Assuch,asparagineavailabilitypromotedEMT.14Fig.3Epithelial–mesenchymaltransition(EMT):EMToccursthroughsingle-celldisseminationorthroughcollectivemigration.TheprocessconsistsofseveraltransitionstagesbetweentheinitialepithelialcellandtheinvasivemesenchymalcellFullsizeimageRecently,ithasbecomebroadlyunderstoodthattheEMTprogramisaspectrumoftransitionalstagesbetweentheepithelialandmesenchymalphenotypes,incontrasttoaprogressionthatinvolvesabinarychoicebetweenfull-epithelialandfull-mesenchymalphenotypes.15Thetransitionofonestatetoanotherisgovernedbyanumberofgrowthfactors16andsignalingpathways.17SpontaneousEMTinprimarytumorcellsshiftsbetweendifferentintermediatestageswithdifferentinvasive,metastatic,anddifferentiationcharacteristics.18Tumorcellsthatexpressamixofepithelialandmesenchymalphenotypesaremoreeffectiveincirculation,colonizationatthesecondarysite,andthedevelopmentofmetastasis.18Moreover,transcriptional,chromatin,andsingle-cellRNAsequencingshowthatthevariousstagespossessdiversecellularcharacteristics,chromatinlandscapes,andgeneexpressionsignaturesthatareregulatedbycommonanddistincttranscriptionfactorsandsignalingpathways.Moreover,thevariousEMTstagesaresituatedindiversemicroenvironmentsandareincontactwithdiversestromalcells.18Forexample,metastaticcellswiththemostpronouncedmesenchymalphenotypeproliferatenearendothelialandinflammatorycells.Thesetumorcellsreleaselargequantitiesofchemokinesandproteinstoattractimmunecellsandstimulateangiogenesis,thuspromotingthedevelopmentofauniqueinflammatoryandhighlyvascularizedniche.18Cancer-associatedfibroblastshavealsobeenshowntodriveanddirectcancercellmigrationthroughfibronectinalignment.19Inaddition,hypoxia,20metabolicstressors,andmatrixstiffness21triggertheEMTprogramincancercells.Transitioningisoftendrivenbytranscriptionfactorsthatareprogrammedtorepressepithelialgenesandactivatemesenchymalgenes.22EpigeneticandposttranslationalmodulatorsalsoplayavitalroleincontrollingtheEMTprocess.15Inrecentyears,therehasbeenanimportantdebateonwhetherEMThasacentralroleincancermetastasisandresistancetochemotherapy.17,23,24,25ResearchinlungandpancreaticcancersshowsthateventhoughEMTmightnotbeessentialformetastasis,itdoescontributetochemoresistance.23,24Nevertheless,moreevidenceisneededtocompletelyandclearlyelucidatetheroleofEMTincancerprogressionandthemetastaticprocess.AlthoughEMTmightberequiredformetastasisinitiation,theoppositeprocessofmesenchymal–epithelialtransition(MET)isneededformetastaticprogression.Inbonemetastasis,E-selectininthebonevasculatureinducesMETandWNTactivationincancercellstodrivemetastatictumorformation.26GeneticprofileofmetastaticcellsMetastaticcancerencompassesadiversecollectionofcellsthatpossessdifferentgeneticandphenotypiccharacteristics,whichdifferentiallydriveprogression,metastasis,anddrugresistance.27Hundredsofgeneshavebeenreportedtodetermineinvasivepotential,suggestingthatprimarytumorcellsexhibitametastaticgeneticsignature.28,29,30However,specificmutationscanstillpromoteinvasionandmetastasisinthecontextofsomehomozygousallelicexpressions.Integrativeclinicalgenomicsshowedthatthemostpredominantgenesthatweresomaticallychangedinmetastasisincludedtumorproteinp53(TP53),cyclin-dependentkinaseinhibitor2A(CDKN2A),phosphataseandtensinhomolog(PTEN),phosphatidylinositol-4,5-bisphosphate3-kinasecatalyticsubunitalpha(PIK3CA),andretinoblastoma(RB1).31,32Putativepathogenicgermlinevariantswerepresentin12.2%ofcases,ofwhich75%wereassociatedwithDNArepairdefects.31Markersthatpredictmetastaticprogressionshowedthatadvancedcancersarisefromdiversecelltypes,whichdeeplyaffectstheeventualgeneticandepigeneticalterationsthatpromotemetastaticprogression.33Metastaticsmallcelllungcancer(SCLC)cellsdifferedinthegenesthattheyexpressed.33Thismightexplainwhysomecancercellsrespondtotreatment,whereasothersdonot.Assuch,understandingintertumoralheterogeneityamongdifferentcancerscanrevealthemechanismsofmetastaticprogressionandhowthecelltypeoforigincontributestotumordevelopment.Incolorectalcancer,cellsexpressingL1celladhesionmolecule(L1CAM)confermetastasis-initiatingabilitiesandchemoresistance.L1CAMhijackstheregenerativecapacityofintestinalcellstopromotemetastasis.34Inaddition,thecytotoxicimmunesignatureandthepresenceoflymphaticvesselsplayanimportantroleinthegenerationofdistantmetastases,regardlessofgenomicinstability.35MetabolicprofileofmetastaticcellsGeneticexpressionthatisinvolvedindifferentbiologicalprocessesrelatedtometastasisisalsoaffectedbyoxygenhomeostasisinthetumormicroenvironment.36Hypoxia‐induciblefactors(HIF)permitcancercellstoadapttotheircellularenvironmentbyregulatingangiogenesis,EMT,invasion,metastasis,andenergymetabolism.4,37,38,39,40Furthermore,AXL,areceptortyrosinekinase,hasbeenidentifiedasavitalmediatorofHIF-dependentinvasionandmetastasis.Inaddition,HIFsignalingdrivesthesecretionoflysyloxidase(LOX),LOX-likeproteins,andexosomes,toestablishaprometastaticenvironmentwithinthelungandbonesofpatientswithbreastcancer.20Tumorhypoxiaisassociatedwithpoorprognosisinclinicalscenarios;37,41,42,43,44HIF‐1αandHIF‐2αexpressionislinkedtopatientmortality.41,42Ingeneral,thesehypoxicfactors,alongwithothers,areassociatedwithtumoraggressivenessandresistancetotherapy.38Moreover,tumorswithmoreextensivehypoxicandanoxicareasexhibithigherratesofmetastasis.45Metabolicdifferencesamongcancercellsleadtodifferencesinmetastaticpotential.Metastaticcancercellsdependonmonocarboxylatetransporter1(MCT1)todealwithoxidativestress.MCT1playsamajorroleincirculatinglactate,whichisaprominentenergysourceformetastasizingcells.46Assuch,highlymetastaticcellshaveincreasedlevelsofMCT1,whereastheinhibitionofMCT1decreaseslactateuptakebymetastaticcellsand,thus,reducestheirmetastaticcapability.46ChangesinATP/ADPandATP/AMPratiosalsopromotemetastaticbehavior.Inpancreaticductaladenocarcinoma,ECMremodelingthroughcellularadhesionandcompressionaffectstheseratios.47Metabolomicsshowsthatsuchalterationsincreasephosphocreatineproduction,whichhasaroleintheinvasivemigration,chemotaxis,andlivermetastasisofcancercells.47PrimingthepremetastaticnicheSecondarysitesdonotreceiveinvadingcancercellspassively.Infact,thehostmicroenvironment,termedthepremetastaticniche(PMN),isselectivelyprimedbytheprimarytumorevenbeforetheinitiationofmetastasis.48ThedevelopmentofaPMNisamultistepprocessinvolvingsecretoryfactorsandextracellularvesiclesthatinducevascularleakage,ECMremodeling,andimmunosuppression.48High-definitionmicroscopeshaveobtainedimagesofcancercellssharingbiologicalmaterialwithlessmalignantcells,makingthesecellsmorecancerous.49CancercellsreleasevesiclesthatcarrymessengerRNAtranscribedfromgenesthatareinvolvedincellmigrationandmetastasis,whicharethenacceptedbyothercells.49,50Afterhostcellsengulfthesevesicles,humancellsthatdidnotexpressamalignantphenotypestarttomigratefaster.Thetransferredgenesalsoenhancetheabilityofcellstoinvadeotherorgans.49Assuch,metastaticcharacteristicscanbetransferredthroughextracellularvesicleexchange.49Primarytumorsreleasesignificantamountsofexosomesthattransferinvasion-promotingfactors,suchasmicroRNAs(miRNAs),totumorigeniccancercells.51,52,53Forexample,miR-10biscarriedandreleasedbyexosomesanddrivesmetastaticpropertiesinbreastcancercells.54Inaddition,signalingfactorsmediatedbyexosomesactivateepidermalgrowthfactorreceptor(EGFR)signalingtosupportcancermetastasis.55ExosomesthatexpressEGFRligands,suchasamphiregulin,tissue-typeplasminogenactivator,and/orannexinII,considerablyincreasecancercellinvasion.56,57,58,59Moreover,exosomessecreteEMTinducersthatstimulateEMTprogressioninhostepithelialcells,providingthemwiththeabilitytoinvadeandmetastasize.60,61,62,63,64,65Furthermore,exosomeshavetheabilitytoremodeltheECMbyinteractingwithfibroblasts,stromalcells,andendothelialcellstodegradeprotease-associatedcomponentssuchascollagen,laminin,andfibronectin.66Exosome-alteredECMexhibitsincreasedstromalcellproliferation,cancercellmigrationandsurvival,andtumorcellresistancetoapoptoticsignals.This,alongwiththeeffectofchemokinesandgrowthfactors,leadstotheformationofanewmicroenvironmentforcancercells,immunecells,andotherstromalconstituentsthatisreferredtoasthePMN,67,68,69,70wheremetastaticcellsmayarrest,extravasate,andultimatelycolonize.71,72,73InadditiontotheirroleinprimingthePMN,exosomesexhibitpropertiesthatdrivecancercellorganotropism.Thismetastaticbiastowardscertainorgansstemsfromexosomalavidityforspecifichostcells.60Studyingtheexosomalproteomicexpressionofbonecancershoweddifferentintegrinpatterns,wherebytheexosomalintegrinsα6β4andα6β1werecorrelatedwithlungmetastasis,whereasexosomalintegrinαvβ5wasassociatedwithlivermetastasis.74UptakeofintegrinsinthesecondarysiteledtothephosphorylationofSrcandtheexpressionoftheproinflammatorygeneS100.74Targetingthoseintegrinsdecreasedexosomaluptake,andlungandlivermetastasis.74OthermembraneproteinsandlipidsthatareassociatedwithECMpropertiesandadhesioninfluencethespecifictargetingofexosomestotheirspecifichostcells.74,75,76,77,78Inaddition,exosomalinternalizationbytargethostcellsactivatesheterogeneousendocyticpathwayssuchasclathrin,lipidraft,andcaveolin-mediateduptake.65,79,80Exosome-mediatedmetastasisisnotsolelydependentupontumor-releasedexosomes.Infact,astrocyte-derivedexosomesmediatetheintercellulartransferofmiRNAsthattargetthePTENtumorsuppressorgenetometastaticcancercells,promotinginvasionandbrainmetastasis.81This,inturn,leadstotheincreasedsecretionofchemokineligand2(CCL2),whichrecruitsmyeloidcells,enhancingtheoutgrowthofbrainmetastaticcellsandreducingtheeffectofapoptoticsignaling.81InhibitionofastrocyticexosomalreleasepreventsPTENlossandsuppressesbrainmetastasis.81Canmetastasisbedrivenbyepigeneticfactors?Age-relatedphysicalchangesintheECMpromoteorinhibittumorcellmotility,invasion,andmetastasis.Alterationsinthemotilityofimmunecellsleadtochangesintheimmunemicroenvironment.82Elderlypatientswithmelanomatendtodevelopfewermetastasesinproximallymphnodesbuthavemoredistalmetastases,withworsesurvivalthanthatofyoungercohorts.83Throughinvitroanalysis,increasedlymphaticpermeabilityofendothelialmembraneswasshowntobethereasonforthisphenomenon,aslymphnodesofolderpatientsexhibitedlessECMcomplexityincomparisonwiththatoflymphnodesofyoungerpatientswithmetastaticmelanoma.83Furtheranalysisrevealedthathyaluronanandproteoglycanlinkprotein1(HAPLN1)isresponsibleforcontrollingendothelialpermeability.82,83Geneknockoutincreasedendothelialpermeabilityandtheinvasiveabilityofdisseminatingmelanomacells.83Otherfactors,suchasdecreasedvascularendothelial-cadherin-dependentcell–celladhesionandweakcell–ECMadhesionthroughα1andβ1integrins,playaroleinincreasinglymphnodepermeability.83Chromatinmutationshaverecentlycometolightasimportantmediatorsofcancerdevelopment.Chromatinalterationsinducecellstogainfulloncogeniccharacteristics.84Furthermore,genetic,environmental,andmetabolicconditionsinfluencechromatintobecomepermissiveorrestrictive.84Epigeneticplasticityisexhibitedwhenpermissivechromatininducesoncogenicexpressiontopromotemetastaticdevelopment.84Howdoesthemicrobiomecontributetocancermetastasis?Theconceptofthe“tumormicrobiome”originatesfromthefactthatbacteriahavebeendetectedwithintumorsthemselves.Althoughnolinkstopatientoutcomesandsurvivalhavebeenestablished,microbeshavebeenreportedtoconfervulnerabilitytospecificcancers.85Bacterialtranslocationselectivelytargetstumorsthathaverichvascularnetworksandchemotacticmagnetism.Anaerobicand/orfacultativebacteria,specifically,vigorouslysurviveinhypoxictumormicroenvironments.86,87Tumoralbacteriaaremetabolicallyactive,leadingtoalterationsinthechemicalstructureofsomechemotherapeuticagentsandaffectingtheresponsetotherapy.88,89Gammaproteobacterialocatedinpancreatictumorsconferresistancetogemcitabine,acommonlyuseddrugingastrointestinalcancers.89,90,91FusobacteriumnucleatumalsopromotesresistanceincolorectalcancerbyinitiatingautophagyandactivatingToll-likereceptorsoncancercells.92Intratumoralbacteriafurthermodulatetheimmunesystem.Althoughsomebacteriastimulateantitumoralimmunity,otherspromoteimmunosuppression,affectingtheresponsetoimmunotherapy.86,93,94,95,96,97,98TheFap2proteinofFusobacteriumpreventstheactivationofnaturalkiller(NK)cells,protectingadenocarcinomacelllinesfromNKcellantitumoractivity.99Doesthecircadiancycleplayaroleintumorigenesis?Thecircadianclockcontrolsawidespectrumofprocessesincellularphysiologythroughmetabolicandgeneexpressionpathways.100Inthepastdecade,epidemiologicalstudiesonnight-shiftworkers,mealtiming,andexposuretolighthavelinkedalterationsincircadianpatternstotumorigenesis,101,102,103,104,105,106,107indicatingthatanactiveepigeneticmechanismmayberesponsibleforwide-genomealterations.Circadianclockdisruptionshavebeencorrelatedwithcancerinitiationandprogression.Furtheralterationsintranscriptioncomplexesandcellularmetabolismdrivecancerprogressionbyinfluencingcancercellinteractionswiththemicroenvironment.100TheMYConcogeneplaysaroleincyclicalmetabolisminosteosarcomacells,leadingtoincreasedconsumptionofglucoseandglutamine.108Moreover,anumberofcircadianregulatinggeneshavebeenlinkedtoMYCexpression.Cryptochromecircadianregulator2,acircadianrepressor,promotesMYCdegradation.109Furthermore,zincfingerandBTBdomain-containingprotein17(MIZ1),aMYC-bindingprotein,downregulatescoreclockgeneexpression.110Inaddition,brainandmuscleARNT-like1expressionisinverselycorrelatedwithMYC.110However,furtherresearchisneededtoelucidatethemechanismthroughwhichothercircadianinputs,suchasnutrition,affectcircadianmetabolismandmetastasis.CD36+metastasis-initiatingcellsrelyonpalmiticacid,adietarylipid,topromotemetastasis.BlockingCD36inhibitsmetastaticability,suggestingthatahigh-fatdietspecificallybooststhemetastaticpotentialofmetastasis-initiatingcells.111Invasivecancercells:remodelingtheextracellularmatrixTheECMisascaffoldofinterconnectedmacromoleculesformingnetworksthatencompasscellspresentintissuesandorgans.112Thisspecializednichealtersthephenotypicpropertiesofcellsandaffectstheirpropensitytoproliferate,migrate,andsurvive.113,114Uponphysiologicalandpathologicaltriggers,ECM-degradingenzymes,calledmatrikines,arereleasedtoremodeltheECM,tore-establishanappropriatefunctionalmeshworkandmaintaintissuehomeostasis.114,115Incancermetastasis,ECMremodelingishijacked,leadingtostromaltumorigenesis.116,117,118,119,120AvarietyofmajorECMcomponents,suchasproteoglycans,collagen,laminins,fibronectin,elastin,otherglycoprotein,andproteinases,areinvolvedintheinvasiveandmetastaticprocessesofcancercells.OneimportantstepininvasionisthedisassemblyoftheECManditsconstituentsthroughenzymessuchasmatrixmetalloproteinases(MMPs).121MMPsplayamajorroleincellproliferation,survival,immuneresponse,andangiogenesis,inadditiontoinvasion.122,123MMPsareelevatedinmostcancertypesandarecontinuouslyassociatedwithpoorprognosis.124,125CancercellsadjustthemetastaticnichetodrivegrowthbyremodelingtheECM.Thechangesinnutrientaccessibilityandmetabolicreactionsintissuesdeterminethelikelihoodofcancercellstometastasize.Forexample,metastaticbreastcancercellsmetabolizepyruvate,whichisplentifulinthelungs,todrivecollagen-basedECMremodelinginthelungmetastaticniche.126Versican,ahyalectanthatispresentininterstitialECM,activatesEGFRsignalingviaitsEGF-likerepeats,whichleadstocancercellgrowthandinvasion.127,128Chondroitinsulfateproteoglycan4(CSPG4)isanotherECMcomponentthatplaysanintegralroleinstabilizingtheinteractionsbetweencellsintheECMmatrix.CSPG4interactswithintegrinα2β1uponcollagentypeVIbindingtoactivatethephosphatidylinositol3-kinase(PI3K)pathwayinsarcomacells.129Inaddition,CSPG4formscomplexeswithMMP-2andmembranetype3MMPonthesurfaceofmelanomacellstofacilitateMMP-2activationandeventualdegradationoftheECM.130LumicanisanECMproteinthatorganizesfibrilorganizationandcircumferentialgrowth.Itplaysamajorroleincornealtransparency,epithelialcellmigration,andtissuerepair.Incancer,lumicanattenuatestheproliferation,migration,andinvasionofbreastcancercells.ItmodifiescellularjunctionsandpromotesMET131throughdirectinteractionswithotherECMmoleculesorbythemodulationofmembranereceptors132,133andMMP-14.134,135,136Glypicansareproteoglycansthatparticipateindevelopmentalmorphogenesis.Theyplayadualroleinfosteringorsuppressingtumorigenesis.114,137Glypican-3exhibitsatumorsuppressorphenotype.Decreasedglypican-3expressionleadstotheprogressionofmalignancies,whereasitslossisassociatedwithpooroverallsurvival.138However,elevatedexpressionofglypican-3correlateswithreducedcancercelldifferentiationandthepresenceoflymphnodemetastasesinlungcancer.139,140Glypican-5overexpressionalsopromotestumorprogressionandmetastasisinsalivaryadenoidcysticcarcinomaandinrhabdosarcoma.141,142,143Serglycinisanintracellularproteoglycanthatisexpressedbyhematopoieticcells.Itsexpressiondrivescancergrowthandmetastasis.144SerglycininducesEMTandchemoresistance,aswellasenhancesthebiosynthesisofproteolyticenzymesthataidinECMremodeling.145Inbreastcancer,serglycinactivatesCD44/CREB1signalingtoenhancethesecretionoftransforminggrowthfactor-β(TGF-β2)andEMT.146Innon-SCLCandhead-and-neckcancers,serglycinactivatesCD44/NF-κB/claudin-1cellsandmitogen-activatedproteinkinase(MAPK)/β-cateninsignalingtodriveEMTandchemoresistance.147,148SerglycininhibitionrestrictsthedevelopmentofmetastasisthroughdecreasedexpressionofchemokinessuchasCCL2.149Serglycinoverexpressioncontrolsthesecretionoftumor-derivedexosomesandtheirabilitytotriggercancercellinvasionandmetastasis.150Hyaluronicacid(HA)isaglycosaminoglycanthatisaprincipalconstituentofthetumorstromaandcancercellsurfaces.ItisanimportantEMTmediatorandmetastaticcancersexpressincreasedlevelsofHA,itsCD44receptor,anditssynthaseinthetumorcellmicroenvironment,151particularlyinbreast,oral,prostate,andovariancancers.152,153HA-mediatedEMTenhancementisdrivenbytheexpressionofzincfingerE-box-bindinghomeobox1(ZEB1)anditsinteractionwithCD44,whichinturnactivatesHAsynthase2(HAS2)expression.154HAS2expressionregulatesTGFβ-inducedEMT155throughtheexpressionoffibronectin,snail1,andZEB1.HAS2hasalsobeenshowntobevitalforthecommunicationbetweencancerstemcellsandtumor-associatedmacrophages(TAMs).156Thisinteractionleadstoenhancedsecretionofplatelet-derivedgrowthfactor-BBfromTAMs,whichactivatesstromalcellsandrejuvenatescancerstemcells.156InhibitingHAS2activityvia4-methylumbelliferonelimitsHAsynthesisandpreventsmetastasisinseveralcancermodels.156,157,158,159ThestrikingeffectofHAontumorprogressionishighlyassociatedwithitsmolecularweightandinteractionswithotherproteinsintheECM.160,161Lowmolecularweight(LMW)HAhaswell‐establishedtumorigenicproprieties.161,162Inbreastcancer,decreasingLMW‐HAproductionsignificantlyinhibitscancercellmigrationandinvasion.163Moreover,excessLMW‐HAinthetumormicroenvironmentfacilitateslymphaticmetastasisviadisruptionofintercellularadhesionamonglymphaticendothelialcells.164Inaddition,inthetumorinterstitialfluidofcolorectalcancerpatients,LMW‐HAconcentrationsareincreasedandassociatedwithlymphaticvesselinvasionbycancercells,andthedevelopmentoflymphnodemetastases.160Altogether,theECMisacomplexanddynamicsystemthatiscomposedofawidespectrumofcellsandmatrikinesthatparticipateininvasionandmetastasis.Howdoesautophagycontributetocancercellinvasion?Autophagy,theautophagosomal–autolysosomalprocess,isinitiatedbytheadvancementofvarioushumancancerstometastasis.Invivostudiesshowthatautophagyisinvolvedinmodulatingtumorcellmotilityandinvasion,cancerstemcellviabilityanddifferentiation,resistancetoanoikis,EMT,metastaticcelldormancy,andescapefromimmunesurveillance,withdevelopingfunctionsinformingthePMNandothermetastaticfacets.165Autophagyinhibitiondoesnotaffectcellviability,proliferation,ormigrationbutsignificantlyreducescellularinvasion.166Itwassuggestedthatmembrane-traffickingmayplayacriticalroleinthebenign-to-malignanttransitionthatisalsocentraltotheinitiationofmetastasis.166Canneuronsinitiatemetastasis?Ithasalwaysbeenpuzzlinghownervesemergeinthetumormicroenvironmentandwhattheirrolemightbe.Neuralprogenitorsfromthecentralnervoussystemthatexpressdoublecortininfiltrateprostatetumorsandmetastases.167Theseprogenitorsinitiateneurogenesis,whichistheprocessbywhichneuronsareproducedfromneuralstemcells.168Thesenervefibersinthetumormicroenvironmentregulatecancerinitiationanddissemination,providinginsightsintohowdoublecortin-expressingneuronscanbetargetedfortherapy.Doestheimmuneenvironmentattheprimarysiteplayaroleinmetastasis?Theimmunemicroenvironmentaroundthetumorplaysamajorroleindictatingthemetastaticpotentialofthedisseminatingcells.Astudyanalyzedtumorsfrommorethan800peoplewithcolorectalcancer,comparingpeoplewhosetumorsweremetastaticwiththosewhowerenot.35Theprimarytumorsfrombothgroupshadanalogousmutationpatternsincancergenes;however,tumorsthathadmetastasizedhadfewercytotoxicTcells.35Inaddition,theinvasiveendsofthespreadtumorcellshadreduceddensitiesoflymphaticvesselsthatcarryimmunecells.35SuchchangescontributetometastasisandsuggestthatimmunotherapiesthatenhanceT-cellresponsescanstopmetastasisinpeoplewithearly-stagecancer.169Moreover,silencingtheIFNregulatoryfactor(Irf)-7pathwayhelpsmetastaticcellstoescapeimmunesurveillance.170Infact,asubstantialnumberofgenesthataresuppressedinbonemetastasesaretargetsofIrf7andrestorationofIrf7intumorcellsoradministrationofIFNledtodecreasedbonemetastasesandlongersurvivaltime.170InmicethataredeficientintheIFNreceptororinNKandCD8(+)T-cellresponses,metastasiswasfaster,indicatingthatIrf7-drivensuppressionofmetastasisdependsonIFNsignalingtohostimmunecells.170,171Cansurgicalinterventioncontributetometastaticdissemination?Sometimes,disseminatedcancercellssurviveandretaintheabilitytoinvadeevenaftertheremovaloftheprimarytumor.Often,patientswithpancreaticductaladenocarcinomadeveloplivermetastasesfollowingsurgicalexcisionoftheprimarytumor.172Metastasispossiblyarisesfromdormantdisseminatedcancercellsthatevadeeliminationbytheimmunesystemandarepresentatthetimeofsurgery.172AnalyzingmousemodelsandtissuesamplesfrompatientswithpancreaticductaladenocarcinomashowedthatdormantdisseminatedcancercellsdonotexpressacellsurfacemoleculethatelicitsT-cell-mediatedattacks.172Thisphenotypeisrelatedtotheirinabilitytorelieveendoplasmicreticulumstress.172Whenthisstressislifted,disseminatedcellsstartmultiplyingandinvadingtoformmetastases.172Anestheticsduringsurgeryalsohaveanunderlyingmechanisminpromotingmetastaticdissemination.Inmurinemodelsofbreastcancer,sevofluraneledtosignificantlyincreasedlungmetastasiscomparedwiththatofpropofol.173Interestingly,sevofluraneincreasedinterleukin(IL)-6levels,whichinturnledtosignaltransducerandactivatoroftranscription(STAT)-3activationandthesubsequentinfiltrationofmyeloidcellsintothelung.173Byalteringthetumormicroenvironmentthroughcytokines,anestheticscanpromotecancermetastasis.IntravasationIntravasation,thedisseminationofcancercellstoorgansthroughthelumenofthevasculature,ismediatedactivelyorpassively.12,174Thisdependsonthetumortype,microenvironment,andvasculature.175Athree-dimensionalmicrofluidicmodelshowsthattheendotheliumposesabarriertotumorcellintravasationandisregulatedbyfactorsthatarepresentinthetumormicroenvironment.176Usinglive-cellfluorescencemicroscopyandatissue-engineeredtumor-microvesselplatform,amitosis-mediatedmechanismwherebytumorcellslocatedalongthevesselperipherydisruptthevesselendotheliumthroughcelldivisionanddetachintocirculationwaselucidated.177Furthermore,thearchitecturalconstraintsoftissueimposesomemechanicalpressuresoninvadingtumorcellsduringintravasation.178Nuclearsqueezingisparticularlychallengingontheintegrityofthenucleusoftheinvadedcell.Thiscausesgenomicrearrangementtooccur,whichincreasesthemetastaticpotential.178Integrinsarethekeycellularadhesionreceptorsthatareinvolvedinnearlyeverystepofcancerprogressionfromprimarytumordevelopmenttometastasis.179Alteredintegrinexpressionisfrequentlydetectedintumors,whereintegrinshaverolesinsupportingoncogenicgrowthfactorreceptor(GFR)signalingandGFR-dependentcancercellmigrationandinvasion.179Furthermore,integrinsregulatethecolonizationprocessinmetastaticlocationsbyeasinganchorage-independentsurvivalofcirculatingtumorcells(CTCs).MetastaticcellsuseE-cadherininmetastaticsitestodetach,disseminate,andseed.180Thispromotesmetastaticcellsurvivalandblocksreactiveoxygen-mediatedapoptosis.180Assuch,inhibitingE-cadherininmetastaticbreastcancercellsmayholdtherapeuticpotentialagainstbreastcancer.180CirculationHowdotumorcellssurviveincirculation?Thecirculatoryjourneyisharshformostintravasatingcancercells.InteractionsbetweenCTCsandthemicroenvironmentalcomponentsofcirculationdeterminesurvivalandtheabilityofCTCstoeventuallyextravasateindistantsites.181,182,183MostCTCscirculateassinglecells,whereasotherstravelinclusters(Fig.4).However,circulatingclustersaremuchmorelikelytoformmetastases.184Inadditiontotheinvadingcancercells,clusterscontainstromalcellsandimmunecomponentsfromtheoriginalmicroenvironmentthatcontributetotheheterogeneityoftheclusterandenhanceitssurvival.184,185,186,187,188Neutrophilsparticipateinclusterformationandsuppressleukocyteactivation,whichincreasesthechancesofCTCsurvival.189Moreover,theinteractionofCTCswithplateletsleadstotheformationofacoatingshieldofplateletsaroundcancercellsthatpreventsCTCdetectionbyimmunecellsandprovidesthestructureneededtobearthephysicalstressesofcirculation.190,191,192Fig.4Cancercellscirculateassingleunitsorinclusters.Afterarrestingatsecondarysitesorbecomingstuckincapillaries,circulatingtumorcells(CTCs)extravasateandcolonizetheirnewniches.SomecellsundergodormancyasanadaptationmechanismtothenewstressfulenvironmentFullsizeimageAnimportantfactorinthemetastaticprocessistheabilityofCTCstoadhereandextravasatethroughendothelialcellsandcolonizethePMN.193AssoonasCTCsarrestincapillaries,theyeitherextravasatebytransendothelialmigrationorgrowwithinthevesselbeforeeventualextravasationandcolonizationofthePMN.194,195,196,197Docirculatingtumorcellsinteractwithimmunecells?CTCsmustadapttothestrictselectiveenvironmentpresentinthelumenofthevasculature.ThedisseminationofCTCsissupportedbycloseassociationwithactivatedplateletsandmacrophages.198Therefore,CTCsformheteroaggregatesthatsustainadhesiontotheendotheliumandthuscontributetometastasis.190However,thisbeliefhasbeenchallengedbyshowingthatanincreaseinmegakaryocytesconferssomemeasureofprotectionagainstmetastasis.199Inaddition,neutrophilsincirculationhavebeenfoundtoinhibitmetastasis.6,200Bloodsamplingin70womenwithadvanced-stagebreastcancershowedaCTC–immunecellassociation.201Thewhitebloodcellsthatshowedthegreatestinteractionwereneutrophils,suggestingthatneutrophilclusteringwithCTCsincreasesthemetastaticpotentialofCTCs.201TheadvancementofthediseaseinpeoplewithadvancedbreastcancerwasfasteramongindividualswhohadCTC–neutrophilclusterswhencomparedwiththatofpeoplewholackedsuchclusters.201Furthermore,CTCsfrombothCTC–neutrophilclustersandothersthathadnotbeenpartofaneutrophilclusterwereinjectedintothebloodstreamoftumor-freemice.AsubstantiallyincreasednumberofmetastaseswerefoundinthemicethatreceivedCTCsfromCTC–neutrophilclusters.Inaddition,upontheeradicationofneutrophilsinmicewithbreasttumors,thenumberofCTC–neutrophilclusterswasmarkedlydecreased.201Thesemicehaddelayedmetastasesinthelungswhencomparedwiththoseofmicebearingbreasttumorsthatdidnothavetheirneutrophilsdepleted.201Moreover,thecomplexinterchangebetweencancercellsandwhitebloodcellsfacilitatesmetastasis,becausemetastaticcellspossesssugarontheircellsurfacethatbindstogalectin-3.202Thisenhancestheabilityofcellstocolonizebyinteractingwithmobilizedwhitebloodcells.202ResistingvascularforcesandmechanicalpressureThejourneyofCTCsinthebloodvesselsisnoteasy.CTCssenseandrespondtotissuemechanicsandinstigatebrieforlastingtissuealterations,includingECMstiffening,compressionanddeformation,proteinunfolding,proteolyticremodeling,andjammingtransitions.203MechanicalpressuresarelikelytobefoundduringarrestofCTCsatdistantsites,whenexitingvessels(extravasation),andduringmetastaticgrowth.Permissiveflowregimensinvascularregions,inadditiontothelocationandefficiencyofCTClodgingatdistantsites,playlargerolesinthedistantmetastasisprocess.204ThepassageofCTCsthroughthebloodstreamishaltedwhentheiradhesivecapacitybecomesgreaterthantheshearforcesimposedonthembythebloodflow.204Therefore,regionswithlowhemodynamicflowaretheregionswheremostCTCsstabilizeandengagewithendothelialcells.ItisinsuchregionsthatsingleCTCsmightsequentiallyformintravascularclusters.205OnceCTCsarefixedinthemicrovasculature,theyarefragmentedbytheflowofblood.Thisgeneratesimmune-interactingintermediatemoleculesthatpromoteextravasationanddevelopmetastasesfromthesurvivingCTCs.206,207Thishypothesiswasfurthertestedinacohortof100patientswithbrainmetastasesandfoundthatthesemetastasesformedinregionswithlowcerebralbloodflow.204Therefore,shearforcesplayanimportantroleinhematogenousmetastasisandindeterminingthelocationofthefinalarrest.Howdoesthereleaseofchemokinesandcytokineshelpcirculatingtumorcells?Themigrationofmetastaticcellsincirculationoftenreliesonaspectrumofchemokinesandcomplementcomponentsthatdirecttumorcellsthroughthevasculature208,209andmetabolicfactorsthatresultinanantioxidanteffect.210Granulocytemacrophagecolony-stimulatingfactorandcytokinessuchasIL-5,whichareinducedinobesity,leadtolungneutrophiliainobesemiceandaidinbreastcancermetastasis.211Inaddition,whencrowded,cancercellsboosttheproductionofIL-6andIL-8,twoimmunemoleculesthatstimulatebiochemicalpathwaysandfacilitatetumormigration.212Inmousebreastcancermodels,blockingIL-6andIL-8receptorsthroughexperimentaltreatmentsminimizedmetastasisatlymphnodes,lungs,andlivercomparedwiththoseofthecontrolgroups.212FurtherdatasuggestthatmetastatictumorsinducethereleaseofIL-1β,whichinducesgammadelta(γδ)TcellstoreleaseIL-17,suppressingcytotoxicCD8+Tlymphocytesandpromotingmetastasis.213Inaddition,thelossofTP53incancercellsinducesthesecretionofWNTligandsthatstimulatetheproductionofIL-1β,thusdrivingprometastaticneutrophilicinflammation.214Istumorcellcirculationcontingentontherouteofthebloodstream?ItisnowacceptedthatCTCscanexploitandsurviveinthebloodstreamduringtumormetastasis.204,207However,CTCshavealsobeenfoundtocausedistantmetastasesthroughthelymphaticcirculation.215,216,217The“sequentialprogressionmodel”isthebasisforexcisionoftumor-draininglymphnodesduringsurgery.215Metastaticcancercellscantravelfromaprimarytumortoadistantsiteviatwocourses:directlythroughthebloodstreamorthroughalymphnodeneartheprimarycancersite.218Thebiologicalmechanismsbywhichtumorcellssurviveandgrowwithinlymphnodesarenotyetclear.Inmurinemodels,cancercellsacclimatizetothelymphnodemicroenvironmentbyshiftingtheirmetabolismtofattyacidoxidation.218Thesignalingpathwayonwhichtheadaptationprocessisbasedisdrivenandactivatedbytheyes-associatedprotein(YAP)transcriptionfactor.218Notably,inhibitionoffattyacidoxidationorYAPsignalingblockedlymphnodemetastasisinmice.218Diagnosticsincirculation:wherearewenow?EnrichmentofCTCsallowedtheirclassificationandsubsequenttumoranalysis.219CTCcharacterizationhelpsreflectonthemolecularfoundationsofmetastatictumors,whereascell-freeDNA(cfDNA)offersnewgeneticmaterialforfurtherexplorationintrials.220cfDNAreflectstheheterogeneityofCTCsinpatientswithhighcountsofCTCsandthusenablesmonitoringofthemetastaticburdenforclinicaldecision-making.221Inaddition,cfDNAprofilingtracksthesubclonalnatureofcancermetastasis.222Assuch,liquidbiopsyofCTCsand/orcfDNAintheperipheralbloodmighthavethepotentialtofurtherthecurrentunderstandingofmetastasisbiology.219However,itisworthwhiletoponderwhethercurrentlyusedtechniquesforenrichmentanddetectionofCTCsallowustoidentifyactualmetastasis‐initiatingcellsandwhetherliquidbiopsycanbeusedtoinvestigatetheeffectivenessofcancertreatment.Targetingcirculatingtumorcells:canitbedone?Foralongtime,thelowsensitivityofCTCdetectionassayshashaltedCTCelimination.Inaddition,theexclusionofpatientswithmetastasisfromclinicaltrialspreventedfasterprogress.223However,advancementsinthefieldhavechangedthereigningparadigmandofferedhopeforfuturesuccess.Aphotoacousticmethodfordirectuseinpatientswithmelanomahasbeendeveloped,allowingforthedetectionofverylownumbersofCTCsinvivoandtheirsubsequentdestructionwithlaserpulses.224Thisreflectsthetherapeuticpotentialofsuchapproaches.Inaddition,distinctDNAmethylationprofilesarepresentamongCTCclustersfrompatientsandmurinemodelswithbreastcancerwhencomparedwiththatofsingleCTCs.225This,alongwiththephenotypicdifferences,canbetargetedinfuturetherapeuticoptions.ExtravasationHowdocirculatingtumorcellsextravasate?WhenCTCspassthroughsmallcapillaries,theybecomeentrapped.Thiseitherleadstomicrovascularruptureorforcesthecelltoundergoextravasation.3Asorganssuchastheliverandbonehavehighlypermeablesinusoidalvessels,CTCsexhibitahighrateofmetastasisintheseorgans.12Inotherorgans,extravasatingcellsarefacedwithtightbarriersandbasementmembranesthatrequiregeneticandmolecularmediationtobeabletotransmigrate.Extravasationisacomplexprocessthatinvolvesligand–receptorinteractions,chemokines,andcirculatingnontumorcells.174,226,227Integrins,again,playavitalroleindeterminingthesitesatwhichextravasationandcolonizationoccurbyfacilitatinganchorage-independentsurvivalofCTCs.179Manyhavereportedthatcancercellextravasationoccursinasimilarfashiontoleukocytetransendothelialmigration.174,228,229Inrecentyears,ithasbeenshownthatcancercellsinduceprogrammednecrosisofendothelialcells,drivingmetastaticcellstoextravasate.Treatmentwiththereceptor-interactingserine/threonine-proteinkinase(RIPK)-1-inhibitornecrostatin-1orendothelial-cell-specificdeletionofRIPK3reducedendothelialnecroptosisandmetastaticextravasation.230Arecirculatingtumorcellstarget-specific?OrganotropismwasfirsttoucheduponbyPagetaspartofthe“seedandsoil”hypothesis.231Breastcancerresearchhassupportedthishypothesis,232,233withresearcherselucidatingthegeneticbasisforcancercolonizationindistantorgans.234Moreover,thehostmicroenvironmentandtheadaptiveprocessthatinvadingcancercellsundergoplayaroleinextravasationandcolonizationofcancercellsatspecificsites.235Forexample,breastcancermostfrequentlymetastasizestothebone,oftenafterlonglatency,suggestingthatmetastaticseedsareresistanttotherapyandcanregrow(Fig.5).Calciumflux,forinstance,hasbeenidentifiedasamechanismofcrosstalkbetweentheosteogenicnicheandcancercells,whichpromotestheprogressionofbonemetastasis.236Anotherexampleinvolvespatientswithpostpartumbreastcancer,whoareatelevatedriskforlivermetastasis.237Theidentificationofthe“weaning-inducedliverinvolution,”whichestablishesametastaticmicroenvironment,mayaccount,inpart,forthepoorprognosisofpatientswithpostpartumbreastcancer.237Fig.5MetastastaticOrganotropism:Clinicalobservationssuggestthatmostcancersmetastasizetospecifictargetorgans,aprocessknownas“metastaticorganotropism”FullsizeimageColonizationHowdoesthecolonizingcellovercomestromalchallenges?Circulatingcellsthatextravasateatthetargetsitearechallengedwithharshconditionsthatmakesurvivaldifficult.22Anumberofsecretedtumor-derivedfactorsandbonemarrow-derivedcellssignaltheformationofthePMN,inwhichthetumorcellscolonizeandgrow.12,238,239,240Inadditiontotumor-derivedfactors,exosomesplayamajorrole(discussedearlier).Exosomeshavearoleineducatingbonemarrowprogenitorcellstobecomemetastatic.240Furtherresearchshowedsimilarresultsinpancreaticcancer,wherebyexosomesinitiatedPMNformationintheliver.73However,cancercell–hostcellinteractionsarealsoimportantforpropercolonization.Hepatocytescontrolmyeloidcellaccumulationandfibrosiswithintheliverandthusincreasethesusceptibilityofthelivertometastaticcolonization.Inmurinemodelsofpancreaticcancer,hepatocytesinduceIL-6-mediatedSTAT3signalingandincreasesecretionofserumamyloidA1andA2(SAA).InhibitionofIL-6-STAT3-SAAsignalingpreventstheestablishmentofaPMNandinhibitslivermetastasis.241Establishingavascularnetworkiscrucialforpropermetastaticcolonization.VascularmimicrydrivestheabilityofsomebreastcancercellstocontributetodistantmetastasesthroughtheoverexpressionofSERPINE2andSLPI.242Thesetwogenesareoverexpressedpreferentiallyinhumanpatientswithbreastcancerlungmetastases,suggestingtheirpotentialformetastaticprogression.242Colonizingcancercellsarealsocapableofutilizingneuronalsignalingpathwaysforgrowthandadaptation.TheproximityofbreastcancercellstoneuronalsynapsesallowscancercellstohijackN-methyl-d-aspartatereceptorsignalingtopromotebrainmetastasis.243Protocadherin7isaproteinthatpromotestheassemblyofcancercell–astrocytegapjunctionscomposedofconnexin43.MetastaticcancercellsusethesejunctionstotransferthesecondmessengercGAMPtoastrocytes,activatingthestimulatorofinterferongenespathwayandproducinginflammatorycytokinessuchasIFNαandtumornecrosisfactor.Inturn,thesefactorsactivateSTAT1andNF-κBpathwaysinbrainmetastaticcells,therebysupportingtumorgrowthandchemoresistance.244Dormancy:whydocancercellsgotosleep?Bydefinition,cancerdormancyisanarrestphaseincancerprogressionthatoccursduringtheprimarytumorformationphaseorafterinvasionintosecondarysites.245Metastaticdormancyspecificallyoccursduetothedelayedacclimatizationofdisseminatingcancercellstotheirsecondaryniches246andaffectssingleinvadingcellsorcancerclustersaftercirculation.Inmanycancersurvivors,dormantcancercellsarepresentlongafterradicalremovaloftheprimarytumorandarethoughttoberesponsibleforlaterelapses.246Dormancyconstitutesquiescence,angiogenicdormancyinwhichanequilibriumisrealizedbetweendividinganddying(vascular-lacking)cancercells,andimmune-mediateddormancyinwhichthetumormassispreservedbyimmunecellcytotoxicity.12,247SomebelievethatthetargetorganmicroenvironmentinstructsCTCstoenterdormancy,whereasothersthinkthatprimarytumorspre-encodeadormancysignatureonCTCsthatonlybecomesevidentwhenCTCsenterthehostmicroenvironment.AnotherpotentialexplanationisthatearlydisseminationspawnsCTCsthatrespondtodormancy-inducingsignalsandenterdormancyintargetorgans.248Whatarethemechanismsthatgoverndormancy?Regulationoftumorcelldormancyinvolvesreciprocalcrosstalkbetweentheenvironmentandmechanismsthatcontroltranscriptionalprograms.249Single-celldormancydescribesthereversiblestateofquiescencethatthemetastaticcellentersinresponsetostressfulstimuli,whileexpressingtheKi67proliferationmarker.245Metabolichomeostasisismaintainedinthedormantstatethroughthedownregulationoftwoofthemostwell-studiedpathwaysthatareactivatedduringoncogenesis,theRAS–MEK–ERK/MAPKandPI3K-AKTsignalingcascades,whichplaycriticalrolesingoverningcancercelldormancy.250FactorssecretedbythePMN,suchasmesenchymalcell‐derivedbonemorphogeneticproteins(BMPs)andgrowtharrest‐specific6producedbyosteoblasts,alsoshiftcancercellstowardsdormancy.251,252BMP7activatesthemetastaticsuppressorgeneN‐mycdownstream‐regulatedgene1(NDGR1),leadingtoanincreaseinp38MAPKactivation,cellcycleinhibitorp21expression,andcellcyclearrest.251Molecularinteractionsbetweenmitogen‐andstress‐inducedsignalingarevitalinregulatingthedormancy/activationstateofmetastaticcancercells.Theratioofextracellularsignal‐regulatedkinase(ERK1/2)top38MAPKregulatesthecellcycle.HighlevelsofERK1/2activityfavorproliferation,whereashighlevelsofp38favordormancy.Increasedp38MAPKactivitytriggerstheactivationoftheunfoldedproteinresponse,whichupregulatesactivatingtranscriptionfactor6,thuspromotingcellarrestandsurvival.253,254Theseobservationssupportthenotionthattheactivationofstresssignalingpathwaysinducesasustainedstateofquiescencethatislinkedtodormancy(Fig.6).Fig.6Dormancyandreactivationofcancercells:Thegeneticandsignalingpathwaysthatgoverncancercelldormancyandsubsequentreactivationinvolveintracellularsignaling,extracellularsignaling,andinductionsignalsoriginatingfromthebonemarrownicheFullsizeimageHowdoesdormancyoccurinmetastaticclusters?Dormancyinmetastaticcancerclustersoccurswhentherateofcellularproliferationwithintheclusterisequaltotherateofapoptosis.Assuch,thetumorclusterdoesnotexpandintomicrometastasis.Thisbalanceisachievedthroughsuppressivegenesignaling,restrictedangiogenesis,and/oranactiveimmunemicroenvironment.245Suppressivegenesignalingcanbeachievedthroughtheinductionofdifferentiallyexpressedinchondrocytes2(DEC2),atumorsuppressorgene.TGFβinducesDEC2,whichinhibitscyclin-dependentkinase4andactivatesp27,forcingthecelltoenterastateofquiescence.255Blockingbloodvesselformationthroughactivationofthrombospondin-1256orthroughtheinhibitionofchaperones,suchasheatshock27 kDaprotein,pushesmetastaticclustersintoadormantstate.257Theimmunesystemisalsoamajorfactorincancerantiproliferation.TcellsandNKcells,inadditiontomacrophages,clearmetastaticcellsthroughcytolysis.258Dormanttumorcellsexpressweakantigenstoescapetheimmunesystem,whichcouldbethereasonbehindrelapsefollowingimmunotherapy.249Fromdormancytoactivation:howdoesthedormantcellwakeup?Researchershavebeguntounderstandtheprocessthatallowscertaincancercellstobecomedormantforperiodsoftimeandemergelaterwithrecurringdisease.ThesecancercellsenterastateoflatencyandslowdivisionbyinhibitingaWNTprotein-drivensignalingpathway.246Inaddition,thesecellsexhibitincreasedlevelsofthestemcellgenesSRY-box(SOX)-2andSOX9,whichallowforthegrowthofnewtumorsifcertainconditionsexist.Toreducetheabilityoftheimmunesystemtoidentifythem,thesedormantcancercellsdownregulatetheexpressionofimmunecell-recognizablemolecules.246Thisallowstumorcellstoevadeanimmuneresponseuntilconditionsallowthedevelopmentofmetastasis.Persistenthostorganinflammationandthecomplementaryestablishmentofneutrophilicextracellulartrapsmaytransformdormantcancercellsintoaggressivemetastases.259Othersbelievethattheshiftfromdormancytoactivationoccurswithrespecttoorganotropism,3indicatingthatthehostmicroenvironmentplaysaroleinwakingthecellsfromtheirdormantstate.260Moreimportantly,ithasbeenestablishedthathighlevelsofERK1/2withrespecttop38MAPKpromotereactivation.CancercellplasticityandtumorprogressionCancercellplasticityfacilitatesthedevelopmentoftherapyresistanceandmalignantprogression.Plasticitybestowsuponcancercellstheabilitytodynamicallyswitchbetweenadifferentiatedstate,withlimitedtumorigenicpotential,andanundifferentiatedorcancerstem-likecellstate,whichisresponsibleforlong-termtumorgrowth.However,researchersremainhopefulthatcancercellplasticitycanbeexploitedtherapeutically.SomehaveforcedthetransdifferentiationofEMT-derivedbreastcancercellsintopost-mitoticandfunctionaladipocytesbyusingacombinationtherapyofMEKinhibitorsandtheantidiabeticdrugrosiglitazone,therebyinhibitingthemetastaticprocess.261Genome-wideinvivoscreenscanidentifynovelhostregulatorsofmetastaticcolonization.Invivostudieshaveidentifiedmultiplegenesthat,whendisrupted,modifytheabilityoftumorcellstoestablishmetastases.262Often,endovascularprogenitorcellsfunctionasprecursorsofendothelialcells.263TheseprogenitorcellsexpressthetranscriptionfactorSOX18andarethusunaffectedbytherapiesthattargetvascularendothelialgrowthfactor.ByablatingNotchsignaling,SOX18isinhibited,whichsubsequentlyhaltsmelanomametastasisinmurinemodels.263Inmanyinstances,glucocorticoidsareusedtotreatpatientswithcancer-relatedcomplications.Theprogressionofbreastcancerisinitiatedbyincreasingstresshormoneandglucocorticoidlevels,whichsubsequentlyactivatessecondarysiteglucocorticoidreceptors,enhancescancercolonization,anddecreasessurvivalrates.202Thissuggeststheuseofcautionwhentreatingcancerpatientswithglucocorticoidtherapy.Despitethedisplayedeffectivenessofcytotoxicchemotherapyintreatinginvasivebreastcancer,ithasbeenshownthatthetreatmentdisplaysprometastaticeffects.264Paclitaxelanddoxorubicintriggertheproductionoftumor-derivedextracellularvesiclesinmodelsofchemoresistantbreastcancerinmice.264Thesevesiclesfacilitatethecolonizationoftumorsatmetastaticsitesinthelungs.264SuppressingthesuppressorMetastasissuppressorsinhibitcancergrowthandproliferationatthemetastaticsitewithoutaffectingtheprimarytumor.265,266Theytargetoncogenicpathwaysandproteinsthatareinvolvedininvasionandeventualmetastaticcolonization.Forexample,A-kinaseanchorprotein8isasplicingregulatoryfactorthatsuppressesEMTandbreastcancermetastasis.267Inhighlymetastaticcells,metastasissuppressorsareusuallydownregulatedincomparisonwithprimarytumorcells.265,268,269Inthepastdecade,asignificantnumberofmetastasissuppressorshavebeenidentified(Fig.7).Mostnotably,miRNAsthatsuppressoncogenesandinhibittumorigenicsignalinghavebeenrecognizedandexploredaspotentialbiomarkersandtargetsofmetastasis.265,270,271,272,273,274,275,276,277,278,279,280,281,282,283,284,285,286,287,288,289,290,291,292,293Fig.7Metastasissuppressorgenesthathavebeenidentifiedintheliterature:Metastasissuppressorshaltmetastaticproliferationatthesecondarysitewithoutchangingtheprimarycancer.TheyworkthroughoncogenicsignalingpathwaystosuppressinvasionandeventualcolonizationFullsizeimageTherapeuticstrategiestotargetthepathwaysofmetastasisThefieldofmetastasisresearchismorethan100yearsold.However,metastasisremainstheprimarycauseofcancer-relateddeaths.Majorobstacleslieinthelackofclinicaltrialsthattargetmetastasisandthelackofknowledgeofthebiologicalunderpinningsthatgovernthemetastaticprocess.169,171,220,223Designingtargetedtherapiesformetastaticcancercellsshouldtakeintoaccountthegeneticandphenotypicdifferencesbetweenparentalandmetastatic/circulatingcells.294Today,thediagnosisofmetastaticcancercontinuestobeassociatedwithaterminallabel.Althoughpreventionofmetastasishasbeendemonstratedpreclinically,drugdevelopmenthasbeenhinderedduetopoortrialdesignandtherapeuticstrategies.Advancementsinimmunotherapyhaveimprovedsurvivalandpatientoutcomesinmetastaticmelanoma.295,296Inaddition,thedevelopmentofnovelandrogenreceptorinhibitorsextendedthesurvivalofmetastaticprostatecancer.297However,long-termfollow-upshavefailedtodemonstrateconsistencyinthesurvivalbenefitsofpatientswithmetastaticbreastcancer.298Strategiesthattargetpathwaysinthemetastaticcascadehavebeenstudiedandexplored.294Theseedingofcancercellscanbetargetedbyinhibitingintratumoralinteractions,intercellularcrosstalkthroughECMadhesionmolecules,thereleaseofproteases,EMT,andintravasation.However,atthetimeofmetastasisdiagnosis,cancercellsmayhavealreadyseededinthecirculatorysystemorcolonizedadistantsite.220Therefore,targetingmetastaticcolonizationseemstobethemostplausibletherapeuticstrategy,asitcorrelatesmostlywiththeclinicalscene.Dormancyhasalsobeenstudiedasapotentialtargetofmetastaticcolonization.Somehaveproposedtherapiesthathelpsustainthedormantstate.299OthershavedesignedcombinationtreatmentsthattargetG0tumorcells.Moreover,monoclonalantibodieshavebeendevelopedtotargetsinglecancercellsatthisstage.300InadditiontoCTCs(discussedearlier),thediagnosticandpredictivepotentialofexosomesrendersthemkeyforliquidbiopsies.220,301Intermsoftargetingtumor-secretedfactors,exosomeaffinityplasmapheresishasbeendevelopedtotrapexosomeswithimmunosuppressiveortumorigenicmaterial(NCT02439008);however,thetrialhasbeenterminatedduetoalackofpatientaccrual.Thebraincontinuestobeaspecialsiteformetastasis,ascolonizingcellsareofferedasafehaventhroughtheexistenceoftheblood–brainbarrier(BBB).TheBBBallowsthecrossingoftumorcellsandpreventsthepassageoftherapeuticagents.302Therefore,agentsthatareknowntocrosstheBBBmustbetestedinbrainmetastasissettingsandnovelagentswiththeabilitytocrosstheBBBmustbedesigned.223Overall,metastasisisacomplexchallengethatrequiresmorethanonetherapeuticagentforeffectiveinhibition.Therefore,embracingthecombinationtherapymodelandtargetingmultiplepathwayssimultaneouslyseemstobekeytocounteringthesignificantgenomicandphenotypicalterationspresentedbymetastaticcancercells.303ConcludingremarksMetastasisisthefinalfrontierincancerforwhichmoreefficacioustherapiesareneeded.However,thedevelopmentofeffectivetreatmentsiscontingentuponunderstandingtheunderpinningsthatgovernthemetastaticprocessfromstarttofinish.Assuch,exploringmetastaticevolutionisnecessarytobeabletodesignbettertherapeuticsinthefuture. ReferencesLuzzi,K.J.etal.Multistepnatureofmetastaticinefficiency:dormancyofsolitarycellsaftersuccessfulextravasationandlimitedsurvivalofearlymicrometastases.Am.J.Pathol.153,865–873(1998).CAS  PubMed  PubMedCentral  Article  GoogleScholar  Maitra,A.Molecularenvoyspavethewayforpancreaticcancertoinvadetheliver.Nature567,181–182(2019).CAS  PubMed  Article  PubMedCentral  GoogleScholar  Massague,J.&Obenauf,A.C.Metastaticcolonizationbycirculatingtumourcells.Nature529,298–306(2016).CAS  PubMed  PubMedCentral  Article  GoogleScholar  Hanahan,D.&Weinberg,R.A.Hallmarksofcancer:thenextgeneration.Cell144,646–674(2011).CAS  Article  GoogleScholar  Steeg,P.S.Tumormetastasis:mechanisticinsightsandclinicalchallenges.Nat.Med.12,895–904(2006).CAS  PubMed  Article  PubMedCentral  GoogleScholar  Lambert,A.W.,Pattabiraman,D.R.&Weinberg,R.A.Emergingbiologicalprinciplesofmetastasis.Cell168,670–691(2017).CAS  PubMed  PubMedCentral  Article  GoogleScholar  Bakhoum,S.F.etal.ChromosomalinstabilitydrivesmetastasisthroughacytosolicDNAresponse.Nature553,467(2018).CAS  PubMed  PubMedCentral  Article  GoogleScholar  Tabassum,D.P.&Polyak,K.Tumorigenesis:ittakesavillage.Nat.Rev.Cancer15,473–483(2015).CAS  PubMed  Article  PubMedCentral  GoogleScholar  Gundem,G.etal.Theevolutionaryhistoryoflethalmetastaticprostatecancer.Nature520,353(2015).CAS  PubMed  PubMedCentral  Article  GoogleScholar  Clark,A.G.&Vignjevic,D.M.Modesofcancercellinvasionandtheroleofthemicroenvironment.Curr.Opin.CellBiol.36,13–22(2015).CAS  PubMed  Article  GoogleScholar  Cheung,K.J.&Ewald,A.J.Acollectiveroutetometastasis:seedingbytumorcellclusters.Science352,167–169(2016).CAS  PubMed  Article  GoogleScholar  Fouad,Y.A.&Aanei,C.Revisitingthehallmarksofcancer.Am.J.CancerRes.7,1016–1036(2017).CAS  PubMed  PubMedCentral  GoogleScholar  Ye,X.&Weinberg,R.A.Epithelial-mesenchymalplasticity:acentralregulatorofcancerprogression.TrendsCellBiol.25,675–686(2015).CAS  PubMed  PubMedCentral  Article  GoogleScholar  Knott,S.R.V.etal.Asparaginebioavailabilitygovernsmetastasisinamodelofbreastcancer.Nature.554,378–381(2018).Nieto,M.A.,Huang,R.Y.J.,Jackson,R.A.&Thiery,J.P.Emt:2016.Cell166,21–45(2016).CAS  PubMed  Article  GoogleScholar  Katsuno,Y.,Lamouille,S.&Derynck,R.TGF-betasignalingandepithelial-mesenchymaltransitionincancerprogression.Curr.Opin.Oncol.25,76–84(2013).CAS  PubMed  Article  GoogleScholar  DeCraene,B.&Berx,G.RegulatorynetworksdefiningEMTduringcancerinitiationandprogression.Nat.Rev.Cancer13,97–110(2013).PubMed  Article  CAS  GoogleScholar  Pastushenko,I.etal.IdentificationofthetumourtransitionstatesoccurringduringEMT.Nature556,463(2018).CAS  PubMed  Article  GoogleScholar  Erdogan,B.etal.Cancer-associatedfibroblastspromotedirectionalcancercellmigrationbyaligningfibronectin.J.CellBiol.216,3799–3816(2017).CAS  PubMed  PubMedCentral  Article  GoogleScholar  Rankin,E.B.&Giaccia,A.J.Hypoxiccontrolofmetastasis.Science352,175–180(2016).CAS  PubMed  PubMedCentral  Article  GoogleScholar  Lamouille,S.,Xu,J.&Derynck,R.Molecularmechanismsofepithelial-mesenchymaltransition.Nat.Rev.Mol.CellBiol.15,178–196(2014).CAS  PubMed  PubMedCentral  Article  GoogleScholar  Valastyan,S.&Weinberg,R.A.Tumormetastasis:molecularinsightsandevolvingparadigms.Cell147,275–292(2011).CAS  PubMed  PubMedCentral  Article  GoogleScholar  Fischer,K.R.etal.Epithelial-to-mesenchymaltransitionisnotrequiredforlungmetastasisbutcontributestochemoresistance.Nature527,472–476(2015).CAS  PubMed  PubMedCentral  Article  GoogleScholar  Zheng,X.F.etal.Epithelial-to-mesenchymaltransitionisdispensableformetastasisbutinduceschemoresistanceinpancreaticcancer.Nature527,525(2015).CAS  PubMed  PubMedCentral  Article  GoogleScholar  Diepenbruck,M.&Christofori,G.Epithelial-mesenchymaltransition(EMT)andmetastasis:yes,no,maybe?Curr.Opin.CellBiol.43,7–13(2016).CAS  PubMed  Article  GoogleScholar  Esposito,M.etal.BonevascularnicheE-selectininducesmesenchymal-epithelialtransitionandWntactivationincancercellstopromotebonemetastasis.Nat.CellBiol.21,627–639(2019).CAS  PubMed  PubMedCentral  Article  GoogleScholar  Lawson,D.A.etal.Tumourheterogeneityandmetastasisatsingle-cellresolution.Nat.CellBiol.20,1349–1360(2018).CAS  PubMed  PubMedCentral  Article  GoogleScholar  Van’tVeer,L.J.etal.Geneexpressionprofilingpredictsclinicaloutcomeofbreastcancer.Nature415,530(2002).Article  GoogleScholar  Ramaswamy,S.,Ross,K.N.,Lander,E.S.&Golub,T.R.Amolecularsignatureofmetastasisinprimarysolidtumors.Nat.Genet.33,49–54(2003).CAS  PubMed  Article  GoogleScholar  Hunter,K.,Welch,D.R.&Liu,E.T.Geneticbackgroundisanimportantdeterminantofmetastaticpotential.Nat.Genet.34,23(2003).CAS  PubMed  Article  PubMedCentral  GoogleScholar  Robinson,D.R.etal.Integrativeclinicalgenomicsofmetastaticcancer.Nature548,297–303(2017).CAS  PubMed  PubMedCentral  Article  GoogleScholar  Birkbak,N.J.&McGranahan,N.Cancergenomeevolutionarytrajectoriesinmetastasis.CancerCell.37,8–19(2020).PubMed  Article  PubMedCentral  GoogleScholar  Yang,D.etal.IntertumoralheterogeneityinSCLCisinfluencedbythecelltypeoforigin.CancerDiscov.8,1316–1331(2018).CAS  PubMed  PubMedCentral  Article  GoogleScholar  Ganesh,K.etal.L1CAMdefinestheregenerativeoriginofmetastasis-initiatingcellsincolorectalcancer.Nat.Cancer1,28–45(2020).Article  GoogleScholar  Mlecnik,B.etal.ThetumormicroenvironmentandImmunoscorearecriticaldeterminantsofdisseminationtodistantmetastasis.SciTranslMed.8,327ra26(2016).PubMed  Article  CAS  PubMedCentral  GoogleScholar  Carnero,A.&Lleonart,M.Thehypoxicmicroenvironment:adeterminantofcancerstemcellevolution.Bioessays38(Suppl1),S65–S74(2016).PubMed  Article  PubMedCentral  GoogleScholar  Ratcliffe,P.J.Oxygensensingandhypoxiasignallingpathwaysinanimals:theimplicationsofphysiologyforcancer.J.Physiol.591,2027–2042(2013).CAS  PubMed  PubMedCentral  Article  GoogleScholar  Semenza,G.L.Oxygensensing,hypoxia-induciblefactors,anddiseasepathophysiology.Annu.Rev.Pathol.9,47–71(2014).CAS  PubMed  Article  PubMedCentral  GoogleScholar  Harris,A.L.Hypoxia–akeyregulatoryfactorintumourgrowth.Nat.Rev.Cancer2,38–47(2002).CAS  PubMed  Article  PubMedCentral  GoogleScholar  Garcia-Heredia,J.M.,Felipe-Abrio,B.,Cano,D.A.&Carnero,A.Geneticmodificationofhypoxiasignalinginanimalmodelsanditseffectoncancer.Clin.Transl.Oncol.17,90–102(2015).CAS  PubMed  Article  PubMedCentral  GoogleScholar  Semenza,G.L.VHLandp53:tumorsuppressorsteamuptopreventcancer.Mol.Cell.22,437–439(2006).CAS  PubMed  Article  PubMedCentral  GoogleScholar  Semenza,G.L.Cancer-stromalcellinteractionsmediatedbyhypoxia-induciblefactorspromoteangiogenesis,lymphangiogenesis,andmetastasis.Oncogene32,4057–4063(2013).CAS  PubMed  Article  PubMedCentral  GoogleScholar  Hockel,M.etal.Tumoroxygenation:anewpredictiveparameterinlocallyadvancedcanceroftheuterinecervix.Gynecol.Oncol.51,141–149(1993).CAS  PubMed  Article  PubMedCentral  GoogleScholar  Brizel,D.M.etal.Tumoroxygenationpredictsforthelikelihoodofdistantmetastasesinhumansofttissuesarcoma.CancerRes.56,941–943(1996).CAS  PubMed  PubMedCentral  GoogleScholar  Noman,M.Z.etal.CrosstalkbetweenCTC,immunesystemandhypoxictumormicroenvironment.CancerMicroenviron.7,153–160(2014).CAS  PubMed  PubMedCentral  Article  GoogleScholar  Tasdogan,A.etal.Metabolicheterogeneityconfersdifferencesinmelanomametastaticpotential.Nature577,115–120(2020).CAS  PubMed  Article  PubMedCentral  GoogleScholar  Papalazarou,V.etal.Thecreatine–phosphagensystemismechanoresponsiveinpancreaticadenocarcinomaandfuelsinvasionandmetastasis.Nat.Metab.2,62–80(2020).Article  GoogleScholar  Peinado,H.etal.Pre-metastaticniches:organ-specifichomesformetastases.Nat.Rev.Cancer17,302–317(2017).CAS  Article  GoogleScholar  Zomer,A.etal.Invivoimagingrevealsextracellularvesicle-mediatedphenocopyingofmetastaticbehavior.Cell161,1046–1057(2015).CAS  PubMed  PubMedCentral  Article  GoogleScholar  Cancer-celltransferfilmed.Nature521,396–396(2015).https://www.nature.com/articles/521396d.Weidle,U.H.,Birzele,F.,Kollmorgen,G.&Ruger,R.Themultiplerolesofexosomesinmetastasis.CancerGenomicsProteom.14,1–15(2017).CAS  Article  GoogleScholar  Tickner,J.A.etal.Functionsandtherapeuticrolesofexosomesincancer.FrontOncol.4,127(2014).PubMed  PubMedCentral  Article  GoogleScholar  Harris,D.A.etal.Exosomesreleasedfrombreastcancercarcinomasstimulatecellmovement.PLoSONE10,e0117495(2015).PubMed  PubMedCentral  Article  CAS  GoogleScholar  Singh,R.etal.Exosome-mediatedtransferofmiR-10bpromotescellinvasioninbreastcancer.Mol.Cancer13,256(2014).CAS  PubMed  PubMedCentral  Article  GoogleScholar  Higginbotham,J.N.etal.Amphiregulinexosomesincreasecancercellinvasion.Curr.Biol.21,779–786(2011).CAS  PubMed  PubMedCentral  Article  GoogleScholar  McCready,J.,Sims,J.D.,Chan,D.&Jay,D.G.Secretionofextracellularhsp90alphaviaexosomesincreasescancercellmotility:aroleforplasminogenactivation.BMCCancer10,294(2010).PubMed  PubMedCentral  Article  CAS  GoogleScholar  Fu,H.,Yang,H.,Zhang,X.&Xu,W.Theemergingrolesofexosomesintumor-stromainteraction.J.CancerResClin.Oncol.142,1897–1907(2016).CAS  PubMed  Article  PubMedCentral  GoogleScholar  Soung,Y.H.etal.Emergingrolesofexosomesincancerinvasionandmetastasis.BMBRep.49,18–25(2016).CAS  PubMed  PubMedCentral  Article  GoogleScholar  Goubran,H.A.etal.Regulationoftumorgrowthandmetastasis:theroleoftumormicroenvironment.CancerGrowthMetastasis.7,9–18(2014).CAS  PubMed  PubMedCentral  Article  GoogleScholar  Syn,N.etal.Exosome-mediatedmetastasis:fromepithelial-mesenchymaltransitiontoescapefromimmunosurveillance.TrendsPharm.Sci.37,606–617(2016).CAS  PubMed  Article  PubMedCentral  GoogleScholar  Aga,M.etal.ExosomalHIF1alphasupportsinvasivepotentialofnasopharyngealcarcinoma-associatedLMP1-positiveexosomes.Oncogene33,4613–4622(2014).CAS  PubMed  PubMedCentral  Article  GoogleScholar  You,Y.etal.Matrixmetalloproteinase13-containingexosomespromotenasopharyngealcarcinomametastasis.CancerSci.106,1669–1677(2015).CAS  PubMed  PubMedCentral  Article  GoogleScholar  Franzen,C.A.etal.Urothelialcellsundergoepithelial-to-mesenchymaltransitionafterexposuretomuscleinvasivebladdercancerexosomes.Oncogenesis4,e163(2015).CAS  PubMed  PubMedCentral  Article  GoogleScholar  Jeppesen,D.K.etal.QuantitativeproteomicsoffractionatedmembraneandlumenexosomeproteinsfromisogenicmetastaticandnonmetastaticbladdercancercellsrevealdifferentialexpressionofEMTfactors.Proteomics14,699–712(2014).CAS  PubMed  Article  PubMedCentral  GoogleScholar  Escrevente,C.,Keller,S.,Altevogt,P.&Costa,J.Interactionanduptakeofexosomesbyovariancancercells.BMCCancer11,108(2011).CAS  PubMed  PubMedCentral  Article  GoogleScholar  Tarbe,N.etal.Identificationofratpancreaticcarcinomagenesassociatedwithlymphogenousmetastasis.AnticancerRes.22,2015–2027(2002).CAS  PubMed  PubMedCentral  GoogleScholar  Mu,W.,Rana,S.&Zoller,M.Hostmatrixmodulationbytumorexosomespromotesmotilityandinvasiveness.Neoplasia15,875–887(2013).PubMed  PubMedCentral  Article  CAS  GoogleScholar  Fabbri,M.etal.MicroRNAsbindtoToll-likereceptorstoinduceprometastaticinflammatoryresponse.Proc.NatlAcad.Sci.USA109,E2110–E2116(2012).CAS  PubMed  Article  PubMedCentral  GoogleScholar  Ye,S.-betal.Tumor-derivedexosomespromotetumorprogressionandT-celldysfunctionthroughtheregulationofenrichedexosomalmicroRNAsinhumannasopharyngealcarcinoma.Oncotarget5,5439(2014).PubMed  PubMedCentral  Article  GoogleScholar  Clayton,A.etal.CancerexosomesexpressCD39andCD73,whichsuppressTcellsthroughadenosineproduction.J.Immunol.187,676–683(2011).CAS  PubMed  Article  PubMedCentral  GoogleScholar  Peinado,H.etal.Melanomaexosomeseducatebonemarrowprogenitorcellstowardapro-metastaticphenotypethroughMET.Nat.Med.18,883(2012).CAS  PubMed  PubMedCentral  Article  GoogleScholar  Hood,J.L.,San,R.S.&Wickline,S.A.Exosomesreleasedbymelanomacellspreparesentinellymphnodesfortumormetastasis.CancerRes.71,3792–3801(2011).CAS  PubMed  Article  PubMedCentral  GoogleScholar  Costa-Silva,B.etal.Pancreaticcancerexosomesinitiatepre-metastaticnicheformationintheliver.Nat.CellBiol.17,816–826(2015).CAS  PubMed  PubMedCentral  Article  GoogleScholar  Hoshino,A.etal.Tumourexosomeintegrinsdetermineorganotropicmetastasis.Nature527,329–335(2015).CAS  PubMed  PubMedCentral  Article  GoogleScholar  Yue,S.,Mu,W.,Erb,U.&Zöller,M.ThetetraspaninsCD151andTspan8areessentialexosomecomponentsforthecrosstalkbetweencancerinitiatingcellsandtheirsurrounding.Oncotarget6,2366(2015).PubMed  PubMedCentral  GoogleScholar  Luga,V.etal.ExosomesmediatestromalmobilizationofautocrineWnt-PCPsignalinginbreastcancercellmigration.Cell151,1542–1556(2012).CAS  PubMed  Article  PubMedCentral  GoogleScholar  Smyth,T.J.,Redzic,J.S.,Graner,M.W.&Anchordoquy,T.J.Examinationofthespecificityoftumorcellderivedexosomeswithtumorcellsinvitro.Biochim.Biophys.Acta1838,2954–2965(2014).CAS  PubMed  PubMedCentral  Article  GoogleScholar  Zoller,M.Tetraspanins:pushandpullinsuppressingandpromotingmetastasis.Nat.Rev.Cancer9,40–55(2009).PubMed  Article  CAS  PubMedCentral  GoogleScholar  Nanbo,A.,Kawanishi,E.,Yoshida,R.&Yoshiyama,H.ExosomesderivedfromEpstein-Barrvirus-infectedcellsareinternalizedviacaveola-dependentendocytosisandpromotephenotypicmodulationintargetcells.J.Virol.87,10334–10347(2013).CAS  PubMed  PubMedCentral  Article  GoogleScholar  Mulcahy,L.A.,Pink,R.C.&Carter,D.R.Routesandmechanismsofextracellularvesicleuptake.J.Extracell.Vesicles.3(2014).Zhang,L.etal.Microenvironment-inducedPTENlossbyexosomalmicroRNAprimesbrainmetastasisoutgrowth.Nature527,100–104(2015).CAS  PubMed  PubMedCentral  Article  GoogleScholar  Kaur,A.etal.Remodelingofthecollagenmatrixinagingskinpromotesmelanomametastasisandaffectsimmunecellmotility.CancerDiscov.9,64–81(2019).CAS  PubMed  Article  PubMedCentral  GoogleScholar  Ecker,B.L.etal.Age-relatedchangesinHAPLN1increaselymphaticpermeabilityandaffectroutesofmelanomametastasis.CancerDiscov.9,82–95(2019).CAS  PubMed  Article  PubMedCentral  GoogleScholar  Flavahan,W.A.,Gaskell,E.&Bernstein,B.E.Epigeneticplasticityandthehallmarksofcancer.Science.357,pii:eaal2380(2017).Helmink,B.A.etal.Themicrobiome,cancer,andcancertherapy.Nat.Med.25,377–388(2019).CAS  PubMed  Article  PubMedCentral  GoogleScholar  Pushalkar,S.etal.Thepancreaticcancermicrobiomepromotesoncogenesisbyinductionofinnateandadaptiveimmunesuppression.CancerDiscov.8,403–416(2018).CAS  PubMed  PubMedCentral  Article  GoogleScholar  Cronin,M.etal.Orallyadministeredbifidobacteriaasvehiclesfordeliveryofagentstosystemictumors.Mol.Ther.18,1397–1407(2010).CAS  PubMed  PubMedCentral  Article  GoogleScholar  Panebianco,C.,Andriulli,A.&Pazienza,V.Pharmacomicrobiomics:exploitingthedrug-microbiotainteractionsinanticancertherapies.Microbiome6,92(2018).PubMed  PubMedCentral  Article  GoogleScholar  Lehouritis,P.etal.Localbacteriaaffecttheefficacyofchemotherapeuticdrugs.Sci.Rep.5,14554(2015).CAS  PubMed  PubMedCentral  Article  GoogleScholar  Geller,L.T.etal.Potentialroleofintratumorbacteriainmediatingtumorresistancetothechemotherapeuticdruggemcitabine.Science357,1156–1160(2017).CAS  PubMed  PubMedCentral  Article  GoogleScholar  Alexander,J.L.etal.Gutmicrobiotamodulationofchemotherapyefficacyandtoxicity.Nat.Rev.Gastroenterol.Hepatol.14,356–365(2017).CAS  PubMed  Article  PubMedCentral  GoogleScholar  Yu,T.etal.Fusobacteriumnucleatumpromoteschemoresistancetocolorectalcancerbymodulatingautophagy.Cell170,548–563e516(2017).CAS  PubMed  PubMedCentral  Article  GoogleScholar  Zheng,J.H.etal.Two-stepenhancedcancerimmunotherapywithengineeredSalmonellatyphimuriumsecretingheterologousflagellin.Sci.Transl.Med.9,pii:eaak9537(2017).Kim,O.Y.etal.Bacterialoutermembranevesiclessuppresstumorbyinterferon-gamma-mediatedantitumorresponse.Nat.Commun.8,626(2017).PubMed  PubMedCentral  Article  CAS  GoogleScholar  Panda,A.etal.ImmuneactivationandbenefitfromAvelumabinEBV-positivegastriccancer.J.NatlCancerInst.110,316–320(2018).CAS  PubMed  Article  PubMedCentral  GoogleScholar  Host,K.M.etal.Kaposi’ssarcoma-associatedherpesvirusincreasesPD-L1andproinflammatorycytokineexpressioninhumanmonocytes.mBio8,e00917–e00917(2017).CAS  PubMed  PubMedCentral  Article  GoogleScholar  Smola,S.ImmunopathogenesisofHPV-associatedcancersandprospectsforimmunotherapy.Viruses.9,pii:E254(2017).ThieleOrberg,E.etal.ThemyeloidimmunesignatureofenterotoxigenicBacteroidesfragilis-inducedmurinecolontumorigenesis.MucosalImmunol.10,421–433(2017).CAS  PubMed  Article  PubMedCentral  GoogleScholar  Gur,C.etal.BindingoftheFap2proteinofFusobacteriumnucleatumtohumaninhibitoryreceptorTIGITprotectstumorsfromimmunecellattack.Immunity42,344–355(2015).CAS  PubMed  PubMedCentral  Article  GoogleScholar  Masri,S.&Sassone-Corsi,P.Theemerginglinkbetweencancer,metabolism,andcircadianrhythms.Nat.Med.24,1795–1803(2018).CAS  PubMed  PubMedCentral  Article  GoogleScholar  Lie,J.-A.S.,Roessink,J.&Kjaerheim,K.BreastcancerandnightworkamongNorwegiannurses.CancerCausesControl.17,39–44(2006).PubMed  Article  PubMedCentral  GoogleScholar  Papantoniou,K.etal.Nightshiftwork,chronotypeandprostatecancerriskintheMCC-Spaincase-controlstudy.IntJ.Cancer137,1147–1157(2015).CAS  PubMed  Article  PubMedCentral  GoogleScholar  Schernhammer,E.S.etal.Rotatingnightshiftsandriskofbreastcancerinwomenparticipatinginthenurses’healthstudy.J.NatlCancerInst.93,1563–1568(2001).CAS  PubMed  Article  PubMedCentral  GoogleScholar  Knutsson,A.etal.Breastcanceramongshiftworkers:resultsoftheWOLFlongitudinalcohortstudy.Scand.J.WorkEnviron.Health39,170–177(2013).Article  GoogleScholar  Straif,K.etal.Carcinogenicityofshift-work,painting,andfire-fighting.LancetOncol.8,1065–1066(2007).PubMed  Article  GoogleScholar  Kakizaki,M.etal.Sleepdurationandtheriskofprostatecancer:theOhsakiCohortStudy.Br.J.Cancer99,176–178(2008).CAS  PubMed  PubMedCentral  Article  GoogleScholar  Srour,B.etal.Circadiannutritionalbehavioursandcancerrisk:NewinsightsfromtheNutriNet-santeprospectivecohortstudy:disclaimers.Int.J.Cancer143,2369–2379(2018).CAS  PubMed  Article  PubMedCentral  GoogleScholar  Altman,B.J.etal.MYCdisruptsthecircadianclockandmetabolismincancercells.CellMetab.22,1009–1019(2015).CAS  PubMed  PubMedCentral  Article  GoogleScholar  Huber,A.L.etal.CRY2andFBXL3cooperativelydegradec-MYC.Mol.Cell.64,774–789(2016).CAS  PubMed  PubMedCentral  Article  GoogleScholar  Shostak,A.etal.MYC/MIZ1-dependentgenerepressioninverselycoordinatesthecircadianclockwithcellcycleandproliferation.Nat.Commun.7,11807(2016).CAS  PubMed  PubMedCentral  Article  GoogleScholar  Pascual,G.etal.Targetingmetastasis-initiatingcellsthroughthefattyacidreceptorCD36.Nature541,41–45(2017).CAS  PubMed  Article  GoogleScholar  Karamanos,N.K.etal.Proteoglycanchemicaldiversitydrivesmultifunctionalcellregulationandtherapeutics.Chem.Rev.118,9152–9232(2018).CAS  PubMed  Article  GoogleScholar  Frantz,C.,Stewart,K.M.&Weaver,V.M.Theextracellularmatrixataglance.J.CellSci.123,4195–4200(2010).CAS  PubMed  PubMedCentral  Article  GoogleScholar  Theocharis,A.D.,Skandalis,S.S.,Gialeli,C.&Karamanos,N.K.Extracellularmatrixstructure.Adv.DrugDeliv.Rev.97,4–27(2016).CAS  PubMed  Article  GoogleScholar  Maquart,F.-X.etal.Anintroductiontomatrikines:extracellularmatrix-derivedpeptideswhichregulatecellactivity:implicationintumorinvasion.Crit.Rev.Oncol.Hematol.49,199–202(2004).PubMed  Article  PubMedCentral  GoogleScholar  Sonnenschein,C.&Soto,A.M.Carcinogenesisexplainedwithinthecontextofatheoryoforganisms.Prog.Biophys.Mol.Biol.122,70–76(2016).CAS  PubMed  PubMedCentral  Article  GoogleScholar  Maffini,M.V.etal.Thestromaasacrucialtargetinratmammaryglandcarcinogenesis.J.CellSci.117,1495–1502(2004).CAS  PubMed  Article  GoogleScholar  Barcellos-Hoff,M.H.&Ravani,S.A.Irradiatedmammaryglandstromapromotestheexpressionoftumorigenicpotentialbyunirradiatedepithelialcells.CancerRes.60,1254–1260(2000).CAS  PubMed  GoogleScholar  Guerra,L.,Odorisio,T.,Zambruno,G.&Castiglia,D.StromalmicroenvironmentintypeVIIcollagen-deficientskin:Thegroundforsquamouscellcarcinomadevelopment.MatrixBiol.63,1–10(2017).CAS  PubMed  Article  GoogleScholar  Iozzo,R.V.&Gubbiotti,M.A.Extracellularmatrix:thedrivingforceofmammaliandiseases.MatrixBiol.71,1–9(2018).PubMed  Article  CAS  GoogleScholar  Curran,S.&Murray,G.I.Matrixmetalloproteinases:molecularaspectsoftheirrolesintumourinvasionandmetastasis.Eur.J.Cancer36,1621–1630(2000).CAS  PubMed  Article  GoogleScholar  Kessenbrock,K.,Plaks,V.&Werb,Z.Matrixmetalloproteinases:regulatorsofthetumormicroenvironment.Cell141,52–67(2010).CAS  PubMed  PubMedCentral  Article  GoogleScholar  Moss,L.A.S.,Jensen-Taubman,S.&Stetler-Stevenson,W.G.Matrixmetalloproteinaseschangingrolesintumorprogressionandmetastasis.Am.J.Pathol.181,1895–1899(2012).CAS  Article  GoogleScholar  Egeblad,M.&Werb,Z.Newfunctionsforthematrixmetalloproteinasesincancerprogression.Nat.Rev.Cancer2,161–174(2002).CAS  PubMed  Article  GoogleScholar  Hadler-Olsen,E.,Winberg,J.O.&Uhlin-Hansen,L.Matrixmetalloproteinasesincancer:theirvalueasdiagnosticandprognosticmarkersandtherapeutictargets.TumorBiol.34,2041–2051(2013).CAS  Article  GoogleScholar  Elia,I.etal.Breastcancercellsrelyonenvironmentalpyruvatetoshapethemetastaticniche.Nature568,117(2019).CAS  PubMed  PubMedCentral  Article  GoogleScholar  Du,W.W.etal.TheroleofversicanG3domaininregulatingbreastcancercellmotilityincludingeffectsonosteoblastcellgrowthanddifferentiationinvitro-evaluationtowardsunderstandingbreastcancercellbonemetastasis.BMCCancer12,341(2012).CAS  PubMed  PubMedCentral  Article  GoogleScholar  Du,W.W.etal.VersicanG3promotesmousemammarytumorcellgrowth,migration,andmetastasisbyinfluencingEGFreceptorsignaling.PLoSONE5,e13828(2010).PubMed  PubMedCentral  Article  CAS  GoogleScholar  Cattaruzza,S.etal.NG2/CSPG4-collagentypeVIinterplaysputativelyinvolvedinthemicroenvironmentalcontroloftumourengraftmentandlocalexpansion.J.Mol.CellBiol.5,176–193(2013).CAS  PubMed  PubMedCentral  Article  GoogleScholar  Iida,J.etal.Cellsurfacechondroitinsulfateglycosaminoglycaninmelanoma:roleintheactivationofpro-MMP-2(pro-gelatinaseA).BiochemJ.403,553–563(2007).CAS  PubMed  PubMedCentral  Article  GoogleScholar  Karamanou,K.etal.Lumicaneffectivelyregulatestheestrogenreceptors-associatedfunctionalpropertiesofbreastcancercells,expressionofmatrixeffectorsandepithelial-to-mesenchymaltransition.Sci.Rep.7,45138(2017).CAS  PubMed  PubMedCentral  Article  GoogleScholar  Nikitovic,D.etal.Lumican,asmallleucine-richproteoglycan.IUBMBLife.60,818–823(2008).CAS  PubMed  Article  PubMedCentral  GoogleScholar  Brézillon,S.,Pietraszek,K.,Maquart,F.X.&Wegrowski,Y.Lumicaneffectsinthecontroloftumourprogressionandtheirlinkswithmetalloproteinasesandintegrins.FEBSJ.280,2369–2381(2013).PubMed  Article  CAS  PubMedCentral  GoogleScholar  Pietraszek,K.etal.Lumican:anewinhibitorofmatrixmetalloproteinase-14activity.FEBSLett.588,4319–4324(2014).CAS  PubMed  Article  PubMedCentral  GoogleScholar  Stasiak,M.etal.LumicaninhibitsSNAIL-inducedmelanomacellmigrationspecificallybyblockingMMP-14activity.PLoSONE11,e0150226(2016).PubMed  PubMedCentral  Article  CAS  GoogleScholar  Pietraszek-Gremplewicz,K.etal.Smallleucine-richproteoglycansandmatrixmetalloproteinase-14:Keypartners?MatrixBiol.75-76,271–285(2019).CAS  PubMed  Article  PubMedCentral  GoogleScholar  Filmus,J.&Capurro,M.TheroleofglypicansinHedgehogsignaling.MatrixBiol.35,248–252(2014).CAS  PubMed  Article  PubMedCentral  GoogleScholar  Han,S.etal.IdentificationofGlypican-3asapotentialmetastasissuppressorgeneingastriccancer.Oncotarget7,44406–44416(2016).PubMed  PubMedCentral  GoogleScholar  Lin,Q.etal.ExpressionofGPC3proteinanditssignificanceinlungsquamouscellcarcinoma.Med.Oncol.29,663–669(2012).CAS  PubMed  Article  PubMedCentral  GoogleScholar  Yu,X.etal.Differentialexpressionofglypican-3(GPC3)inlungsquamouscellcarcinomaandlungadenocarcinomaanditsclinicalsignificance.GenetMol.Res.14,10185–10192(2015).CAS  PubMed  Article  PubMedCentral  GoogleScholar  Zhang,Y.etal.TheroleofGPC5inlungmetastasisofsalivaryadenoidcysticcarcinoma.Arch.Oral.Biol.59,1172–1182(2014).CAS  PubMed  Article  PubMedCentral  GoogleScholar  Williamson,D.etal.Roleforamplificationandexpressionofglypican-5inrhabdomyosarcoma.CancerRes.67,57–65(2007).CAS  PubMed  Article  PubMedCentral  GoogleScholar  Li,F.,Shi,W.,Capurro,M.&Filmus,J.Glypican-5stimulatesrhabdomyosarcomacellproliferationbyactivatingHedgehogsignaling.J.CellBiol.192,691–704(2011).CAS  PubMed  PubMedCentral  Article  GoogleScholar  Korpetinou,A.etal.Serglycinisimplicatedinthepromotionofaggressivephenotypeofbreastcancercells.PLoSONE8,e78157(2013).CAS  PubMed  PubMedCentral  Article  GoogleScholar  Bouris,P.etal.Serglycinpromotesbreastcancercellaggressiveness:Inductionofepithelialtomesenchymaltransition,proteolyticactivityandIL-8signaling.MatrixBiol.74,35–51(2018).CAS  PubMed  Article  PubMedCentral  GoogleScholar  Liu,T.,Zhang,L.,Joo,D.&Sun,S.C.NF-kappaBsignalingininflammation.SignalTransduct.Target.Ther.2,pii:17023(2017).Guo,J.Y.etal.Serglycinintumormicroenvironmentpromotesnon-smallcelllungcanceraggressivenessinaCD44-dependentmanner.Oncogene36,2457–2471(2017).CAS  PubMed  Article  PubMedCentral  GoogleScholar  Chu,Q.etal.ExtracellularserglycinupregulatestheCD44receptorinanautocrinemannertomaintainself-renewalinnasopharyngealcarcinomacellsbyreciprocallyactivatingtheMAPK/beta-cateninaxis.CellDeathDis.7,e2456(2016).PubMed  PubMedCentral  Article  GoogleScholar  Roy,A.etal.Targetingserglycinpreventsmetastasisinmurinemammarycarcinoma.PLoSONE11,e0156151(2016).PubMed  PubMedCentral  Article  CAS  GoogleScholar  Purushothaman,A.etal.Chondroitinsulfateproteoglycanserglycininfluencesproteincargoloadingandfunctionsoftumor-derivedexosomes.Oncotarget8,73723–73732(2017).PubMed  PubMedCentral  Article  GoogleScholar  Passi,A.,Vigetti,D.,Buraschi,S.&Iozzo,R.V.Dissectingtheroleofhyaluronansynthasesinthetumormicroenvironment.FEBSJ.286,2937–2949(2019).CAS  PubMed  Article  PubMedCentral  GoogleScholar  Chanmee,T.,Ontong,P.&Itano,N.Hyaluronan:amodulatorofthetumormicroenvironment.CancerLett.375,20–30(2016).CAS  PubMed  Article  PubMedCentral  GoogleScholar  Zhang,Z.etal.Hyaluronansynthase2expressedbycancer-associatedfibroblastspromotesoralcancerinvasion.J.Exp.Clin.CancerRes.35,181(2016).CAS  PubMed  PubMedCentral  Article  GoogleScholar  Preca,B.T.etal.AnovelZEB1/HAS2positivefeedbacklooppromotesEMTinbreastcancer.Oncotarget8,11530–11543(2017).PubMed  PubMedCentral  Article  GoogleScholar  Porsch,H.etal.EfficientTGFbeta-inducedepithelial-mesenchymaltransitiondependsonhyaluronansynthaseHAS2.Oncogene32,4355–4365(2013).CAS  PubMed  Article  PubMedCentral  GoogleScholar  Okuda,H.etal.HyaluronansynthaseHAS2promotestumorprogressioninbonebystimulatingtheinteractionofbreastcancerstem-likecellswithmacrophagesandstromalcells.CancerRes.72,537–547(2012).CAS  PubMed  Article  PubMedCentral  GoogleScholar  Nagy,N.etal.Hyaluronaninimmunedysregulationandautoimmunediseases.MatrixBiol.78-79,292–313(2019).CAS  PubMed  Article  PubMedCentral  GoogleScholar  Piccioni,F.etal.4-methylumbelliferoneinhibitshepatocellularcarcinomagrowthbydecreasingIL-6productionandangiogenesis.Glycobiology25,825–835(2015).CAS  PubMed  Article  PubMedCentral  GoogleScholar  Yates,T.J.etal.Dietarysupplement4-methylumbelliferone:aneffectivechemopreventiveandtherapeuticagentforprostatecancer.J.NatlCancerInst.107,pii:djv085(2015).Schmaus,A.etal.Accumulationofsmallhyaluronanoligosaccharidesintumourinterstitialfluidcorrelateswithlymphaticinvasionandlymphnodemetastasis.Br.J.Cancer111,559–567(2014).CAS  PubMed  PubMedCentral  Article  GoogleScholar  Caon,I.etal.Revisitingthehallmarksofcancer:Theroleofhyaluronan.Semin.CancerBiol.pii:S1044-579X(19)30042–2(2019).Misra,S.,Hascall,V.C.,Markwald,R.R.&Ghatak,S.Interactionsbetweenhyaluronananditsreceptors(CD44,RHAMM)regulatetheactivitiesofinflammationandcancer.Front.Immunol.6,201(2015).PubMed  PubMedCentral  Article  CAS  GoogleScholar  Wu,M.etal.Anovelroleoflowmolecularweighthyaluronaninbreastcancermetastasis.FASEBJ.29,1290–1298(2015).CAS  PubMed  Article  GoogleScholar  Du,Y.etal.Low-molecular-weighthyaluronan(LMW-HA)accelerateslymphnodemetastasisofmelanomacellsbyinducingdisruptionoflymphaticintercellularadhesion.Oncoimmunology5,e1232235(2016).PubMed  PubMedCentral  Article  CAS  GoogleScholar  Mowers,E.E.,Sharifi,M.N.&Macleod,K.F.Autophagyincancermetastasis.Oncogene36,1619–1630(2017).CAS  PubMed  Article  PubMedCentral  GoogleScholar  Macintosh,R.L.etal.Inhibitionofautophagyimpairstumorcellinvasioninanorganotypicmodel.CellCycle11,2022–2029(2012).CAS  PubMed  PubMedCentral  Article  GoogleScholar  Mauffrey,P.etal.Progenitorsfromthecentralnervoussystemdriveneurogenesisincancer.Nature569,672–678(2019).CAS  PubMed  Article  PubMedCentral  GoogleScholar  Fares,J.,BouDiab,Z.,Nabha,S.&Fares,Y.Neurogenesisintheadulthippocampus:history,regulation,andprospectiveroles.IntJ.Neurosci.129,598–611(2019).CAS  PubMed  Article  PubMedCentral  GoogleScholar  Fares,J.,Fares,M.Y.&Fares,Y.Immunecheckpointinhibitors:Advancesandimpactinneuro-oncology.Surg.Neurol.Int.10,9(2019).PubMed  PubMedCentral  Article  GoogleScholar  Bidwell,B.N.etal.SilencingofIrf7pathwaysinbreastcancercellspromotesbonemetastasisthroughimmuneescape.Nat.Med.18,1224–1231(2012).CAS  PubMed  Article  PubMedCentral  GoogleScholar  Fares,J.,Fares,M.Y.&Fares,Y.Naturalkillercellsinthebraintumormicroenvironment:defininganewerainneuro-oncology.Surg.Neurol.Int.10,43(2019).PubMed  PubMedCentral  Article  GoogleScholar  Pommier,A.etal.Unresolvedendoplasmicreticulumstressengendersimmune-resistant,latentpancreaticcancermetastases.Science360,1202(2018).CAS  Article  GoogleScholar  Li,R.,Huang,Y.&Lin,J.DistincteffectsofgeneralanestheticsonlungmetastasismediatedbyIL-6/JAK/STAT3pathwayinmousemodels.Nat.Commun.11,642(2020).CAS  PubMed  PubMedCentral  Article  GoogleScholar  Reymond,N.,d’Agua,B.B.&Ridley,A.J.Crossingtheendothelialbarrierduringmetastasis.Nat.Rev.Cancer13,858–870(2013).CAS  PubMed  Article  PubMedCentral  GoogleScholar  Bockhorn,M.,Jain,R.K.&Munn,L.L.Activeversuspassivemechanismsinmetastasis:docancercellscrawlintovessels,oraretheypushed?LancetOncol.8,444–448(2007).CAS  PubMed  PubMedCentral  Article  GoogleScholar  Zervantonakis,I.K.etal.Three-dimensionalmicrofluidicmodelfortumorcellintravasationandendothelialbarrierfunction.Proc.NatlAcad.Sci.USA109,13515–13520(2012).CAS  PubMed  Article  PubMedCentral  GoogleScholar  Wong,A.D.&Searson,P.C.Mitosis-mediatedintravasationinatissue-engineeredtumor-microvesselplatform.CancerRes.77,6453–6461(2017).CAS  PubMed  PubMedCentral  Article  GoogleScholar  Denais,C.M.etal.Nuclearenveloperuptureandrepairduringcancercellmigration.Science352,353–358(2016).CAS  PubMed  PubMedCentral  Article  GoogleScholar  Hamidi,H.&Ivaska,J.Everystepoftheway:integrinsincancerprogressionandmetastasis.Nat.Rev.Cancer18,532–547(2018).Article  CAS  GoogleScholar  Padmanaban,V.etal.E-cadherinisrequiredformetastasisinmultiplemodelsofbreastcancer.Nature573,439–444(2019).CAS  PubMed  Article  PubMedCentral  GoogleScholar  Pantel,K.&Speicher,M.R.Thebiologyofcirculatingtumorcells.Oncogene35,1216–1224(2016).CAS  PubMed  Article  PubMedCentral  GoogleScholar  Gao,H.etal.TheBMPinhibitorCocoreactivatesbreastcancercellsatlungmetastaticsites.Cell150,764–779(2012).CAS  PubMed  PubMedCentral  Article  GoogleScholar  Lu,X.etal.VCAM-1promotesosteolyticexpansionofindolentbonemicrometastasisofbreastcancerbyengagingalpha4beta1-positiveosteoclastprogenitors.CancerCell.20,701–714(2011).CAS  PubMed  PubMedCentral  Article  GoogleScholar  Aceto,N.etal.Circulatingtumorcellclustersareoligoclonalprecursorsofbreastcancermetastasis.Cell158,1110–1122(2014).CAS  PubMed  PubMedCentral  Article  GoogleScholar  Zhang,Y.etal.VN-NDP:aneighbordiscoveryprotocolbasedonvirtualnodesinmobileWSNs.Sensors.19,pii:E4739(2019).Yu,M.etal.Circulatingbreasttumorcellsexhibitdynamicchangesinepithelialandmesenchymalcomposition.Science339,580–584(2013).CAS  PubMed  PubMedCentral  Article  GoogleScholar  Ankrum,J.A.,Ong,J.F.&Karp,J.M.Mesenchymalstemcells:immuneevasive,notimmuneprivileged.Nat.Biotechnol.32,252(2014).CAS  PubMed  PubMedCentral  Article  GoogleScholar  Duda,D.G.etal.Malignantcellsfacilitatelungmetastasisbybringingtheirownsoil.Proc.NatlAcad.Sci.USA107,21677–21682(2010).CAS  PubMed  Article  PubMedCentral  GoogleScholar  Leach,J.,Morton,J.P.&Sansom,O.J.Neutrophils:Hominginonthemyeloidmechanismsofmetastasis.Mol.Immunol.110,69–76(2019).CAS  PubMed  PubMedCentral  Article  GoogleScholar  Gay,L.J.&Felding-Habermann,B.Contributionofplateletstotumourmetastasis.Nat.Rev.Cancer11,123–134(2011).CAS  PubMed  PubMedCentral  Article  GoogleScholar  Placke,T.etal.Platelet-derivedMHCclassIconfersapseudonormalphenotypetocancercellsthatsubvertstheantitumorreactivityofnaturalkillerimmunecells.CancerRes.72,440–448(2012).CAS  PubMed  Article  PubMedCentral  GoogleScholar  Hu,C.etal.Thrombocytosisisasignificantindictorofhypercoagulability,prognosisandrecurrenceingastriccancer.Exp.Ther.Med.8,125–132(2014).PubMed  PubMedCentral  Article  GoogleScholar  Strilic,B.&Offermanns,S.Intravascularsurvivalandextravasationoftumorcells.CancerCell32,282–293(2017).CAS  PubMed  Article  PubMedCentral  GoogleScholar  Leong,H.S.etal.Invadopodiaarerequiredforcancercellextravasationandareatherapeutictargetformetastasis.CellRep.8,1558–1570(2014).CAS  PubMed  Article  PubMedCentral  GoogleScholar  Stoletov,K.etal.Visualizingextravasationdynamicsofmetastatictumorcells.J.CellSci.123,2332–2341(2010).CAS  PubMed  PubMedCentral  Article  GoogleScholar  Schumacher,D.etal.Platelet-derivednucleotidespromotetumor-celltransendothelialmigrationandmetastasisviaP2Y2receptor.CancerCell.24,130–137(2013).CAS  PubMed  Article  PubMedCentral  GoogleScholar  Raskov,H.,Orhan,A.,Salanti,A.&Gögenur,I.Premetastaticniches,exosomesandcirculatingtumorcells:Earlymechanismsoftumordisseminationandtherelationtosurgery.Int.J.Cancer(2019).https://doi.org/10.1002/ijc.32820(inpress).Smith,H.A.&Kang,Y.Themetastasis-promotingrolesoftumor-associatedimmunecells.J.Mol.Med(Berl.).91,411–429(2013).CAS  PubMed  PubMedCentral  Article  GoogleScholar  Jackson,W.etal.Roleofmegakaryocytesinbreastcancermetastasistobone.CancerRes.77,1942–1954(2017).CAS  PubMed  Article  PubMedCentral  GoogleScholar  Granot,Z.etal.Tumorentrainedneutrophilsinhibitseedinginthepremetastaticlung.CancerCell20,300–314(2011).CAS  PubMed  PubMedCentral  Article  GoogleScholar  Szczerba,B.M.etal.Neutrophilsescortcirculatingtumourcellstoenablecellcycleprogression.Nature566,553(2019).CAS  PubMed  Article  PubMedCentral  GoogleScholar  Obradovic,M.M.S.etal.Glucocorticoidspromotebreastcancermetastasis.Nature567,540–544(2019).CAS  PubMed  Article  PubMedCentral  GoogleScholar  vanHelvert,S.,Storm,C.&Friedl,P.Mechanoreciprocityincellmigration.Nat.CellBiol.20,8–20(2018).PubMed  Article  CAS  PubMedCentral  GoogleScholar  Follain,G.etal.Hemodynamicforcestunethearrest,adhesion,andextravasationofcirculatingtumorcells.Dev.Cell.45,33–52e12(2018).CAS  PubMed  Article  PubMedCentral  GoogleScholar  Entenberg,D.etal.Apermanentwindowforthemurinelungenableshigh-resolutionimagingofcancermetastasis.Nat.Methods15,73(2018).CAS  PubMed  Article  PubMedCentral  GoogleScholar  Goetz,J.G.Metastasesgowiththeflow.Science362,999–1000(2018).CAS  PubMed  Article  PubMedCentral  GoogleScholar  Headley,M.B.etal.Visualizationofimmediateimmuneresponsestopioneermetastaticcellsinthelung.Nature531,513–517(2016).CAS  PubMed  PubMedCentral  Article  GoogleScholar  Boire,A.etal.Complementcomponent3adaptsthecerebrospinalfluidforleptomeningealmetastasis.Cell168,1101(2017).CAS  PubMed  PubMedCentral  Article  GoogleScholar  Bonecchi,R.etal.Chemokinesandchemokinereceptors:anoverview.FrontBiosci.Landmrk.14,540–551(2009).CAS  Article  GoogleScholar  LeGal,K.etal.Antioxidantscanincreasemelanomametastasisinmice.Sci.Transl.Med.7,308re8(2015).Quail,D.F.etal.ObesityaltersthelungmyeloidcelllandscapetoenhancebreastcancermetastasisthroughIL5andGM-CSF.Nat.CellBiol.19,974(2017).CAS  PubMed  PubMedCentral  Article  GoogleScholar  Jayatilaka,H.etal.SynergisticIL-6andIL-8paracrinesignallingpathwayinfersastrategytoinhibittumourcellmigration.Nat.Commun.8,15584(2017).Coffelt,S.B.etal.IL-17-producinggammadeltaTcellsandneutrophilsconspiretopromotebreastcancermetastasis.Nature522,345–348(2015).CAS  PubMed  PubMedCentral  Article  GoogleScholar  Wellenstein,M.D.etal.Lossofp53triggersWNT-dependentsystemicinflammationtodrivebreastcancermetastasis.Nature572,538–542,(2019).Naxerova,K.etal.Originsoflymphaticanddistantmetastasesinhumancolorectalcancer.Science357,55–60(2017).CAS  PubMed  PubMedCentral  Article  GoogleScholar  Brown,M.etal.Lymphnodebloodvesselsprovideexitroutesformetastatictumorcelldisseminationinmice.Science359,1408–1411(2018).CAS  PubMed  Article  GoogleScholar  Pereira,E.R.etal.Lymphnodemetastasescaninvadelocalbloodvessels,exitthenode,andcolonizedistantorgansinmice.Science359,1403–1407(2018).CAS  PubMed  PubMedCentral  Article  GoogleScholar  Lee,C.K.etal.TumormetastasistolymphnodesrequiresYAP-dependentmetabolicadaptation.Science363,644(2019).CAS  PubMed  Article  GoogleScholar  Joosse,S.A.,Gorges,T.M.&Pantel,K.Biology,detection,andclinicalimplicationsofcirculatingtumorcells.EMBOMol.Med.7,1–11(2015).CAS  PubMed  Article  GoogleScholar  Fares,J.etal.Diagnosticclinicaltrialsinbreastcancerbrainmetastases:barriersandinnovations.Clin.BreastCancer19,383–391(2019).PubMed  Article  PubMedCentral  GoogleScholar  Shaw,J.A.etal.Mutationanalysisofcell-freeDNAandsinglecirculatingtumorcellsinmetastaticbreastcancerpatientswithhighcirculatingtumorcellcounts.Clin.CancerRes.23,88–96(2017).CAS  PubMed  Article  PubMedCentral  GoogleScholar  Abbosh,C.etal.PhylogeneticctDNAanalysisdepictsearly-stagelungcancerevolution.Nature545,446(2017).CAS  PubMed  PubMedCentral  Article  GoogleScholar  Fares,J.etal.Currentstateofclinicaltrialsinbreastcancerbrainmetastases.Neurooncol.Pract.6,392–401(2019).PubMed  PubMedCentral  GoogleScholar  Galanzha,E.I.etal.InvivoliquidbiopsyusingCytophoneplatformforphotoacousticdetectionofcirculatingtumorcellsinpatientswithmelanoma.Sci.Transl.Med.11,eaat5857(2019).CAS  PubMed  Article  PubMedCentral  GoogleScholar  Gkountela,S.etal.CirculatingtumorcellclusteringshapesDNAmethylationtoenablemetastasisseeding.Cell176,98(2019).CAS  PubMed  PubMedCentral  Article  GoogleScholar  Alix-Panabieres,C.&Pantel,K.ClinicalapplicationsofcirculatingtumorcellsandcirculatingtumorDNAasliquidbiopsy.CancerDiscov.6,479–491(2016).CAS  PubMed  Article  GoogleScholar  Stegner,D.,Dutting,S.&Nieswandt,B.Mechanisticexplanationforplateletcontributiontocancermetastasis.Thromb.Res.133(Suppl2),S149–S157(2014).CAS  PubMed  Article  PubMedCentral  GoogleScholar  Labelle,M.&Hynes,R.O.Theinitialhoursofmetastasis:theimportanceofcooperativehost-tumorcellinteractionsduringhematogenousdissemination.CancerDiscov.2,1091–1099(2012).CAS  PubMed  PubMedCentral  Article  GoogleScholar  Joyce,J.A.&Pollard,J.W.Microenvironmentalregulationofmetastasis.Nat.Rev.Cancer9,239–252(2009).CAS  PubMed  Article  PubMedCentral  GoogleScholar  Strilic,B.etal.Tumour-cell-inducedendothelialcellnecroptosisviadeathreceptor6promotesmetastasis.Nature536,215–218(2016).CAS  Article  GoogleScholar  Langley,R.R.&Fidler,I.J.Theseedandsoilhypothesisrevisited–theroleoftumor-stromainteractionsinmetastasistodifferentorgans.Int.J.Cancer128,2527–2535(2011).CAS  PubMed  PubMedCentral  Article  GoogleScholar  Minn,A.J.etal.Distinctorgan-specificmetastaticpotentialofindividualbreastcancercellsandprimarytumors.J.Clin.Invest.115,44–55(2005).CAS  PubMed  PubMedCentral  Article  GoogleScholar  Lorusso,G.&Ruegg,C.Newinsightsintothemechanismsoforgan-specificbreastcancermetastasis.Semin.CancerBiol.22,226–233(2012).CAS  PubMed  Article  GoogleScholar  Nguyen,D.X.&Massague,J.Geneticdeterminantsofcancermetastasis.Nat.Rev.Genet.8,341–352(2007).CAS  PubMed  Article  PubMedCentral  GoogleScholar  Croucher,P.I.,McDonald,M.M.&Martin,T.J.Bonemetastasis:theimportanceoftheneighbourhood.Nat.Rev.Cancer16,373–386(2016).CAS  PubMed  Article  GoogleScholar  Wang,H.etal.Theosteogenicnicheisacalciumreservoirofbonemicrometastasesandconfersunexpectedtherapeuticvulnerability.CancerCell.34,823(2018).CAS  PubMed  PubMedCentral  Article  GoogleScholar  Goddard,E.T.etal.Therodentliverundergoesweaning-inducedinvolutionandsupportsbreastcancermetastasis.CancerDiscov.7,177–187(2017).CAS  PubMed  Article  PubMedCentral  GoogleScholar  Salvador,F.etal.Lysyloxidase-likeproteinLOXL2promoteslungmetastasisofbreastcancer.CancerRes.77,5846–5859(2017).CAS  PubMed  PubMedCentral  Article  GoogleScholar  Psaila,B.,Kaplan,R.N.,Port,E.R.&Lyden,D.Primingthe‘soil’forbreastcancermetastasis:thepre-metastaticniche.BreastDis.26,65–74(2006).CAS  PubMed  Article  GoogleScholar  Peinado,H.,Lavotshkin,S.&Lyden,D.Thesecretedfactorsresponsibleforpre-metastaticnicheformation:Oldsayingsandnewthoughts.Semin.CancerBiol.21,139–146(2011).CAS  PubMed  Article  PubMedCentral  GoogleScholar  Lee,J.W.etal.Hepatocytesdirecttheformationofapro-metastaticnicheintheliver.Nature567,249–252(2019).CAS  PubMed  PubMedCentral  Article  GoogleScholar  Wagenblast,E.etal.Amodelofbreastcancerheterogeneityrevealsvascularmimicryasadriverofmetastasis.Nature520,358–362(2015).CAS  PubMed  PubMedCentral  Article  GoogleScholar  Zeng,Q.etal.SynapticproximityenablesNMDARsignallingtopromotebrainmetastasis.Nature573,526–531(2019).CAS  PubMed  PubMedCentral  Article  GoogleScholar  Chen,Q.etal.Carcinoma-astrocytegapjunctionspromotebrainmetastasisbycGAMPtransfer.Nature533,493–498(2016).CAS  PubMed  PubMedCentral  Article  GoogleScholar  Gomis,R.R.&Gawrzak,S.Tumorcelldormancy.Mol.Oncol.11,62–78(2017).PubMed  PubMedCentral  Article  CAS  GoogleScholar  Giancotti,F.G.MechanismsgoverningmetastaticdormancyandReactivation.Cell155,750–764(2013).CAS  PubMed  PubMedCentral  Article  GoogleScholar  Sosa,M.S.,Bragado,P.&Aguirre-Ghiso,J.A.Mechanismsofdisseminatedcancercelldormancy:anawakeningfield.Nat.Rev.Cancer14,611–622(2014).CAS  PubMed  PubMedCentral  Article  GoogleScholar  Aguirre-Ghiso,J.A.&Sosa,M.S.Emergingtopicsondisseminatedcancercelldormancyandtheparadigmofmetastasis.Annu,Rev.CancerBiol.2,377–393(2018).Article  GoogleScholar  Sosa,M.S.,Bernstein,E.&Aguirre-Ghiso,J.A.inTumorDormancyandRecurrence(edsYuzhuoWang&FrancescoCrea)1–16(SpringerInternationalPublishing,2017).Yeh,A.C.&Ramaswamy,S.Mechanismsofcancercelldormancy—anotherhallmarkofcancer?CancerRes.75,5014–5022(2015).CAS  PubMed  PubMedCentral  Article  GoogleScholar  Kobayashi,A.etal.Bonemorphogeneticprotein7indormancyandmetastasisofprostatecancerstem-likecellsinbone.J.Exp.Med.208,2641–2655(2011).CAS  PubMed  PubMedCentral  Article  GoogleScholar  Shiozawa,Y.etal.GAS6/AXLaxisregulatesprostatecancerinvasion,proliferation,andsurvivalinthebonemarrowniche.Neoplasia12,116–127(2010).CAS  PubMed  PubMedCentral  Article  GoogleScholar  Aguirre-Ghiso,J.A.etal.UrokinasereceptorandfibronectinregulatetheERKMAPKtop38MAPKactivityratiosthatdeterminecarcinomacellproliferationordormancyinvivo.Mol.Biol.Cell.12,863–879(2001).CAS  PubMed  PubMedCentral  Article  GoogleScholar  Aguirre-Ghiso,J.A.,Estrada,Y.,Liu,D.&Ossowski,L.ERKMAPKactivityasadeterminantoftumorgrowthanddormancy;regulationbyp38SAPK.CancerRes.63,1684–1695(2003).CAS  PubMed  PubMedCentral  GoogleScholar  Bragado,P.etal.TGF-β2dictatesdisseminatedtumourcellfateintargetorgansthroughTGF-β-RIIIandp38α/βsignalling.Nat.CellBiol.15,1351–1361(2013).CAS  PubMed  PubMedCentral  Article  GoogleScholar  Ghajar,C.M.etal.Theperivascularnicheregulatesbreasttumourdormancy.Nat.CellBiol.15,807–817(2013).CAS  PubMed  PubMedCentral  Article  GoogleScholar  Straume,O.etal.Suppressionofheatshockprotein27induceslong-termdormancyinhumanbreastcancer.Proc.NatlAcad.Sci.USA109,8699–8704(2012).CAS  PubMed  Article  PubMedCentral  GoogleScholar  Endo,H.&Inoue,M.Dormancyincancer.CancerSci.110,474–480(2019).CAS  PubMed  PubMedCentral  Article  GoogleScholar  Albrengues,J.etal.Neutrophilextracellulartrapsproducedduringinflammationawakendormantcancercellsinmice.Science361,1353(2018).CAS  Article  GoogleScholar  Gay,L.J.&Malanchi,I.Thesleepingugly:tumourmicroenvironment’sacttomakeorbreakthespellofdormancy.BBARev.Cancer1868,231–238(2017).CAS  GoogleScholar  Ishay-Ronen,D.etal.Gainfat-losemetastasis:convertinginvasivebreastcancercellsintoadipocytesinhibitscancermetastasis.CancerCell.35,17(2019).CAS  PubMed  Article  PubMedCentral  GoogleScholar  vanderWeyden,L.etal.Genome-wideinvivoscreenidentifiesnovelhostregulatorsofmetastaticcolonization.Nature541,233–236(2017).PubMed  PubMedCentral  Article  CAS  GoogleScholar  Donovan,P.etal.Endovascularprogenitorsinfiltratemelanomasanddifferentiatetowardsavarietyofvascularbedspromotingtumormetastasis.Nat.Commun.10,18(2019).Keklikoglou,I.etal.Chemotherapyelicitspro-metastaticextracellularvesiclesinbreastcancermodels.Nat.CellBiol.21,190(2019).CAS  PubMed  Article  PubMedCentral  GoogleScholar  Khan,I.&Steeg,P.S.Metastasissuppressors:functionalpathways.LabInvest.98,198–210(2018).CAS  PubMed  Article  PubMedCentral  GoogleScholar  Shevde,L.A.&Welch,D.R.Metastasissuppressorpathways–anevolvingparadigm.CancerLett.198,1–20(2003).CAS  PubMed  Article  PubMedCentral  GoogleScholar  Hu,X.etal.TheRNA-bindingproteinAKAP8suppressestumormetastasisbyantagonizingEMT-associatedalternativesplicing.Nat.Commun.11,486(2020).CAS  PubMed  PubMedCentral  Article  GoogleScholar  Steeg,P.S.Metastasissuppressorsalterthesignaltransductionofcancercells.Nat.Rev.Cancer3,55–63(2003).CAS  PubMed  Article  PubMedCentral  GoogleScholar  Mao,L.etal.ULK1phosphorylatesExo70tosuppressbreastcancermetastasis.Nat.Commun.11,117(2020).PubMed  PubMedCentral  Article  CAS  GoogleScholar  Li,M.,Cai,O.&Tan,S.LOXL1-AS1drivestheprogressionofgastriccancerviaregulatingmiR-142-5p/PIK3CAaxis.OncoTargetsTher.12,11345–11357(2019).PubMed  PubMedCentral  Article  GoogleScholar  Kong,J.,Shen,S.,Yang,X.&Wang,W.Transhepatic-intrahepaticbranchesoftheportalveincatheterizationforexvivoliverresectionandautotransplantation:twocasereportsofnovelapproachtoperfusetheliver.Medicine98,e14706(2019).PubMed  PubMedCentral  Article  GoogleScholar  Wang,X.,Su,D.,Qin,Z.&Chen,Z.IdentificationofFOXN4asatumorsuppressorofbreastcarcinogenesisviatheactivationofTP53anddeactivationofNotchsignaling.Gene722,144057(2020).CAS  PubMed  Article  PubMedCentral  GoogleScholar  Lu,G.&Zhang,Y.MicroRNA-340-5psuppressesnon-smallcelllungcancercellgrowthandmetastasisbytargetingZNF503.CellMol.Biol.Lett.24,34(2019).PubMed  PubMedCentral  Article  CAS  GoogleScholar  Ablikim,M.etal.Determinationofthepseudoscalardecayconstantf(Ds+)viaDs+→μ+νμ.Phys.Rev.Lett.122,071802(2019).CAS  PubMed  Article  PubMedCentral  GoogleScholar  Liao,X.etal.PartialnephrectomyvscryoablationforT1arenalcellcarcinoma:acomparisonofsurvivalbenefitstratifiedbytumoursize.CancerEpidemiol.59,221–226(2019).PubMed  Article  PubMedCentral  GoogleScholar  Xu,J.etal.Surufatinibinadvancedwell-differentiatedneuroendocrinetumors:amulticenter,single-arm,open-label,phaseIb/IItrial.Clin.CancerRes.25,3486–3494(2019).PubMed  PubMedCentral  GoogleScholar  Yu,M.etal.miR-10bdownregulatedbyDNAmethylationactsasatumorsuppressorinHPV-positivecervicalcancerviatargetingTiam1.Cell.Physiol.Biochem.51,1763–1777(2018).CAS  PubMed  Article  PubMedCentral  GoogleScholar  Huang,B.,Huang,M.&Li,Q.MiR-137suppressesmigrationandinvasionbytargetingEZH2-STAT3signalinginhumanhepatocellularcarcinoma.Pathol.Res.Pract.214,1980–1986(2018).CAS  PubMed  Article  PubMedCentral  GoogleScholar  Zhang,Q.etal.MicroRNA-3619-5psuppressesbladdercarcinomaprogressionbydirectlytargetingbeta-cateninandCDK2andactivatingp21.CellDeathDis.9,960(2018).PubMed  PubMedCentral  Article  CAS  GoogleScholar  Duan,S.etal.MicroRNA-135a-3pisdownregulatedandservesasatumoursuppressorinovariancancerbytargetingCCR2.BiomedicinePharmacother.107,712–720(2018).CAS  Article  GoogleScholar  Yang,L.,Km,Y.&Tie,J.miR-340-5pisapotentialprognosticindicatorofcolorectalcancerandmodulatesANXA3.Eur.Rev.MedPharm.Sci.22,4837–4845(2018).CAS  GoogleScholar  Croset,M.etal.miRNA-30familymembersinhibitbreastcancerinvasion,osteomimicry,andbonedestructionbydirectlytargetingmultiplebonemetastasis-associatedgenes.CancerRes.78,5259–5273(2018).CAS  PubMed  Article  GoogleScholar  Xu,R.D.etal.miR-149-5pinhibitscellgrowthbyregulatingTWEAK/Fn14/PI3K/AKTpathwayandpredictsfavorablesurvivalinhumanosteosarcoma.IntJ.Immunopathol.Pharmacol.32,2058738418786656(2018).PubMed  PubMedCentral  Article  CAS  GoogleScholar  Ablikim,M.etal.ObservationofthesemileptonicdecayD0→a0(980)−e+νeandevidenceforD+→a0(980)0e+νe.Phys.Rev.Lett.121,081802(2018).CAS  PubMed  Article  GoogleScholar  Gao,W.etal.DownregulationofMiR-1297predictspoorprognosisandenhancesgastriccancercellgrowthbytargetingCREB1.Biomed.Pharmacother.105,413–419(2018).CAS  PubMed  Article  PubMedCentral  GoogleScholar  Pan,S.etal.TumorsuppressiveroleofARHGAP17incoloncancerthroughWnt/β-cateninsignaling.Cell.Physiol.Biochem.46,2138–2148(2018).CAS  PubMed  Article  PubMedCentral  GoogleScholar  Zhang,X.etal.MicroRNA-26aisakeyregulonthatinhibitsprogressionandmetastasisofc-Myc/EZH2doublehighadvancedhepatocellularcarcinoma.CancerLett.426,98–108(2018).CAS  PubMed  Article  PubMedCentral  GoogleScholar  Zhao,L.etal.TheRNAbindingproteinSORBS2suppressesmetastaticcolonizationofovariancancerbystabilizingtumor-suppressiveimmunomodulatorytranscripts.GenomeBiol.19,35(2018).PubMed  PubMedCentral  Article  CAS  GoogleScholar  Gergely,J.E.,Dorsey,A.E.,Dimri,G.P.&Dimri,M.TimosaponinA-IIIinhibitsoncogenicphenotypeviaregulationofPcGproteinBMI1inbreastcancercells.Mol.Carcinog.57,831–841(2018).CAS  PubMed  PubMedCentral  Article  GoogleScholar  Wang,L.etal.HOXD3targetedbymiR-203asuppressescellmetastasisandangiogenesisthroughVEGFRinhumanhepatocellularcarcinomacells.Sci.Rep.8,2431(2018).PubMed  PubMedCentral  Article  CAS  GoogleScholar  Tu,C.,Wang,F.&Wan,J.MicroRNA-381inhibitscellproliferationandinvasioninendometrialcarcinomabytargetingtheIGF-1R.Mol.Med.Rep.17,4090–4098(2018).CAS  PubMed  PubMedCentral  GoogleScholar  Zhu,S.etal.LINC00473antagonizesthetumoursuppressormiR-195tomediatethepathogenesisofWilmstumourviaIKKα.CellProlif.51,e12416(2018).Article  CAS  GoogleScholar  Wang,N.etal.TargetingofNT5EbymiR-30bandmiR-340attenuatesproliferation,invasionandmigrationofgallbladdercarcinoma.Biochimie146,56–67(2018).PubMed  Article  CAS  PubMedCentral  GoogleScholar  Steeg,P.S.Targetingmetastasis.Nat.Rev.Cancer16,201–218(2016).CAS  PubMed  PubMedCentral  Article  GoogleScholar  Hodi,F.S.etal.Improvedsurvivalwithipilimumabinpatientswithmetastaticmelanoma.N.Engl.J.Med.363,711–723(2010).CAS  PubMed  PubMedCentral  Article  GoogleScholar  Tawbi,H.A.etal.CombinedNivolumabandIpilimumabinmelanomametastatictothebrain.N.Engl.J.Med.379,722–730(2018).CAS  PubMed  Article  PubMedCentral  GoogleScholar  Scher,H.I.etal.Increasedsurvivalwithenzalutamideinprostatecancerafterchemotherapy.N.Engl.J.Med.367,1187–1197(2012).CAS  PubMed  Article  PubMedCentral  GoogleScholar  Tevaarwerk,A.J.etal.Survivalinpatientswithmetastaticrecurrentbreastcancerafteradjuvantchemotherapy:littleevidenceofimprovementoverthepast30years.Cancer119,1140–1148(2013).PubMed  Article  PubMedCentral  GoogleScholar  Marshall,J.C.etal.Effectofinhibitionofthelysophosphatidicacidreceptor1onmetastasisandmetastaticdormancyinbreastcancer.J.NatlCancerInst.104,1306–1319(2012).CAS  PubMed  PubMedCentral  Article  GoogleScholar  Goss,P.E.&Chambers,A.F.Doestumourdormancyofferatherapeutictarget?Nat.Rev.Cancer10,871(2010).CAS  PubMed  Article  PubMedCentral  GoogleScholar  Wee,I.etal.Roleoftumor-derivedexosomesincancermetastasis.BiochimBiophys.ActaRev.Cancer1871,12–19(2019).CAS  PubMed  Article  PubMedCentral  GoogleScholar  Ulasov,I.,Fares,J.,Timashev,P.&Lesniak,M.S.Editingcytoprotectiveautophagyinglioma:anunfulfilledpotentialfortherapy.TrendsMol.Med.26,P252–262(2019).Article  CAS  GoogleScholar  Fares,J.etal.Landscapeofcombinationtherapytrialsinbreastcancerbrainmetastasis.Int.J.Cancer(2020).https://doi.org/10.1002/ijc.32937(inpress).DownloadreferencesAuthorinformationAffiliationsDepartmentofNeurologicalSurgery,FeinbergSchoolofMedicine,NorthwesternUniversity,Chicago,IL,60611,USAJawadFaresHigh-ImpactCancerResearchProgram,HarvardMedicalSchool,Boston,MA,02115,USAJawadFaresFacultyofMedicine,AmericanUniversityofBeirut,Beirut,LebanonMohamadY.Fares, HusseinH.Khachfe & HamzaA.SalhabNeuroscienceResearchCenter,FacultyofMedicalSciences,LebaneseUniversity,Beirut,LebanonMohamadY.Fares, HusseinH.Khachfe, HamzaA.Salhab & YoussefFaresAuthorsJawadFaresViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarMohamadY.FaresViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarHusseinH.KhachfeViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarHamzaA.SalhabViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarYoussefFaresViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarCorrespondingauthorCorrespondenceto JawadFares.Ethicsdeclarations Competinginterests Theauthorsdeclarenocompetinginterests. Rightsandpermissions OpenAccessThisarticleislicensedunderaCreativeCommonsAttribution4.0InternationalLicense,whichpermitsuse,sharing,adaptation,distributionandreproductioninanymediumorformat,aslongasyougiveappropriatecredittotheoriginalauthor(s)andthesource,providealinktotheCreativeCommonslicense,andindicateifchangesweremade.Theimagesorotherthirdpartymaterialinthisarticleareincludedinthearticle’sCreativeCommonslicense,unlessindicatedotherwiseinacreditlinetothematerial.Ifmaterialisnotincludedinthearticle’sCreativeCommonslicenseandyourintendeduseisnotpermittedbystatutoryregulationorexceedsthepermitteduse,youwillneedtoobtainpermissiondirectlyfromthecopyrightholder.Toviewacopyofthislicense,visithttp://creativecommons.org/licenses/by/4.0/. ReprintsandPermissionsAboutthisarticleCitethisarticleFares,J.,Fares,M.Y.,Khachfe,H.H.etal.Molecularprinciplesofmetastasis:ahallmarkofcancerrevisited. SigTransductTargetTher5,28(2020).https://doi.org/10.1038/s41392-020-0134-xDownloadcitationReceived:30October2019Revised:05February2020Accepted:11February2020Published:12March2020DOI:https://doi.org/10.1038/s41392-020-0134-xSharethisarticleAnyoneyousharethefollowinglinkwithwillbeabletoreadthiscontent:GetshareablelinkSorry,ashareablelinkisnotcurrentlyavailableforthisarticle.Copytoclipboard ProvidedbytheSpringerNatureSharedItcontent-sharinginitiative Furtherreading Longnon-codingRNAAC087388.1asanovelbiomarkerincolorectalcancer ArashPoursheikhani MohammadRezaAbbaszadegan MohammadAminKerachian BMCCancer(2022) IC261inhibitstheepithelial-mesenchymaltransitioninducedbyTGF-βinA549lungcancercells SungJimKim Myoung-SookShin AppliedBiologicalChemistry(2022) EffectofPAIP1onthemetastaticpotentialandprognosticsignificanceinoralsquamouscellcarcinoma NeetiSwarup Kyoung-OkHong Seong-DooHong InternationalJournalofOralScience(2022) TargetingCLK4inhibitsthemetastasisandprogressionofbreastcancerbyinactivatingTGF-βpathway EunjiKang SangwooKim WonshikHan CancerGeneTherapy(2022) Vesselco-optionandangiotropicextravascularmigratorymetastasis:acontinuumoftumourgrowthandspread? ClaireLugassy PeterB.Vermeulen RaymondL.Barnhill BritishJournalofCancer(2022) DownloadPDF Advertisement Explorecontent Researcharticles Reviews&Analysis News&Comment Signupforalerts RSSfeed Aboutthejournal Aims&Scope JournalInformation OpenAccessPublishing AbouttheEditors EditorialBoard JournalStaff AboutthePartner Contact Journalopenlectures Publishwithus ForAuthors&Referees Submitmanuscript Search Searcharticlesbysubject,keywordorauthor Showresultsfrom Alljournals Thisjournal Search Advancedsearch Quicklinks Explorearticlesbysubject Findajob Guidetoauthors Editorialpolicies