The systemic hallmarks of cancer

Specifically, he and his team discovered that non-metastatic breast tumors may influence the endocrine and the immune systems of the hosts. jcmt Search OAEJournals SearchinallOAEJournals Advanced JournalofCancerMetastasisandTreatment Advanced HotKeywords BiomarkerDiscovery AutophagyandCancer BreastCancerMetastasis BrainMetastases GastricCancerMetastasis LungCancer GeneticHeterogeneity ColorectalCancer ProstateCancer CancerImmunotherapy CirculatingTumorCells NeuroendocrineTumors NavigationBar Menu jcmt Home About AbouttheJournal AimsandScope EditorialPolicies EditorialBoard JuniorEditorialBoard OrderOffprints News JournalHistory Partners ContactUs ForAuthors AuthorInstructions ArticleProcessingCharges EditorialProcess ManuscriptTemplates SubmitaManuscript ForReviewers PeerReviewGuidelines ReviewerAcknowledgments Articles SpecialIssues AllSpecialIssues OngoingSpecialIssues SpecialIssueEbooks SpecialIssueGuidelines Volumes Webinars AcceptedManuscripts AbouttheJournal EditorialPolicies APCs Articles EditorialProcess AllSpecialIssues News ContactUs SignIn Submit Top Home  Articles  ArticleJCancerMetastasisTreat 2020;6:29.10.20517/2394-4722.2020.63©TheAuthor(s)2020.OpenAccessReviewThesystemichallmarksofcancerViews: 14056 | Downloads: 2107 | Cited:  8DoruPaul MedicalOncology,WeillCornellMedicine,NewYork,NY10021,USA.CorrespondenceAddress:Dr.DoruPaul,MedicalOncology,WeillCornellMedicine,1305YorkAvenue12thFloor,NewYork,NY10021,USA.E-mail:[email protected]:14056 | Downloads:2107 | Cited:8 | Comments:0 | :7Received:19Jun2020|FirstDecision:17Jul2020|Revised:22Jul2020|Accepted:6Aug2020|Published:28Aug2020AcademicEditor:CiroIsidoro|CopyEditor:Cai-HongWang|ProductionEditor:JingYu©TheAuthor(s)2020.OpenAccessThisarticleislicensedunderaCreativeCommonsAttribution4.0InternationalLicense(https://creativecommons.org/licenses/by/4.0/),whichpermitsunrestricteduse,sharing,adaptation,distributionandreproductioninanymediumorformat,foranypurpose,evencommercially,aslongasyougiveappropriatecredittotheoriginalauthor(s)andthesource,providealinktotheCreativeCommonslicense,andindicateifchangesweremade.AbstractCancerisnotjustalumpofcellsthatdivide,invade,andspreadrandomly,butratheramulti-layeredpreciselytunedprocessthatrequirestheparticipationofthewholeorganism.Thereisanurgentneedtozoom-outfromthecellularandthelocalstromalviewandbroadenourperspectivebyincludingthewholeorganismlevel.Geographicallyseparatedcancertissuescommunicatebetweenthemselves,formingasystemthatinteractswiththerestoftheorganismthroughcancerinducedsystemicpathogenicnetworks.Inthepresentpaper,Iintroducesixsystemichallmarksofcancerthatemergeasaresultoftheseinteractions.Ialsodescribeseveralpotentialtherapeuticapproachesthatcanbedevelopedusingthecancersystemconcept.Overall,Iarguethatthetumoricentricparadigmshouldbereplacedwithabroaderapproachthatbringsintofocusthe“cancerized”organism. KeywordsCancersystem,metastasis,cancerhallmarks,organism,tissue,systemofcancer,systemicnetworks,systembiologyIntroductionThecancersystemFromthesystemicbiologypointofview,organismsarecomplex,embedded,multi-layerednetworksofinteractions.Atthecellularlevel,thenetworksarecomprisedofgenes,metabolicintermediates,miRNAandsignalingmolecules(proteins,lipids,ions).Atthetissularlevel,thenetworksarecomprisedofinteractionsbetweendifferentcelltypesandbetweenthecellsandthesupportingstroma.Attheorganismiclevel,thenetworksarecomprisedofinteractionsbetweendifferentbodysystems(endocrine,nervous,immune,etc.).AsdescribedbytheseminalworkofDenisNoble[1-3]thesethreelevelsofnetworks(cellular,tissular,organismic)[Figure1]areco-dependentandthereisnopriviledgedlevelofcausation.Theyinteractandinfluenceeachother.Figure1.ThreelevelsoforganizationCancerisalsoamulti-layereddiseasewithmultiplecomplexnetworksofinteractionslocatedatdifferentlevels,(i.e.,cellular,tissular,organismic).Thefocusonthegenome,thecancercells,oreventhecancertissues,istoonarrowand,inordertobetterunderstandthecancerprocess,thereisanurgentneedtozoom-outandbroadenourperspectivebyincludingabroader,organismiclevel.Wedefineasystemasadynamicentityofseveralinteractingcomponentsthatareco-dependentandfunctioninanintegratedway.Asinglecell,anorgan,theentirehumanbodyareallsystems.Inthepresentpaper,Iwillfocusoncanceratthemacroscopiclevel.Macroscopically,experimentaldataaccumulatedovermorethanadecade,supportstheconceptofacancersystemformedbyseveralgeographicallyseparatedcancertissues(theprimarytumor,thelocalandthedistantmetastasis).Thecancersystemandthebodysystemsareco-dependentand,throughtheirinteraction,newcancerinducedpathologicsystemicnetworks(CISPN)appearandthewholeorganismis“cancerized”tosupportcancerdevelopment[Figure2].Figure2.ThecancersystemandthebodysystemsinteractleadingtonovelcancerinducedsystemicpathologicnetworksCancerasasystemicdiseaseOverthelastdecade,severalmodelsofcancerasasystemicdiseasehavebeenproposed[4-8].In2010,MikalaEgebladandhercollaboratorsintroducedthemodelofthetumorasanorganthatmayinfluencetheimmunity,themetabolismandthecoagulationstatusofthehost[4].Inapaperpublishedthesameyear,SandraMcAllisterandRobertWeinbergsuggestedthattumor-hostinteractionsextendwellbeyondthelocaltissuemicroenvironmentandintroducedthetumor“instigation”conceptinwhichprimarytumorsperturbnormalhostorgansandsupportthegrowthofmetastatictumorsatdistantanatomicsites[5].Theylistedseveralfactorssecretedbythetumorswithsystemiceffects:vascularendothelialgrowthfactor(VEGF),interleukin(IL)-6,IL-8,stromalcell-derivedfactor-1(SDF1),fibroblastgrowthfactor,growth-relatedoncogene-α(CXCL1),platelet-derivedgrowthfactor(PDGF),angiopoietins,transforminggrowthfactorβ(TGF-β),hepatocytegrowthfactor(HGF),angiogenin,leptin,sonichedgehoghomolog,regulateduponactivationnormalT-cellexpressed(CCL5),andosteopontin[5].Theyalsoproposedanoveltreatmentofmetastasesbyblockingtheiraccesstosupportingstromalcellsderivedfromthebonemarrow.Inasubsequentpublication,thesameauthors[7],refinedtheiroriginalmodelbringingadditionalsupporttothecomplementaryideathattumorscanbealsosignificantlyinfluencedbysystemicprocesses.In2014,aresearchteamfromAustria,introducedtheconceptoftumormacroenvironmentanddescribedmainlytheglobalmetabolicchangesthattumorsexertonthewholeorganism[6].ThissystemicperspectiveshouldnotbelimitedsolelytoclinicallystageIVcancers.Often,systemiceffectsappearalsowhenthetumorsarelocalizedand,inmanyinstances,metastasisispresentinasubclinicalformevenwhenthetumorappearslocalized.Thismaybethereasonwhyevenwhendetectedveryearly,asignificantproportionofcancersisincurable.Forexample,the5yearsurvivalofstageInon-smallcelllungcancerdiseaseisapproximately60%(AmericanCancerSocietyStatistics,2020).In2019,aneuroscientist,JeremyBorniger,publishedtwopapers[8,9]focusedonbrain-tumorinteractions,withspecialemphasisontheinteractionofsubcorticalneuralpopulationsandcancer.Specifically,heandhisteamdiscoveredthatnon-metastaticbreasttumorsmayinfluencetheendocrineandtheimmunesystemsofthehosts.Usingabreastcancermousemodel,theydemonstratedthatbyinhibitingthesignalingofthelateralhypothalamicorexin/hypocretinneurons,thesleepqualityandthemetabolicdysregulationsinducedbythetumorwereimproved[9].Wehavealsoproposedpreviouslytheneedforabroader,systemicperspectiveoncancerandintroducedbrieflytheideaofthecancersystem[10].Thenotionofthecancersystemalthoughcloselyrelatedtotheideaofthecancer-systemicdiseaseisdifferentinafundamentalway.Themeaningoftheword“systemic”refersto“affectingthebodygenerally”.Metastaticand,sometimes,localizedcancers,influencethewholeorganismandthereforetheyareclassifiedassystemicdiseases.Ontheotherhand,macroscopically,cancerbehaveslikeasortofanorganismwithinanorganismandmetastasisappearsasafinelyorchestratedprocess.Theconceptofacancersystemtriestocapturepreciselythisdeterministicbehavior.CancerasadevelopmentaldiseaseTheideathatcancerrepresentsanembryonaldevelopmentalprogramgonehaywirehasbeenaroundformorethanfourdecades[11,12].Asshownbyarecentreview[13]therearesometissularandorganismicgenesthatmayplayarolebothinembryogenesisandcancer.Itisimportanttopointoutthatuntilapproximatelythreeweeksafterfertilization,theembryodoesnothaveafunctioningcirculatorysystem,and,therefore,thedevelopmentalprogramsinvolvedintheembyodevelopmentarelikelydifferentfromthatofthemetastaticprocess.Anotableexceptionistheneuralcrestmigrationwhereepithelial-to-mesenchymaltransitionplaysacriticalrole.Similartotheneuralcrestmigration[14],themetastaticprocessrepresentsatransformedcellularprogramthatonceactivatedleadstothedevelopmentofdisseminatedtumorsatdistancefromtheoriginalsite.Thefactthatthatthesamegenes(i.e.,thenuclearhormonereceptors,Hedgehog,Wnt,TGF-β,Notch)areinvolvedinthegenerationandmaintenanceofmulticellularity,and,theyarealsodysregulatedinstemcellsandmetastasis[15],suggestthestrikingideathatcancer,ingeneral,andthemetastaticprocess,inparticular,mayrepresenttheactivationofadevelopmentalprogramthatleadstothecreationofanovel,pervasive,multicellularentity.AspreviouslysuggestedbyMarkVincent,cancerappearstobemuchmorethanasimpledysregulatedgrowthandmayrepresentaformofmulticellularlife,withsymbioticproperties[16,17],thatestablishesacommensualrelationshipwiththeorganismwhereitdevelops.Inthisprocess,thewholeorganism,“cancerized”throughthedevelopmentofCISPN,aswewillargueinthispaper,farfrombeingapassivebystander,becomesanactiveenablerofcancerprogressionandspread.MetastasisasafinelyorchestrateddeterministicprocessAsopposedtotheapparitionofmalignanttumorsthatis,ingeneral,relatedtogeneticmutations,metastasisappearstobemainlyanepigeneticprocess.Inthe2011updatedversionoftheiroriginalhallmarksarticle[18],HannahanandWeinberg,notedthattheabilityofcancercellstoinvadeandmetastasizemaynotrequireadditionalgeneticmutationsinadditiontothosealreadypresentintheprimarytumors[19].Also,themajorityofthegenesproposedbyMassaguéandcollaboratorsmorethanadecadeago[20,21]intheirstepbystepmodelofmetastasisarenotmutated.Inaddition,Vogelsteinetal.[22]notedthatdespiteconsiderableeffort,specificgeneticalterationsthatdistinguishcancersthatmetastasizefromcancersthatdonotmetastasizehavenotbeenyetidentified.Theimmediateconclusion,drawnbytheVogelsteinteam[22],isthattherearenospecificmetastasisgenes.Thisopinionofmetastasisasarandom,nondeterministicprocesshasbeenchallengedfor130yearssincePagetaskedthefamousquestion:“Whatiswhatdecideswhatorganssufferfromdisseminatedcancer?”andlaunchedthe“seedandsoil”hypothesis[23].Bythelate70’s,metastasisstartedtobeunderstoodmoreandmoreastheresultofnon-randomtumor-hostinteractions[24],andthePaget’s“seedandsoil”hypothesishasbeenstronglysupportedbytheworkofFidlerandKripke[25]andPriceetal.[26].Arecentstudydescribedwidespreadepigeneticreprogrammingduringtheevolutionofdistantmetastasisofpancreaticcancerintheabsenceofmetastasis-specificdrivermutations[27].ThismanifestedasglobalreprogrammingofhistoneH3K9andDNAmethylationwithinlargeheterochromatindomains(LOCKs)aswellasregionalchangesingeneregulatorymodifications.Interestingly,theauthorsfoundthattheepigeneticchangeswerecontrolledbyananabolicglucosemetabolismenzyme6-phosphogluconatedehydrogenase(PGD).Glucosedeprivation,RNAinterference(RNAi)againstPGD,and,treatmentwith6-aminonicotinamide,reprogrammedthechromatinstateofthedistantmetastasis.Inaddition,cellstreatedwithRNAiagainstPGDdidnotformdistalmetastasis[27].Anotherrecentstudy[28],foundalsothatinprostatecancerthemasterregulatorgenesofmetastasisaregenesinvolvedinepigeneticregulation.Silencingaparticularhistonemethyltyransferasegene(NuclearreceptorbindingSETDomainprotein2,NSD2)invivoallografts,resultedinsignificantimprovementinsurvivalinthemicetreatedaswellasasignificantreductioninthemetastaticburdenwithoutanyeffectontheprimarytumorgrowth[28].Theseobservationssuggestadifferentviewofmetastasis.Theplethoraofgeneticabnormalitiespresentinestablishedmalignanttumorsmaynotbethemaindriverofmetastasis.Nogeneticmutationormutationshavebeenunequivocallyshowntobeassociatedwithprogressionfromlocalizedtometastaticdisease[29].Asshownbyseveralinvitroexperiments,epigeneticfactorspresentinsideandoutsidetumorcellsmaycontrolthemetastaticprocess.Thecytoplasmofhumanembryonicstemcellscanepigeneticallyreprogrammultipotentmetastaticmelanomacellsandmadethemtoassumeamelanocyte-likephenotype[30].AdamTelermanandRobertAmson,tworesearchersfromÉcoleNormaleSupérieurefromParis,France,whohavebeenmodelingtumorreversionformorethan20years,stated[31]thatthe“reversionprocessinvolvesareprogrammingmechanismusingepigeneticandprobablygenetictoolsthatwillsupersedethechangesincancerbyassemblingandtriggeringalternativewaysleadingtothesuppressionoftumorigenicity”.Someofthemetastasismasterregulatorsmaynotbeevenlocatedinsidethecancercell.TheworkofBissellandRadisky[32]andOrimoandWeinberg[33]demonstratedthecrucialroleofthetumorassociatedstromainpromotingtumormetastasis.Convincingly,arecentreview[34]illustratedhowhyaluronan,anintegratedcomponentoftheextracellularmatrix(ECM),maymodulateseveralkeyhallmarksofcancer:sustainingoftheproliferativesignaling,evasionofapoptosis,angiogenesis,activationofinvasionandmetastasis,reprogrammingofenergymetabolismandevasionoftheimmuneresponse.CancercellprogramsIfcancercellsswitchbackandforthbetweendifferentprograms,cancermayrepresentacontrollablecellularstatethatcanreroutedtoanon-neoplasticphenotype.Themodelofcancerasapotentiallyreversiblecellularprogram[35]complementsandrefinesthegeneticmodel.Ithasbeenpreviouslysuggestedthatmanyofthepropertiesassociatedwithinvasionandmetastasisdonotariseaspurelycellautonomousprocesses[36].Inmostofthecases,themetastaticprocessseemstobeduetoadaptationandnottoselectionofthecancercells[37].ItisthesecretionoffactorssuchasTGF-β,HGF,tumornecrosisfactor(TNF)-α,WntandPDGFbythesurroundingtumorstroma,and,theactivationinthetumorcellsofseveralmasterregulatorsofembryogenesis,suchasthetranscriptionfactorsTwist,Snail,Slug,Zeb1andZeb2,regardedastheepithelialtomesenchymaltransition(EMT)coreregulators,thatdrivemetastasis[13,29].TheseprocessesmaybemediatedbymiRNAs[38],thatcoordinatemultiplegenesatthesametime,soitwillbemoreappropriatetotalkintermsofvariouscellularprograms,i.e.,adivisionprogrampossiblycontrollingkeymitoticgenes[39],aninvasionprogrampossiblycontrollingkeyinvasiongenes[40,41],and,ametastaticprogram,possiblycontrollingkeyEMTgenes[13][Figure3].Themasterregulatorsoftheseprogramsmayormaynotpartiallyoverlap.Forexample,miR-21andmiR-222areinvolvedinuncontrolledproliferation,miR-130andmiR-126areinvolvedintumorangiogenesisandmiR-373andmiR-155areinvolvedbothininvasionandmetastasis[38].Theexistenceofspecificcellularprogramsactivatedduringthecancerprocess,suggeststhepossibilitythatthetransformationsinducedbycancerbothatthelevelofthetissuewhereitoriginallyappears,andatdistantsiteswheremetastasisareformed,arenotsimplerandomby-productsofmalignancybutrepresentawellorchestratedprocessoflocalandglobal“cancerization”.Inthispaper,Iarguethatthemetastaticphenotypeisinitiatedandmaintainedbynon-randomCISPNdevelopedattheorganismiclevel.TheemergenceoftheseCISPNmayresultmainlyfromthefinelyregulatedsecretionbythetumorsandtheirstromaofspecificexosomes[42,43].Exosomeshavebeeninvolvedinthecommunicationbetweentheprimarytumorandremotemetastaticsites[44]and,cancercell-derivedexosomescontainmiRNAsthatmayregulateallthesystemichallmarksofcancerdescribedbelow.InspiteofthepresenceofRNaseinblood,miRNAssurviveduetotheirpresenceinexosomes[45].Boththenatureoftheproteinsexpressedonthesurfaceofexosomesandtheexosomescargoarenon-randomasdemonstratedbytheworkofDavidLyden’slab[46,47].Recentlyhisteamanalyzedtheproteinexosomesfromplasmaofpatientswithfivecancertypes(breast,colorectal,lung,pancreatic,mesothelioma)andfoundthatincancerpatients,thecirculatingplasmaexosomesproteins,derivenotonlyfromthetumoritself,butalsofromthetumorenvironment,distantorgans(i.e.,liver)andtheimmunecells,thisdatasupportingthe“cancerized”organismmodel[43].Figure3.ThecancercellprogramsClinicalimplicationsofthemodelofcancerasamodifiedcellularprogramThedivision,invasionandmetastaticprogramsmaybeactivateddifferentlyandindifferentorderinvariouscancertypes,andthismayexplainthefactthatcancersarisingindifferenttissueshavedifferentpropensitytogrowlocally,toinvadethesurroundingstromaandtometastasize.ThismightberelatedtodistinctmodifiedcellularprogramspresentinCancerStemCells(CSCs).CSCsbydefinitionareasmallsubpopulationofcellswithintumorswithcapabilitiesofself-renewal,differentiation,andtumorigenicitywhentransplantedintoananimalhost.WhenwethinkofCSCwemainlythinkoftheirabilitytogrowandformcoloniesbutCSCspresentindifferenttissuesmaynotbethesamequalitatively,andeven,quantitatively[48].Itislikelythatduetothesedifferences,programsfordivision,invasionandmetastasisaredifferentlyactivatedindifferentCSCs.SomeCSCsmay“instigate”or“educate”thestromalcellsbysecretingsignalsthatinducechangesinthesecellsthatfacilitatelocalinvasionofthetumor[49].Otherdistinctpopulationofstemcells,socalledmigratingcancerstem(MCS)cells,mayberesponsibleformetastasisasproposedoriginallybyBrabletz[50].Recently,thispopulationoftumorcellswithMCSpropertieswasidentifiedinastudyconductedatMemorialSloanKetteringCancerInstitute(MSKCI)[51].Usingacolorectalcancermousemodel,theMSKCIinvestigatorsfoundtwodistinctpopulationofstemcells:anadenomaformingstemcellspopulationwithoncogenicmutationsandaL1CAMpositivetumor-propagatingmetastasis-initiatingstemcellswithoutoncogenicmutations[51].Apervasiveoncologydogmapostulatesthatcancerdevelopsinalinearwaybyinitiallygrowinglocally,thensubsequentlyinvadingthetissuewheretheyappearand,finally,ifgivenenoughtime,inthemajorityofcases,metastasize.Experimentaldataandclinicalpracticesuggestthatthisassumptionisincorrect.Somecancers,likebreastorprostate,forexample,sometimesbehaveasbenigntumorsthatdonotinvadelocallyormetastasizeand,maybe,thisiswhy,theglobal,indiscriminatelyscreeningprogramsforbreastandprostatecancers,mayleadtoovertreatmentofsomepatients.Anotherexampleissarcoma,whereroughly50%ofthesarcomametastasizeand50%donot[52].AsdemonstratedbytheworkofGaneshetal.[51],theclassicalstepbystepgeneticmodelofcolorectalcarcinogenesisofFearonandVogelstein[53]maynotapplytothemetastaticprocesswhodoesnotinvolveaspecificsetofmutatedgenes.Thedifferentactivationofdifferentcancercellsprogramsintumorsofdifferenttypesmightexplainthestrikingdifferenceinclinicalstagepresentationsofdifferentcancerlocations.Forexample,asmanyas55%ofsquamousheadandneckcancerpresentsasstage4mostfrequentlywithlymphnodesmetastasis[54],butonlyapproximately7%ofthyroidcancerspresentasstage4[55].Thepresenceofdistinctcellularprogramsincancermayalsosolvetheenigmaoftheexistenceofcarcinomasofunknownoriginwheretheprimarytumorisneverfound.Itisconceivablethatinmetastasisofcancersofunknownoriginthemetastaticprogramisactivatedbeforethedivisionandinvasiveprograms.ThesystemichallmarksofcancerThehallmarksofcancerdescribedbyHanahanandWeinbergintheirtwoarticles[18,19],refermainlytothecellularandtissularhallmarksofcancer.Morerecently[56],WelchandHurstproposedfourcancerhallmarksspecificallyassociatedwiththemetastaticprocess:motilityandinvasion,colonization,plasticityandmodulationbutthesefourhallmarksarepracticallyidenticalwiththesuccesivestepsofthemetastaticprocessdescribedmorethanadecadeagobyJoaoMassagué[20,21]andhiscollaborators.Inthispaper,wedescribesixnovelsystemiccancerhallmarks,thatappearasaresultoftheinteractionbetweencancerandtheorganismatthemacroscopiclevel.Thefirstsystemichallmarkisthecancersystemitselfestablishedthroughtheconnectionsbetweentheprimarytumor,thebonemarrowandthedistalmetastasis.Thefiveothersystemichallmarksareasfollowing:theglobalinflammation,theimmunityinhibition,themetabolicchangesleadingtocachexia,thepropensitytothrombosis,andtheneuro-endocrinechanges[Figure4].Figure4.SystemichallmarksofcancerEachofthesesixhallmarksisestablishedthroughadifferentCISPN.Inthesectionsbelow,Iwilldiscussonebyone,thesixCISPN.Theaccompanyingfigures[Figures5-10]arerawsketchesillustratingthesalientcomponentsofthedifferentCISPN.Apartfromthenervoussystem,theconnectionsbetweentheCISPNcomponentsaremadethroughexosomes,cytokinesandothersolublefactors,representedbythedottedlines.Figure5.Primarytumor-metastasis-bonemarrownetworkFigure6.ThesystemicinflammationnetworkFigure7.TheimmunityinhibitionnetworkFigure8.Theglobalmetabolism/cachexianetworkFigure9.ThethrombosisnetworkFigure10.Theneuro-endocrinenetworkTheprimarytumor-metastasisnetworkClinically,ithasbeennoticedforalongtimethattheprimarytumorandthedistalmetastasesareinterconnectedandco-dependent.Insomecasesofrenalcellcancer,forexample,resectingtheprimarytumorinducesaregressioninthedistalmetastasis[57].Onthecontrary,inseveralexperimentalmodels,asshownbyFolkmanandhiscollaborators,resectingtheprimarytumormayacceleratethedevelopmentofmetastasis[58,59].Overthelasttwodecades,ithasbeendemonstratedalsothatbesidesthisprimarytumor-metastasisinfluence,thereisapermanent“trialogue”betweentheprimarytumor,themetastaticsitesandthebonemarrow[Figure5].Bonemarrowcanfunctionasasourceofhematogenicprogenitorcellsthatpreparethenicheformetastasis[60,61]and,alsopossibly,asasourceofmalignantstemcells[62].Bonemarrow-derivedcells(BMDCs),whicharefrequentlyrecruitedtositesoftissueinjuryandinflammation,arecrucialforthemalignantprocess.Inanelegantexperiment,Houghtonetal.[63]demonstratedthatinsomecases,BMDCsmayevenrepresenttheoriginofmalignantcells.Thesefindingsweresubsequentlyconfirmedbyadifferentresearchteaminasarcomamousemodel[64].Kaplanetal.[60]pioneeredtheworkonthemetastaticnichebydemonstratingthatBMDCsthatexpressvascularendothelialgrowthfactorreceptor1(VEGFR-1)hometotumor-specificpre-metastaticsitesandformcellularclustersbeforethearrivaloftumorcells.Besides,BMDCsthatfacilitatethegrowthoftumorcellsatdistancefromthesiteoforiginand,cytokinesandvesiclesreleasedintothecirculationalsocontributetothedevelopmentofdistalmetastasis[65-68].Inarecentreview[69],acomprehensivelistof34primary-tumor,tumorstromaandmyeloidderivedfactorsthatmobilizeandrecruitmyeloidcellsdirectlyfromthebonemarrowtothepre-metastaticnichewascompiled.Theauthorsalsoproposedsixcharacteristicsofthepre-metastaticnichethatempowerthenichetofavortumorcellcolonizationandpromotemetastasis:angiogenesisandvascularpermeability,lymphangiogenesis,inflammation,immunosuppression,organotropismandreprogramming.Thesecharacteristicsdeterminewhetherthemetastaticcellspresentinthebloodcirculationcancolonizeandsurviveorbecomedormantafterarrival[69].Thebestwelldescribedtumorsecretedsolublemoleculesresponsibleforthenicheformationanddevelopmentare:VEGF-A,placentalgrowthfactor,andversican[69].Besidesthecancercells,therearealsofactorssecretedbythetumorstromathatplayasimilarrole:TGF-β,TNF-α,hypoxia-induciblefactor-1(HIF-1),granulocytecolony-stimulatingfactor(G-CSF).SomeofthesefactorsaresecretedbytheBDMCsthemselves:VLA-4(integrinα4β1),matrixmetalloproteinase(MMP)9andID3protein(IDisatermthatreferstoitsfunctionalpropertiesasbothaninhibitorofDNAbindingandaninhibitorofcelldifferentiation)[70].Theexosomesarekeyfactorsresponsibleforthepreparationofthepre-metastaticnicheandthecommunicationbetweenthetumor,thebonemarrowandthedistalmetastaticsite[43,71].Differentmaterials(proteins,mRNAs,DNAandmiRNAs)carriedinsidetheexosomescanbefunctionallydeliveredbetweendifferenttypesofcellsandtransferredtodistantlocations,influencingthebiologicalactivitiesoftumorandnon-tumorcellsandpromotingtumorgrowth,invasion,metastasis,angiogenesis,anddrugresistance[43,71].AcomprehensivereviewhighlightedthekeyroleplayedbytheECMcomponentslikesyndecaninregulatingexosomebiogenesis,proteincomposition,function,anddockingtorecipientcells[72].Heparansulphatechainsofsyndecansareessentialforexosomeformationwithinendosomalcompartments,andtrimmingofheparansulphatebyheparanaseactivatestheformationofanendosomalcomplexcontainingsyndecancoupledtosynteninandALIX[73].Reversely,tumorexosomesexpressinghighCD44expressionbindtohyaluronicacidandmodulatetheECMasdemonstratedfordegradationofcollagens,laminins,andfibronectin[74].Tumor-associatedexosomeshavebeenidentifiedinbiological(plasma,urine,saliva)andpathological(malignanteffusions,pleuraleffusions,ascites)fluidsfromcancerpatients.DavidLyden’steamfromWeillCornellMedicalCenter(WCMC),wasabletodemonstratethatinmelanomathetransferoftheMEToncoproteinfromtumor-derivedexosomestoBMprogenitorcellspromotedthemetastaticprocessandtodescribequantitativeandqualitativeexosomesignatures,alongwithspecificBMprogenitorcellpopulationsmobilizedasrepresentativehallmarksofmetastaticdisease[75].CertainmiRNAsareenrichedinexosomescomingfromthecancercells,indicatingthattheexosomescompositionseemstobecontrolled[76].ExosomesfrommutantKRAScolorectalcancercellsforexampleshowadistinctmiRNAprofilecomparedtowildtypecells[77].ThesameWCMCteamshowedthatinpancreaticcancer,theexosomescontainedmacrophageinhibitoryfactor(MIF)thatisinvolvedintherecruitmentofbonemarrow-derivedmacrophagesandtheblockadeofMIFpreventedliverpre-metastaticnicheformationandmetastasis.Byreleasingsolublefactors,tumorcellswereabletospecificallydirectbonemarrowderivedcellstothesitesweretheyweresupposedtogo[68].An“integrincode”presentonthesurfaceoftheexosomesseemstoberesponsibleforthehomingoffuturemetastasistopreciseprespecifieddistalorgans[46].RedigandMcAllisteralsoincludedtheparticipationofthebonemarrowasasinequanoncomponentofthe“instigation”model[78].Theseauthorsdemonstratedaprocessof“systemicinstigation”byinjectingcellscomingfromanaggressivebreasttumorintheflankofamouseandanalyzingtheeffectofthesecellsonthegrowthintheoppositeflankoftumorcellscomingfromanindolentbreastcancertumor.Theexplanationfortheinfluenceatdistanceofonecancertissueonthegrowthofanotherwasestablishedtobebonemarrow-derivedcellsthatwererecruitedtothedistalsitesandinstigatedthepreviouslyindolenttumorcellstogrow[78].TheimportanceofstudyingcancerasasystemicdiseasewasunderscoredbyanotherstudydonebyagroupofresearchersfromHarvardMedicalSchool[79].Theauthorsdescribedasystemiccross-talkbetweenlungtumorsandbones.Inanelegantmousemodel,lungadenocarcinomaswereabletoremotelyactivateosteoblastsinbonesevenintheabsenceoflocalmetastasis.Inturn,theseosteoblastssuppliedtumorswithneutrophils,whichfosteredcancerprogression[79].Sometimes,theinitiatorsofthis“trialogue”arenotthetumorcellsthemselves,butotherstromalcellsderivedfromthe“cancerized”stroma.Cancer-associatedfibroblastshavebeenshown,forexample,toreleasecytokines[80][i.e.,SDF1]thatonceenteredinthecirculationmaytriggerthesystemicreleasefromthebonemarrowofstemcellsandhaematopoieticprogenitorsthatwillsupporttheformationofmetastases[81].AresearchteamfromMDAndersonhaveshownthattheoriginofthesecancer-associatedfibroblastsisprimarilythebonemarrow[82]buttheiroriginandfunctionwithinthetumorstromavaries[83].Theexistenceofthesenetworksofcommunicationbetweengeographicallyseparatedsites,bringsexperimentalevidencetothecancersystemmodel,and,supportstheideathatmetastasisisanon-random,finelyregulatedprocess.ThesystemicinflammationnetworkThelinkbetweenlocalstromalinflammationandcancerprogressioniswellknownandthemolecularpathwaysresponsibleforthislinkhavebeenwellcharacterized[84].Asanypathologistwouldcertify,localinflammationispresentinthestromaofmanytumorsand,inflammatorycellsandmolecules,maybeinvolvedinalmosteveryaspectofcancerprogression,includingthetumourcells’abilitytometastasize.Colottaetal.[85]proposedthatcancerrelatedinflammationrepresentsaseventhhallmarkofcancer.AsdescribedbyGrivennikovetal.[86],thereareseveraltypesofinflammationthatcanpromotecancerdevelopmentandprogression,differingbycause,mechanism,outcome,andintensity.Briefly,thereischronicinflammationassociatedwithinfectionsorautoimmunedisease,thereisinflammationduetoprolongedexposuretoenvironmentalirritantsorobesity,thereisanotherdistincttypeofinflammationrelatedtothetumor,and,finally,thereisinflammationrelatedtocancertherapiesthemselves.Approximately20%ofhumancancersmayberelatedtochronicinflammationcausedbyinfections,exposuretoirritants,orautoimmunedisease[87].Ontheotherhand,notonlychronicinflammationmayleadtocancer,butcancermayalsocauselocalandsystemicinflammation.Oncogeneactivationincancercellsleadtoexpressionofpro-inflammatorytranscriptionfactorswithintumorcells[suchasnuclearfactor-kappaB(NF-κB),signaltransducerandactivatoroftranscription(STAT)3orHIF-1α].Theseactivatedtranscriptionfactorsmediatetheexpressionofkeycytokinesandchemokinesaswellasinflammatoryenzymeswithinthetumormicroenvironment.Atthetissularlevel,differentcytokinescaneitherpromoteorinhibittumordevelopmentandprogression.Someofthemmayleadtotumorprogression(IL-6,IL-17,IL-23),andalsohavedirecteffectsoncancercellgrowthandsurvival[TNF-relatedapoptosis-inducingligand,Fasligand,TNF-α,epidermalgrowthfactorreceptor(EGFR)ligands,TGF-β].Others[IL-12,interferon(IFN)γ]mayhaveananti-tumoreffect[86].Cancerinflammationisnotonlyalocalphenomenon[Figure6].Highserumconcentrationsofinflammatorycytokines,(i.e.,IL-1,IL-6)arefoundinmanyadvancedmalignancies[88].Circulatingcytokinesandsmallinflammatorymolecules,suchaschemokinesandmatrix-degradingproteins,arealsoinvolvedinthesystemicinflammation,andplayacrucialroleinthemetastaticprocess[88].IL-1,forexample,isinvolvedininvasionandangiogenesis.IL-1mayenhancetheinvasivenessofalreadyexistingtumorcellsbytheinductionofinflammatorymolecules,suchasMMPs,VEGF,heparanase,chemokines,andintegrinsonthemalignantcellsandendothelialcells,orbyswitchingontheangiogenesisleadingtotumordisseminationandmetastasis[89].SystemicinhibitionofIL-1withanakinra(arecombinantderivativeofIL-1RN)inhibitsthegrowthanddensityofnewvesselsinIL-1-producinghumantumorcelllinesxenograftedintoimmunodeficientmice,butnotintheircounterpartsthatdonotproduceIL-1[90].Arecentreview[91],providedacomprehensivelistoffactorsassociatedwithcolorectalsystemicinflammationincludingcytokines,chemokinesandgrowthfactors(IL-6,C-CMotifChemokineLigand(CCL)2,CXCL(C-X-CMotifChemokineLigand)8,CSF1[macrophagecolony-stimulatingfactor(M-CSF)],andCSF2[granulocyte-macrophagecolonystimulatingfactor(GM-CSF)].Theauthorsnotedthatimmunecellsandfibroblastsarecapableofproducingmanyofthesefactorsatmuchhigherlevelthantumorcellsandpointedouttotheroleofthestromainsystemicinflammation.Someoftheseimmunomodulatoryeffectsaremodulatedbyexosomesthatcontainintheircargoalargevarietyofmolecules[92,93].ExosomessecretedbytumorscontainIL-8,CCL2,CCL3,CCL4,CCL5,CCL20andTGF-β[93].Theliverisakeyplayerinthesystemicinflammatoryresponse.Alltheacute-phaseproteins,includingC-reactiveprotein(CRP),amyloidA,α1antitrypsin,andα1acidglycoprotein,aresynthesisedintheliverandsecretedintothecirculation[94].ClassicalstudieshaveshownthedeleteriousroleplayedbythecitokinessecretedbytheKupfercellsinacuteinflammation[95].Forexample,completeeliminationoflivermacrophages,decreasedthemortalityofmicechallengedwithzimosan,apotentinflammatoryagent,from27%to0%[96].Anotherkeycomponentoftheglobalinflammationnetworkisthegutmicrobiota.Thehumanbodyisinsymbiosiswiththegutmicrobiota,whichoutnumbershumancellsbya10-foldfactor.AsshownbytwoSciencearticles,gutmicrobiotamodulatesinflammationinboththetumormicroenvironmentandinthesystemiccirculation[97,98].Microbiotaalsoregulatessteady-statemyelopoiesisandneutrophilhomeostasis[99].Mousemodelshaveshownthatgutmicrobespromotethedevelopmentofmammarycarcinomasviaaneutrophil-mediatedmechanism[100],and,microbiota-drivenmobilizationofmyeloid-derivedsuppressorcells,favorsmalignantprogressionthroughsystemictumorpromotinginflammation[101].Increaseofthesystemicmarkersofinflammationasneutrophils,lymphocytesandplateletcountsandacutephaseproteins,suchasCRPandalbuminortheircombinations,computedindifferentscores,i.e.,theneutrophillymphocyteratio,theplateletlymphocyteratioandtheGlasgowPrognosticScore,areassociatedwithadverseprognosisinseveralmalignancies[102].Asystemicimmune-inflammationindex(SII),whichiscalculatedasplatelet(P)×neutrophil(N)/lymphocyte(L)counts,hasalsobeendemonstratedtobecloselyassociatedwiththeprognosisofsolidtumorsespeciallylungcancer[103].Inmostadvancedcancers,systemicinflammationiscausedbycanceritselfandindicatetheaggressivenessofthetumor[104].Unfortunately,despitepre-clinicalefficacydemonstratedinseveralanimalstudies,untilpresent,agentsusedtomanipulatesystemicinflammationinthetreatmentofpatientswithadvanced-stagecancerhaveonlyshownmodestresults[105].Theclinicaltrialsthatusedinhibitorsofprimaryinflammatorycytokines(e.g.,TNF-α,IL-6,IL-8),inthetreatmentofvarioustypesofhumancancers(i.e.,pancreas,renal)showedonlylimitedbenefit.Thisisnotsurprisingasthefunctionofcytokinevarieswiththeclinicalcontextandthesamecytokinemaypromoteorinhibitcancerprogression.Thesamecytokinecanbebeneficialinsomeclinicalcontextanddetrimentalinothers,andthetermyin-yanghasbeenusedforcytokinebehavior[106].Currentlytherearemultipleclinicalstudiesinprogressusingagentsthattargetcytokines(i.e.,IL-1,CXCR4/CXCL12),transcriptionfactors(i.e.,JAK-STATpathwayinhibitors)orlocalimmune/inflammatorycells(i.e.,macrophagesM2)andthefieldofcancerinflammationiscurrentlyaveryactiveareaofresearch[105,107].TheimmunityinhibitionnetworkTumorpromotinginflammationandanti-tumorimmunityarethetwooppositefactorsthatshapetheevolutionoftumors[108].Asillustratedintheabovesection,tumorsactivelyinduceaglobalinflammatorystate.Theyalsoinhibittheimmunesystem,bothlocallyandsystemically[Figure7].Thelocalinhibitionoftheimmunesystembythetumorcheckpointmoleculeshasbeenwellcharacterizedandtheuseofcheckpointinhibitorsiscurrentlyapprovedinmanytypesofcancers.TumorsmayalsohaveaglobalinhibitoryeffectontheimmunesystemasrecentlyshownbyateamfromtheUniversityofPennsylvania.Theresearchersdescribedthereleaseofexosomescarryingprogrammeddeath-ligand1(PD-L1)ontheirsurfacebymetastaticmelanomacells.StimulationwithIFN-γincreasedtheamountofPD-L1onthesevesicles,whichsuppressedthefunctionofCD8Tcellsandfacilitatedtumorgrowth[108].Tumorcell-derivedexosomescanalsoimpairimmunitythroughdifferentmechanisms:exosomescontainingmiR-203secretedbypancreaticcellsmayimpairactivationoftheimmunesystemthroughdownregulationoftoll-likereceptor4andIL-12[109],exosomescandownregulatethefunctionsofimmunecells[110,111],maypromoteTregsexpansion[112],andinhibittheactivityofnaturalkillers(NK)cells[113].Asisthecasewithinflammation,thereisaco-dependentrelationshipbetweentheimmunesystemandthegutmicrobiome.Theimmunesystemplaysanimportantroleindefiningthecompositionofthemicrobiotaandpreservingtheecologyofthemicrobiota.Reversely,themicrobiotainfluencesallaspectsoftheimmunesystem.Gutmicrobiomeplaysanimportantroleinthetrainingandthefunctionaltuningoftheimmunesystemandcanbeseenasoneofthekeymodulatorsoftheimmunesystem[114].Inadditiontoinfluencinglocalizedimmuneresponses,microbiotaalsohasbroadereffectscontributingtoinnateandadaptiveimmunityatmultiplelevels[115].Myeloidcellsrespondtomicrobialsignals,andinitiateinnateandadaptiveimmuneresponses[99].In2013,ithasbeenshownintwomurinemodelsthatgermfreeorantibiotic-treatedanimalsdidnotrespondtochemotherapy,indicatingthatanintactmicrobiomewasrequiredformodulatingthemyeloid-derivedimmunecellresponsesinthetumormicroenvironment[97,98].Alterationsinthegutmicrobiomecanaffectresponsetoimmunotherapyinseveralcancertypes.Matsonetal.[116]identifieddifferentbacterialspeciesasbeingcriticalforresponsetotherapyintheirpatientswithadvancedmelanoma,withBifidobacteriumlongum,Collinsellaaerofaciens,andEnterococcusfaecium,amongothers,foundtobeenrichedinthefecesofpatientsthatrespondedtoanti-PD-L1.SimilarfindingswerereportedbyRoutyetal.[117]inpatientswithadvancedurothelialcarcinoma,non-smallcelllungcancer,andrenalcellcarcinoma.Patientswhohavebeentreatedwithantibioticswithinseveralmonthsbefore,during,oraftertreatmentwithPD-1/PD-L1blockadehadshorterprogression-freesurvivalandloweroverallsurvivalratescomparedwithpatientswhohadnotreceivedantibiotics.Aftersequencingfecalsamplesfromthesepatients,thegeneraAkkermansiaandAlistipeswereenriched,and,thebacterialspeciesA.muciniphila,specifically,wasfoundtobehighlyrepresentedinpatientsthatrespondedtocheckpointblockade.Theimmunecellsplayadualroleincancer[118,119].Classically,someimmunecellsmaypromotecancergrowth(M2macrophages,Tregscells)andothersfightcancer(M1macrophages,CD8cells).Thisisanoversimplificationasthesametypeofcellsmayplayapro,oranti-neoplasticroledependingonthelocalandsystemiccontext.Forexample,inthemajorityofcancers,anincreasednumberofTregsinthetumorisassociatedwithapoorprognostic,butinpatientswithcolonorbreastcarcinomas,thepresenceandfrequencyofTreginthetumoriscorrelatedwithanimprovedprognostic[120].Asimilarphenomenonhasbeenshownfortumorassociatedmacrophages[121].LikemacrophagesandTregcells,tumor-associatedneutrophilsandNKcellsmayhavebothantitumoralandprotumoralfunctions[122].AsshowninbyLabelleetal.[123],plateletsattractneutrophilsintothetumorthrombicontributingtothemetastaticnichedevelopment.Also,ahighneutrophiltolymphocyteratio,predictspooroutcomeinseveraltypesofcancerincludinglungcancer,pancreaticcancerandcolorectalcancer.Thereisnewdatashowingdirectinvolvementofneutrophilsindifferenttypesofcancerandthereisincreasingevidenceinpreclinicalmodelsthatgranulocyte-CSF(G-CSF)canpromotemetastasis[124,125].Also,asshownbyseveralresearchteams,metastaticcancercellscaninduceneutrophilstoformmetastasis-supportingneutrophilextracellulartraps(NETs)anddrugsthatdegradeNETshavebeenshowntohaveaprofoundinhibitoryeffectonthedevelopmentofmetastaticdiseaseinpreclinicalmodels[126,127].Theglobalmetabolism/cachexianetworkInordertoensuresufficientbiomasssynthesisfortheirgrowth,cancercellsneedtomaintainhighmetabolicturnoverrates.Alargeamountofenergyisrequiredtosupportthisprocess.Forexample,anestimated~17,700kcalarerequiredover3monthstosupportmetastaticcolorectalcancergrowth[128].SincetheseminalworkofWarburg[129],ithasbeenobservedcancercellshavedistinctmetabolicprogramsthannormalcellsandmetabolicreprogramminghasbeenacknowledgedasoneoftheclassicalhallmarksofcancer[19].Themostdistinctivemetabolicdifferencesofcancertissuesareincreasedaerobicglycolysis,elevatedglutaminolyticfluxandenhancedaminoacidandlipidmetabolism.Sometypesofcancercellsutilizeinexcessglucoseand,insomecasessecretelactateeveninthepresenceofoxygen(theWarburgphenomenon).Thepropensityofcancercellstowardsaerobicglycolysisdoesnotseemtoberelatedtoanimpairmentoftherespiration,asrespirationisalsoneededfortumorgrowth[130,131].Insomecancerpatients,lactateisconvertedbacktoglucoseintheliver,aprocessknownastheoncogenicCoricycle[132-134]aprocessthatisenergeticallyveryinefficient.Besidesglucoseandlactate,thereareothernutrimentsneededfortumorgrowthforexample,glutamine,glycineandaspartateforpurineandpyrimidinesynthesis,serineformembranelipidcomponentsynthesis,branchedaminoacids,lipids,acetateandothers[135].NotinallcancerstheWarburgphenomenonispresent,and,sometimes,highglycolyticratesintumorsandmitochondrialrespirationoftenoperatesimultaneouslyintumors[136].AsortofmetabolicparasitismhasbeendescribedatthetissularlevelbyagroupofFrenchresearchers[137]whointroducedtheconceptofthe“reverseWarburgeffect”[138,139].Theseauthorsproposedthataggressivecancercellsare“parasites”thatuseoxidativestressasa“weapon”toextractnutrientsfromsurroundingstromalcells,forcedtoundergoaerobicglycolysis,andproduceenergy-richnutrients(suchaslactateandketones)to“feed”cancercells.Theysuggestedthatstromalcatabolism,viaautophagyandmitophagy,fuelstheanabolicgrowthoftumorcells,promotingtumorprogressionandmetastasis.Whatisalsobecomingapparent,isthatcancercellsortissueshaveanalteredmetabolism,but,theyalsoinducesystemicchangesofthewholebodymetabolismbysecretinghumoralfactors(i.e.,TNF-α,IL-1andIL-6)andpro-cachecticfactors(i.e.,proteolysis-inducingfactorandlipidmobilizationfactor)thatleadtoageneralizedcatabolicstatefollowedbysignificantandprogressiveenergylossfromhosttissueinthefinalstagesofcancer[140,141].AgroupofresearchersfromTaiwanmetaphoricallycomparedtheseinfluencesofthetumoronthehost’smetabolismasa“metabolicdictatorship”,thetumorsimposingtheirhighdemandsonthenormalhostthesemetabolicchanges,ultimately,insometypesofcancers(i.e.,pancreaticorgastriccancer)leadingtocachexia[142].Basically,themetabolicparasitismdescribedatthetissularlevelexistsalsoatthelevelofthewholeorganism[143].Cachexiaisamulti-organsyndromeinvolvingchangesinmanytissuesandorgansbesidesthemuscle,theadiposetissueandthetumoritself,otherorgansincludingtheliver,thepancreas,thebrainandthegut[144][Figure8].Itinvolvesup-regulatedtissuecatabolismandimpairedanabolism,releaseoftumor-derivedcatabolicfactorsandinflammatorycytokines,andneuroendocrinedysfunction[145].AspreviouslysuggestedbyAl-ZoughbiandPorporato,theglobalmetabolicchangesthattumorsexertonthewholeorganismareduetoaprecisereprogrammingofthedifferentkeystructuresinvolvedinthenormalbodyenergyexpenditurebalanceandarenotsimplycomplicationsoftumorprogression[6,134].Thisiswhytheseauthorsintroducednewterminologytodescribethisphenomenon,i.e.,“macroenvironment”[6]and“metaboliccancersyndrome”[134].Inadditiontothedirecteffectsoftumor-derivedcytokinesonindividualorgans,thereisalsoaninterplaybetweenmuscle,fat,andliverinvolvingseveralsignalingpathwaysandmetabolitesleadingtopathologicnetworksformationresultingindisruptionofkeymetabolicpathways[140][Figure8].Theincidenceofcachexiaamongcancerpatientsisveryhigh,especiallyingastricandpancreaticcancerwheretheincidenceismorethan80%.Oneofthemaincausesofcancercachexiaisinflammation.Thecytokinessecretedbythetumormayleadtothesymptomscommonlyassociatedwithcachexia(lossofapetite,pain,fever,fatigue,cachexia)but,ultimately,cachexiaisdependentonthepatientresponsetotumorprogressionandtheactivationoftheinflammatoryresponse[146].OneofthekeycytokinesinvolvedincachexiaisIL-6,linkedtobothcachexiaandmetastasisevents[86],but,alsoothercytokines-suchasTNF-α,IL-1β,andTGF-β-areinvolvedandtheymayinduceinflammationandmuscularandadiposetissuewasting[147,148].Pro-inflammatorycytokinespromotealsoashiftinliverproteinsynthesistowardstheproductionofCRPinsteadofalbumin-whichcontributestosustainingchronicinflammation[149].Inflammationisthekeytriggerofmusclewastinginducingalterationsinproteinandaminoacidmetabolism,togetherwithactivationofapoptosisanddecreasedregeneration[144].Besidesmuscleswasting,adiposetissuewastingisalsopresentinthemajorityofcachexiapatients.Indeed,cachecticpatientsmanifesthighlevelsofcirculatingfreefattyacids,glycerolandtriacylglycerol[150]andthetriggeroflipolysismaybealsosystemicinflammation[151].Anothercharacteristicofcancercachexiaistheprogressiveswitchfromwhiteadiposetissuetobrownadiposetissue-brownadiposetissuederivesitsnamefromthedarkercolorassociatedwiththeenrichmentinmitochondria[152].Pro-inflammatoryfactorseitherderivedfromthehostimmunesystemorthetumor,contributetothisswitch[152].Browningstronglycontributestotheincreasedenergyexpenditurecommonincachecticpatientsand,interestingly,cachecticlipidwastingoccursmostlyintumorsactivelysecretingparathyroidhormone-relatedprotein[152,153].Pro-inflammatorycytokines,suchasIL-6,IL-1,TGF-β,andTNF-α,arecommondenominatorsbothformetastasisandinflammationandforthemetabolicreprogrammingassociatedwithcachexia[86,122,133]andtheirunderlyingmolecularpathwaysmightoverlap[154].Oneofthesemolecularpathwaysmightbeexosomesecretionbytumourcellsoradiposetissue.Ithasbeenshownrecentlythattumorrelatedexosomesplayakeyroleinactivatingtheinflammatoryprocessincancer;thus,theymightbeinvolvedinbothhost-wastingprocesses,aswellasmetastaticdissemination[155-158].Asadirectproofofthisconcept,astudy[159]publishedin2014,showedthatcancer-derivedmicrovesiclescontainingmiR-21induceapoptosisofskeletalmuscleandlipolysisoftheadiposetissue.Similarly,anotherstudydemonstratedthatcancerassociatedmicrovesiclesinducemusclewastinginmicethroughreleasingextracellularHsp70andHsp90[155].Wewilldescribebrieflybelowthecontributionofdifferentorgansorbodysystemstocachexia.First,theliverplaysamajorroleincachexia.IntheKRAS/P53mousemodelithasbeenshownthatlungtumorsactdistallyontheliverandreprogramshepaticmetabolismthroughalteredpro-inflammatoryresponseviatheSTAT3-Socs3pathwayresultingininhibitionofhepaticinsulinsignaling,increasedglucoseproductionandaderegulatedlipidsynthesis[160].Theauthorssuggestedthattumor-secreted‘waste’suchaslactateisconvertedtopyruvateandshuntedthroughgluconeogenesistoproduceglucose,whichcanfurthersatisfytheheightenedenergeticdemandofcancercells.AresearchteamcoordinatedbyDouglasFearonalsodemonstratedintwomousemodelsofcancer-inducedcachexiathatinpre-cachecticmice,evenbeforetheonsetoftheweight-losingphaseofthesyndrome,tumor-inducedIL-6hasalteredthecapacityofthelivertorespondtocaloricdeprivation[141].Tumorsinduceareprogrammingofthehepaticmetabolismblockingthehost’scapacitytomakeavailableendogenoussourcesofenergythatcompensatefordecreasedcaloricintake.Throughsupressingketogenesis,thetumorhampersthehost’scapacitytoproduceendogenoussourcesofenergythatcompensatefordecreasedcaloricintake.Thisenergydeficitmagnifiesthehoststressresponseandleadstoincreasedglucocorticoidlevelsthatsuppressthetumorimmunity[141].Usinganinduciblelungcancermousemodel,aresearchgroupfromWCMC,co-ordinatedbyLewisCantley,foundthatcachexiawasassociatedwithlowketonesandincreasedglucocorticoidlevelsthatsuppressestumordirectedimmunity[161].Thelowketoneslevelassociatedwithreducedexpressionofhepaticperoxisomeproliferator-activatedreceptor-α(PPARα)targetsthatregulatefattyacidoxidationandketogenesis.Treatmentwithfenofibrate,aPPARαagonistrestoredhepaticketogenesis,preventedtherelianceonhepaticgluconeogenesis,andskeletalmusclewasting.Thismodelwasconsistentwiththehypothesisthatglobalinflammationinducedbythetumorsignalsthebrainthatincreasescorticotropin-releasinghormone(CRH)leadingtoglucocorticoidproductionthatwillinducetype2-skeletalmusclefibersbreakdown[161].Thepancreasalsoplaysanimportantroleincachexiathroughsecretionofinsulinandglucagon.Insulinresistanceisbothariskfactorforcancerandisassociatedwithcancerprogression.Theincreaseininsulinleveldrivenbyinsulinresistancecandrivecancergrowthbothdirectlythroughinsulinreceptors,andIGF-1receptorspresentonthesurfaceofcancercells[162,163]andindirectlybypromotinglivergluconeogenesisandmuscularwasting.Also,theincreasedproductionofglucagoninthealphaisletofpancreasduringcancerprogression,mayalsoincreaselivergluconeogenesis[164].Branchedaminoacidsreleasedfromthemusclewillbeusedintheliverforgluconeogenesisorproteinsynthesisinlungtumors[165].Interestingly,theincreaseofbranchedaminoacidsbloodlevelsmayprecedetheclinicalappearanceofpancreaticcancerbyseveralyears[166].Theimpactofgutoncachexiaismostlythroughthegutmicrobiota.Alterationofthegutfloraduetoundernutritionandchemotherapyultimatelyaffectsspecificmetaboliteavailabilityandabsorption,whichinturnaffectstumorgrowthandcachexia[167].Hostmetabolismandenergybalancearealsoinfluencedbyaninterplaybetweentheintestinalmicrobiota,bileacidsandnutrientsthatmayhaveanimpactonglobalinflammation,immuneresponses,guthormonesecretionandneuronalactivity[168].Severalhormonesincludinginsulin,cathecolaminesandatrialnatriureticpeptideareinvolvedinlipolysis[169].Besidestheendocrinesystem,thebrainisalsoactivelyinvolvedinthecachecticsyndromebycontrollingfoodintakethroughappetite,satiation,tasteandsmelloffood.ReceptorsofTNF-αandIL-1arefoundinthehypothalamicareasofthebrain,whichregulatefoodintake.AnorexiainducedbybothTNF-αandIL-6canbeblockedbyinhibitorsofcyclooxygenase,suggestingthataprostaglandin,suchasPGE2,maybethedirectmediatorofappetitesuppression[169,170].Autonomicnervoussystemdysfunctionhasbeenalsodescribedincancerpatientswithcachexia[171].IL-6wasfoundtostimulatehypothalamicreleaseofCRH,andincreaseglucocorticoidproduction[172].Structuralandfunctionalheartchangessimilartothosefoundincardiacfailureareoftenassociatedwiththecachexiasyndrome.Inadditiontoalossofskeletalmusclemassandfunction,manypatientswithcancercachexiaalsoexperiencecardiacatrophy,remodeling,anddysfunction,whichinthefieldofcancercachexiaisdescribedascardiaccachexia[173,174].IthasbeenshownformorethantwodecadesthatcardiaccachexiaislinkedtoraisedplasmalevelsofTNF-αandotherinflammatorycytokinesandthatthedegreeofbodywastingisstronglycorrelatedwithneurohormonalandimmuneabnormalities[175].IsraelandSchwartz[176]postulatedthatcancercellshavehybridmetabolicfeaturesthattakeadvantageofthecatabolicstatethattheyalsoinitiallyinduce.ThetwoFrenchauthorsproposedacomprehensivemodelofthesystemicmetabolicchangesinducedbycancerthatIwilldescribebriefly.Normally,instarvation,whenbloodglucoseleveldecreases,glucagonandepinephrineactivategluconeogenesisandketogenesistoformnutriments,mobilizingbodystores.Onthecontrary,whenglycemiaiselevated,thepancreasreleasesinsulin,activatinganabolismandoxidativeglycolysis,energybeingrequiredtoformnewmoleculesorrefillstores.Usually,thesetwooppositephysiologicalstatesexcludeeachother;whenanabolismistriggeredbyinsulin,catabolismisblockedandthenormalorganismmetabolicconfigurationisfinelyregulatedbythestateofkeyenzymes.Dependingontheneeds,enzymesfunctionlikeswitchesanddirectthemetabolismtowardsdifferentpathwaysthatareopenorcloseddependingontheirphosphorylationstate.Incancer,someoftheirenzymesarephosphorylatedasnormallyobservedwhencatabolichormonesstimulateGs-coupledreceptors,whereasotherenzymesadoptaconfigurationnormallyfoundinanabolicsituations,mediatedviatyrosinekinasereceptors.Basically,despitethefactthattheorganismasawholeisinastarvation-likestateinducedbycancer,tumorcellshavetheiranabolicpathwaysturnedONthroughtyrosinekinasereceptors,sometimesconstitutivelyactivatedthroughgeneticmutationsoramplifications.Thepyruvatekinase(PK)andpyruvatedehydrogenase(PDH)ofcancercellsareOFFinaphosphorylatedformbutthecitratesynthaseisONpullingtheglucosefluxintheglycolyticdirection.So,ononehand,cancercells,havetheirPKsandPDHsinhibitedbyphosphorylation,likeingluconeogenesis,ontheotherhandtheyhaveanincreasedglycolysisthatwillbeusedforthesynthesisofnewmolecularbuildingblocksfornewmitoticdaughtercells.Asaresult,cancercellsburnglucoseandincreasethetumormass,atthesametimeconsumingthemuscleproteinsandthelipidstoresoftheorganism.Theoutcomeofthishybridrewiredmetabolismgivesthemaselectiveadvantageovernormalcells[176].Insubsequentpublications,IsraëlproposedthatthereasonforthishybridmetabolismisanalterationoftheGABAselectionswitchbetweenanabolismandcatabolisminthepancreas,leadingtoaconcomitantreleaseofcatabolicglucagonandanabolicinsulin[177].Accordingtohim,thefirstcellsthatmanifestahybridmetabolismarethestemcells.Subsequently,thismetabolicrewiringisstabilizedthroughmutationsorepigeneticchangesselectingthemostaggressivepopulationandcancercellsarise.Inhismodel,thepancreaticalterationistheprimummovensofcancerfollowedbythemetabolismswitchofstemcells.Thestemcells,initiallycommittedtorepairanorgan,subsequentlytransformintocancercellsthatusetheirmetabolicadvantagetocompeteforresourceswiththerestoftheorganism[177-179].ThepracticalvalueofIsraël’smodelisfirstthepredictionthatcancercouldbedetectedseveralyearsbeforeitsclinicalmanifestationsbecauseofspecificmetabolomechanges,and,second,theproposalofcorrectingtheGABAswitchpancreaticanomalyasamethodforcancerprevention.In2016,agroupofGermanresearchersanalyzingdatafromtheEuropeanProspectiveInvestigationintoCancerandNutritionstudyfoundthatabnormalitiesoftwolipidmetabolites(highlevelsofphosphatidylcholinePCaeC30:0andlowlevelsoflysophosphatidylcholines,C18:0,wereconsistentlyassociatedwithincreasedriskofbreast,prostateandcolorectalcancer.Theseabnormalitiesweredetectedseveralyearsbeforetheclinicalapparitionofcancerpointingtoaglobalmetabolicshiftinphosphatidylcholinemetabolismthatmaydrivetumorigenesis[180].ThethrombosisnetworkTheroleofdifferentbloodcomponents[181]andthelymphaticsystem[182]inthemetastaticprocesshasbeencomingmoreandmoreintofocus.Therapiestargetedagainstotherbloodandlymphaticfactorsinvolvedincancerareindevelopment[181,182].Asmanyas20%ofcancerpatientsmayhaveathrombosiseventduringtheirlifetimes[183].Asshowninarecentreview[184],areciprocalconnectionexistsbetweencancerandthrombosis,ononesidecancercellssupportingclotformation,ontheotherside,clottingproteinssupportcancergrowthanddissemination.Cancerisassociatedwithastateofhypercoagulability,driveninpartbythereleaseofprocoagulantfactors,suchastissuefactor(TF),releasedbythemalignanttissue,aswellasbyinflammation-drivenactivationofendothelialcells,platelets,andleukocytes.Also,cancercellsareabletodirectlyadheretohostcells(i.e.,endothelialcells,monocytes,platelets,andneutrophils),therebystimulatingadditionalprothromboticpropertiesofthehostthrombosiseffectorcells[184][Figure9].TFisconsideredtobethemajormoleculardriverofcancer-associatedcoagulopathyandthromboembolicdisorders.Itisexpressedeitherbycancercellsoritsexpressionisinducedbycancercellsinnormalvasculartissuesbyboththereleaseofsolublemediatorsandthedirectcancercell-hostcellcontact.Itsexpressionisrelatedtowelldefinedoncogenicevents:epidermal-to-mesenchymaltransformation,TGF-βsignaling,EGFR,phosphataseandtensinhomolog(PTEN)andSrcpathways,hypoxiainducedsignaling,etc.Themajorityofhumanepithelialcancers(lung,colorectal,prostate,breast,pancreatic,gastric,melanoma,etc.)arecharacterizedbyabundantlevelsofTF[185].Also,asshownbyaCanadiangroupinagliomamodel,TFmayalsocontrolthestateoftumordormancybyrecruitingtothetumornichemyeloidandbloodvesselsformingcells[186].Interestingly,theprocoagulantandthesignalingeffectofTFintumorbiologycanbetargetedseparately,andtherearetherapiesunderinvestigationthattargetsolelythesignalingeffectofTFwithoutaffectingitshomeostaticfunction[187].Inaddition,cancercellinteractionswithplateletsandneutrophilscontributetocancercelladhesion,extravasation,andtheestablishmentofmetastaticlesions[188].Platelet-derivedsignalsarerequiredfortherapidintravascularrecruitmentofneutrophilstocirculatingtumorcells(CTCs)thrombicontributingto“earlymetastaticniches”[123].Also,TGF-βsecretedbydegranulatingplateletsmaycontributetotheactivationtheNF-κBpathwayincarcinomacells,therebyinducingorsustainingtheexpressionofEMTprogramsintheCTCs[189].Selectinsarecarbohydrate-bindingmoleculesthatbindtoglycanstructures,presentonendothelialcells,plateletsandleukocytes.Therearethreemembersoftheselectinfamily:P-selectinexpressedonactivatedplateletsandendothelialcells,L-selectinpresentonleukocytesandE-selectinexpressedonactivatedendothelialcells[190].P-selectininparticularseemstoplayacrucialroleinseveraltypesofcancermetastasisbymediatingtheaggregationofplateletswithtumorcellsformingclots.ArecentstudyshowedthatintravenousinjectionofmelanomacellsintoWTmiceresultedinmultiplelungmetastases,whileinP-selectin-deficientmicepulmonarytumormetastasisandtrappingoftumorcellsinthelungwassignificantlyreduced[191].Modulatingtheinteractionbetweencancercellsandthecirculatingbloodcells,andrespectively,betweencancercellsandtheendothelialcellsmayrepresentnoveltherapeuticapproaches.Forexample,thereisexperimentalevidencethattargetingspecifictypesoftheintegrinreceptorspresentonthesurfaceoftheplateletsefficientlyreducestumorcellcolonizationintothelungs,suggestingthattheycouldrepresentinterestingtargetsforanti-metastaticdrugs[192].AteamfromFrancecharacterizedthemicroparticulosome,therepertoireofplasmamembranevesiclesproducedbydifferenttypesofcellsandwasabletodifferentiateamicroparticlesignatureassociatedwithpancreaticandcolorectalcancer[193].ThesameteamshowedinsyngeneicectopicandorthotopicmicemodelsthattreatmentwiththedrugClopidogrelpreventedthebindingofcancercell-derivedmicroparticlestofibrinogen-plateletsaggregatesatthesiteofthrombosis,andreducedthemetastasisandtheextentofthrombosisassociatedwithcancer[194].Procoagulantfactorsassociatedwithexosomesfromtumorshavebeendescribedforalmostfourdecades[195]TissuefactorassociatedwithexosomeshasbeenfoundtoberesponsiblefortheTrousseausyndromeinonepatientwithlungcancer[196]andthereareseveralstudiesdocumentingtheprocoagulanteffectoftumorexosomes[197].Theneuro-endocrinenetworkBoththecentralnervoussystemandtheneurovegetativenervoussystemareintimatelyinvolvedincancer.Oneofthemoststudiedlinksbetweencentralnervoussystemandcancerisstress.Theneuroendocrinemediatorsreachthecellsoftheimmunesystemeitherthroughtheperipheralcirculationorthroughdirectinnervationoflymphoidorgans[Figure10].AssuggestedbyClaireMagnon[198],apossibleexplanationfortumorformationassociatedwithstressmightrelyontheactivationofthesympatheticnervoussystem(SNS)throughthesympathetic-adrenal-medullaryaxis,whichcontrolsthereleaseofadrenergicneurotransmitterssuchasepinephrineornorepinephrinebytheadrenalsintothebloodstreaminsupportofthefight-or-flightreflex.Catecholamine-mediatedsuppressionofcellularimmunitymayplayaroleinincreasedgrowthofcertaintumors[199].Also,primaryandsecondarylymphoidorgansareinnervatedbysympatheticnervefibers.Lymphocytesandmonocytesexpressreceptorsforseveralstresshormones,includingCRH,adrenocorticotropichormone(ACTH),cortisol,norepinephrine,andepinephrine.Therefore,itispossiblethattheneuroendocrinehormonesreleasedduringastressfuleventcouldalterimmunefunctionandsubsequentlyalterthecourseofimmune-baseddiseases[200].Ithasbeenreportedthatmicelivinginanenrichedhousingenvironment(EE)showreducedtumorgrowthandincreasedremission[201].Thiseffectwasdescribedinmelanomaandcoloncancermodels,and,itwasproventhatitwasnotcausedbyphysicalactivityalone.Serumfromanimalsheldinanenrichedenvironment(EE)inhibitedcancerproliferationinvitroandwasmarkedlylowerinleptin.Hypothalamicbrainderivedneurotrophicfactor(BDNF)wasselectivelyupregulatedbyEE,itsgeneticoverexpressionreducedtumorburden,whereasBDNFknockdownblockedtheeffectofEE.ThehypothalamicBDNFdownregulatedleptinproductioninadipocytesviasympathoneuralβ-adrenergicsignaling[201].Akeycentralnervoussystemstructureinvolvedincanceristhehypothalamus.Inthecontextofsystemicinflammation,thehypothalamusintegratessignalsfromperipheralsystems,translatingthemintoneuroendocrineperturbations,alteredneuronalsignaling,andglobalmetabolicderangements[202].Cytokines,likeIL-1βandTNF-α,forexample,generatedintheperipheryduringcancerprogressionareamplifiedandmodifiedwithinthehypothalamus,leadingtohypothalamicinflammationandaberrantactivityofweight-andactivity-modulatingneuronsthatmayinducemuscleatrophyviaactivationofthehypothalamic-pituitary-adrenalaxis[203,204].Hypothalamicinflammationmaybefollowedbydysregulationofhomeostaticregulationofautonomicnerves(innervationofmuscles,liver,fattissue,endocrineglandsandotherorgans)thatmayfurtherpotentiatedysregulationofmetabolismandenhanceperipheral,pro-inflammatoryreactions[205].Hypothalamusappearstobeanimportantcontributorinthedevelopmentandmaintenanceofthecachecticstate[202].Lowerhypothalamicactivityhasbeendemonstratedbyfunctionalmagneticresonanceimagingscansinpatientswithcachexiaassociatedwithadvancedlungcancer[206].Auniquecrosstalkbetweenthecentralnervoussystemandprostatetumourswasrecentlyrevealed.Inastrikingexperiment[207],usingamousemodelofprostatecancer,aFrenchgroupdemonstratedaprocessoftumour-associatedneo-neurogenesis,inwhichneuralprogenitorsleavethebrainofthemouseandreach,throughthesystemiccirculation,theprimarytumourorthemetastatictissues.Oncearrivedthere,theydifferentiatedintonewadrenergicneuronsthatareknowntosupporttheearlystagesofthedevelopmentofcancer.Theauthorssuggestedthepossibilitythatthetumouritselfmightdepleteneurogenicnichesinthebrainbyattractingneuralprogenitorstosupportitsowndevelopment[207].Recentexperimentssuggestadirectrelationshipbetweentheneurovegetativenervoussystemandcertaintumors.AsreviewedbyCole[208],SNSactivationmodulatesgeneexpressionprogramsthatpromotemetastasisofsolidtumoursbystimulatingmacrophageinfiltration,inflammation,angiogenesis,epithelial-mesenchymaltransition,andtumourinvasion,andbyinhibitingcellularimmuneresponsesandprogrammedcelldeath.SNSactivationmayalsoinfluencecancerprogressionviaindirectpathwaysinwhichSNSinnervationofdistanttissuestriggerssecondaryhormonalorcellulareffectsthatsubsequentlyaffectthetumourmicroenvironment.Forexample,sympatheticinnervationofbonemarrowcanstimulatetheproductionofmyeloidlineageimmunecellswhichmayinfiltratethetumoralmicroenvironmentandpromotemetastasis[209-211].Inprostatecancer,sympatheticnervefibersmayhelptumorsgrowbyinteractingwithbeta-adrenergicreceptorsonstromalcells[212].Epidemiologicalstudiesshowedthatmenwithprostateadenocarcinomawhotakenon-selectivebeta-blockershavelowerprostatecancer-specificmortalityrates[213].Asimilaractivityofbeta-blockershasbeendescribedinmelanomaorbreastcancerpatientsindicatingthatadrenergicsignalingmightbeinvolvedinvarioustypesofcancer[214,215].Iftheroleofthesympatheticsystemincancerhasbeenwelldocumented,thecontributionoftheparasympatheticdivisionoftheautonomicnervoussystemislessclear.AsshownbyKevinTraceyandhiscollaboratorsfromtheFeinsteinInstituteonLongIsland,NewYork,theefferentvagusnerve-mediatedcholinergicsignalingcontrolsimmunefunctionandpro-inflammatoryresponsesviatheinflammatoryreflex[216].TandBcellsexpressmostcholinergicsystemcomponents-e.g.,acetylcholine,cholineacetyltransferase,acetylcholinesterase,and,bothmuscarinicandnicotinicacethycholine(Ach)receptorsandthecholinergicsignalsgeneratedbyimmunecellsappeartobetriggersofboththeinitiationandterminationofcytokinesynthesis(e.g.,IL-2inTcellsandTNF-αinmacrophages)[217].ArecentstudyfromtheUniversityofSichuan,China,suggestedthatparasympatheticinnervationmaycontributetostomachcancerdevelopmentviaacetylcholine-mediatedactivationofmuscarinicacetylcholinereceptors[218].Inamousemodelofstomachcancer,vagotomysuppressedgastrictumorigenesis[219].Alsoinaprostatecancermousemodelcholinergic-inducedtumorinvasionandmetastasiswereinhibitedbypharmacologicalblockadeofthestromaltype1muscarinicreceptor,leadingtoimprovedsurvivalofthemice[212].However,asdiscussedbyColeetal.[208],cholinergicblockademaystimulateindirectlytheSNSpromotionofcancer.Analternativestrategywouldbetotargetneurotrophicgrowthfactorsincancerasmanycancersareassociatedwithnerveinfiltration.Anantineurotrophicantibody(tanezumab)hasbeendevelopedbyPfizerandiscurrentlyusedasananalgesic[220].Asmanyas8%ofcancersmightbeassociatedwithendocrineparaneoplasticsyndromes[221],but,adetaileddiscussiononthesesyndromes,isbeyondthescopeofthisarticle.Inthecontextofourdiscussiononthesystemichallmarksofcancer,itisclear,however,thatproductionofspecifichormonesbytumorsofparticulartypesisnotarandomevent[222].Forexample,squamouscellcarcinomastypicallyproduceparathyroidhormone-relatedproteinandsmallcellcarcinomas(SCC)ofthelungtypicallyproducecalcitonin,adrenocorticotropin(ACTH),orgastrinreleasingpeptide(GRP).Insomecaseforexample,bombesin(BBS)-likeneuropeptidessecretedbySCCcanactasautocrinegrowthfactors[223].Besidestheinvolvementofcathecolaminesincancerdescribedbefore,severalotherhormones(i.e.,estrogens,androgens)arewellknowntopromotecancerdevelopmentandmetastasis[224].Also,theroleofthethyroidhormonesinpromotingthemetastaticprocesshasbeenrecentlydescribed[225].Otherhormones,likemelatonin,forexample,mayinhibitcancermetastasis[226].Patientwithcancerhavepoorsleepandthismayinfluencemelatoninsecretion.Inarecentstudydonebreastcancerwomenserummelatoninlevelscorrelatedsignificantlywithself-reportedsleepqualityandpsychometricprofilesofdepression[227].Interogatingthesystem:cancerinducedsystemicpathologicnetworksIntherecentyears,liquidbiopisesand“omics”becameusefultoolsofthedevelopingfieldofprecisiononcology.Throughliquidbiopsiesand“omics”wecaninterogatetheglobalcharacteristicsofthetumoritself,andobtainusefulinformationthathelpusinthediagnostic,prognosticandtreatmentofcancerpatients.Inthenearfuture,ofgreatimportancewillbethecharacterizationofthedifferentCISPNthroughspecificbiomarkersdesignedtoanalyzethesystemiccancerhallmarks.ThisinformationmightbeusedtorefinethestagingandprognosticofpatientswithmetastaticcancercurrentlylumpedindiscriminativelyunderonelargeumbrellabytheTNMstagingand,also,designandmonitortargetedinterventionsdirectedspecificallyagainstkeyCISPNthatbehaveasmasterregulatorsofthemetastaticprocess.CirculatingmiRNApresentinsidetheexosomesareplausibleCISPNmasterregulators[42].ExosomalproteinsisolatedfromplasmaofcancerpatientshavebeenrecentlycharacterizednotonlyasusefulbiomarkersassociatedwithseveralcancertypesbutalsofordissectingdifferentCISPNinvolvementinthemalignantprocess[43].Potentialsystemicbiomarkersmightbealsofoundanalysingmetabolomicsdata.Inorderforatumortodevelopandspreadneedsenergyand,globalmetabolicreprogramming,mightwellbeoneofthekeysystemiccancerhallmarksdrivingcancerfromitsemergencethroughitsprogressionandmetastasis.TheConsortiumofMetabolomicsStudies(COMETS)wasestablishedin2014tofacilitatelarge-scalecollaborativeresearchonthehumanmetabolomeanditsrelationshipwithdiseaseetiology,diagnosis,andprognosis[228].Systemicmetabolicchangesinadvancedcancershavebeendescribedinthepastforseveraltumortypes[229,230].Theessentialroleofmetabolismatthecellularlevelincontrollingcancerhallmarkswasrecentlyproven.Usingmoleculardataof9,125patientsamplesfromTheCancerGenomeAtlas,agroupofresearchersidentifieddistinctmetabolicexpressionsubtypesin27cancertypesbasedonmRNAexpressionpatternsofsevenmajormetabolicprocesses(aminoacidmetabolism,carbohydratemetabolism,integrationofenergy,lipidmetabolism,nucleotidemetabolism,tricarboxylicacidcycleandvitamin&cofactormetabolism)[231].Themetabolicexpressionsubtypescorrelatedwithclinicaloutcomes:subtypeswithupregulatedcarbohydrate,nucleotide,andvitamin/cofactormetabolismmostconsistentlycorrelatedwithworseprognosis,whereassubtypeswithupregulatedlipidmetabolismshowedtheopposite.Themostinterestingfindingwasthatthesemetabolicsubtypeswerenotrelatedtospecificgeneticsomaticdriversbutwereintrinsicallycoupledwithcancerhallmarkpathways(i.e.,angiogenesis,celldivision,etc.)andweremodulatedbyhighlyrecurrentmasterregulatorsacrosscancertypes,ultimatelyleadingtoconsistentsurvivalpatterns.Asaproof-of-conceptinvitroexperiment,theauthorsalsodemonstratedthatknockdownoftwomasterregulatorsgenesofcarbohydratemetabolicsubtypes(SNAI1inalungcancercelllineorRUNX1inasarcomacellline)significantlydecreasedtheconcentrationsofintracellularglucose.Accordingtothismodel,themastermetabolicregulatorsidentifiedwerekeynodeswiththegreatestinfluenceonsystems-levelmetabolicactivitiesandtargetingthesemetabolicmasterregulatorsmayinhibittumorprogression.Strikingly,allfourmastermetabolismregulatorsgenesidentifiedinthe8cancertypeswithsignificantlyworsesurvivalratesduetoupregulatedcarbohydratemetabolism,SNAI1,RUNX1,RUNX2,andFOSL1[231],playalsoakeyroleinembryonaldevelopmentandEMT[13,232,233]andmightbealsomasterregulatorsofthemetastaticcellularprogram[Figure3].NoveltherapeuticapproachesusingthecancersystemmodelMarkVincentclassifiedcancertreatmentsintwofundamentallydifferentapproaches:a“causality-inhibition”strategy,targetedtowardsthecancercause,whichatpresentisstilla“moonshot”,remotefromourcurrentcancertreatmentpractices,and,an”acausal”approachthattargetaspecificcancermarkerorsignature[234].Atpresent,manyaspectsofcancer,ingeneral,and,bylarge,themetastaticprocessarestillincompletelychartedterritories,and,therefore,mostourcurrentcancertreatmentsarenotdirectedtowardsthespecificcausethattriggeresthecancerprocess.Inthenearfuture,hopefully,oncethemechanismsofthedifferentcancercellularprogramsarebetterdescribed,wewillbeabletodesigneffectivecausality-inhibitiontherapies.Forexample,theimmunomodulatoryfunctionofexosomesmaybeexploitedfortherapeuticeffect.In2008,aChinesegroupfromGuangxiUniversity[235]reportedtheresultsofaPhaseIstudyinwhich40patientswithadvancedcolorectalcancerreceivedfourweeklyintravenousinjectionsofascitesderivedexosomesplusorminusGM-CSF.Stablediseaseandaminorresponsewereobservedintwoofthepatientstreated.Morerecently,anotherChinesegroup[236],suggestedthatmiRNAdepletedpancreaticcancerexosomesmightenhancethekillingcapacityofdendriticorcytokine-inducedkillercells,andactivatetheimmunesystemagainstpancreaticcancer.Theexosomespackagingiscloselyregulated,and,differentclonesevenfromthesametumormaysecretexosomescarryingadifferentcargowithdifferentproperties[237].DismantellingcancernetworksattheorganismlevelNetworks,composedofvariousnodesandedgesmaybedescribedatdifferentlevelsinanorganism.Inacell,nodesmaybeaminoacidsofcancer-relatedproteins,whereedgesaretheirdistancesinthe3Dproteinstructureornodesmayrepresentprotein/RNAmoleculesorDNA-segments,whereedgesaretheirphysicalorsignalingcontacts.Inmetabolicnetworks,nodesaremetabolitesandedgesaretheenzymes,whichcatalyzethereactionstoconvertthemtoeachother.Atthetissularlevels,nodescanbethecancercellsandthestromalcellsandtheedgesthedifferentmoleculesthroughwhichtheycommunicate.Atthelevelofthewholeorganism,nodesmayrepresentthedifferentcomponentsofthecancersystemandthedifferentcomponentsofthenormalbodysystems[Figure2]and,theedges,cellular,exosomalorproteicsignalsexchangedbetweenthem.Cancerisarobustsystemthatisabletomaintainstablefunctioningdespitevariousperturbations.Theessentialrobustnessofcancerismaintainedthroughheterogeneousredundancy,i.e.,thecancertissuecontainsaheterogeneousdistributionofgeneticallydifferentcancercellsmaintainedbygeneticinstability[238].Communicationiscrucialforthedevelopmentofthecancersystem.Inordertobeabletodismantlesuchacomplexmulti-layerednetworkascancer,noveltargetedmulti-scaleapproachesareneededthattargetsimultaneouslykeyelementsofthecellular,tissularandsystemiccancernetworks[239].Targetingthemastergeneticregulatorsorthehubsatthecellularlevelledtopromisingresults[28,240].Also,atherapeuticapproachbasedongametheorytargetingthecollaborationbetweencancercellsatthetissularlevelwasrecentlyproposedbyArchettiandPienta[241].Itisconceivablethatusingsimilarmathematicaltools,treatmentstargetingspecificCISPNelementsattheorganismiclevelcanbedesigned.Evaluatingthecancersystemvulnerabilitiesthroughanalysisofnetworktopologyand,especially,networkdynamicscanpredictnovelanti-cancerdrugtargets[242].Ingeneral,therapeuticapproachestargetinglevelsabovethecellularlevelmaybelessaffectedbycancergeneticinstabilityandheterogeneitythantreatmentstargetingthecancercellsthemselves.Asuggestiveexampleistheimprovementinthelongtermsurvivalassociatedwithcheck-pointinhibitorsthattargetcancertissueasopposedtocancercells[243-245]asopposedtothealmostuniversaldevelopmentofacquiredresistenceassociatedtotheuseoftyrosinekinaseinhibitorsthattargetspecificintra-cellularcancernetworks[246].Anattractivetop-downregulatorofcanceristhenervoussystemandnoveltherapiescouldbedesignedstimulatingorinhibitingsomeofitscomponents[198].Asaproofofprinciple,amplyfingasinglegeneinthehypothalamusofobesemicethroughgenetransferofBDNFinhibitedbreastcancerprogressionandmetastasis[247].“Horizontal”vs.“vertical”approachesModalitiestotargetcanceratthecellularlevel(i.e.,tyrosinekinaseinhibitorsandantibodiesdirectedtotheantigenspresentonthesurfaceofthecancercells)havebeenalreadyinplacenowforalmosttwodecades.ImmunotherapieswithcheckpointinhibitorsandCAR-Tcellapproacheshaverecentlyimprovedthequalityanddurationoflifeofmanycancerpatients.Weenvisionthatagentstargetingthesystemichallmarksofcancerandinterruptingthecommunicationbetweenthedifferentcomponentsofthecancersystemwillrepresentthe“newwave”ofcancertreatments.Inthemulti-scalemodelofcancera“horizontal”approachisconsideredtargetingthecross-talkbetweenthedifferentcomponentsoftheCISPNandblockingthecommunicationbetweenitspartsanda“vertical”approachwouldusedrugsthatactsimultaneouslyatthecellular,tissularandsystemiclevelinaparticularsub-componentoftheCISPN.Anexampleofa“horizontal”approachisthefindingthattheblockadeoftheCXCL5/7receptorCXCR2,orthetransientdepletionofeitherplateletsorgranulocytes,preventstheformationofearlymetastaticnichesandsignificantlyreducedmetastaticseedingandprogression[123].GranulocyterecruitmentdependsonthesecretionofCXCL5andCXCL7chemokinesbyplateletsuponcontactwithtumorcells[123].Anexampleofa“vertical”approachusingtrans-leveldrugsactingsimultaneouslyatthecellular,tissularandorganismiclevelssimultaneouslyistheuseofbeta-blockers.Somebeta-blockers,forexample,likepropranolol,atthetissularlevelhaveanimmunomodulatoryeffect[248]andattheorganismiclevelalterthemetastaticpotentialofcancercells[208].AgroupofresearchersatPennStateUniversityfoundthatmelanomapatientswhoreceivedimmunotherapywhiletakingpanβ-blockerslivedlongerthanpatientswhoreceivedimmunotherapyaloneorpatinetsthatreceivedimmunotherapyandβ1-selectiveblockers[249].Inafollow-upexperimentwithmice,theresearcherssawthesameresults[249].Bisoprololisanotherselectiveβ1-blockercommonlyusedtotreathypertension,cardiacischemia,andcongestiveheartfailure.Bisoprololimprovedsurvival,increasedtotalheartmass,andotherheartparametersand,importantly,improvedfoodintakeandactivitylevelsinanAH-130tumor-bearingratsmodel[250].ClinicalstudieswithBisoprololareplannedinpatientswithcancercachexia(ProfessorAnker,CharitéHospital,Berlin,personalcommunication).ConclusionCancerisamultidimensionalprocesswithspecificcharacteristicsatthecellular,tissularandtheorganismiclevel.Basicresearchandclinicaldataobtainedoverthelastdecadesuggeststhat,atthemacroscopiclevel,cancerbehaveslikeanevolvingco-dependentsystemthatinteractscontinuouslythroughCISPNwiththemodifiedbodysystems.Cancercellsandcancerstromasecretedexosomes,cytokinesandothersolublefactorstogetherwiththemodified,cancer-supportingbodysystems,areresponsibleforestablishingtheCISPNandthesystemichallmarksofcancer.Withouttakingintoconsiderationthislarger,organism-levelpicture,someofthecurrentlocaltreatmentstargetedtowardsthecancercellsortissuesmayleadtocancerprogression.Forexample,insomecasesofheadandneckcancer,(upto29%insomeseries),checkpointinhibitortreatmentsmayinducecancerhyperprogression[251].Treatmentstargetedtowardsthecancersystemandthesystemichallmarksofcancerareurgentlyneeded.Movingtotheorganismiclevelandtargetingthesystemichallmarksofcancerinconcertedtherapeuticapproacheswithcurrentlyexistingtherapiesmayfurtherimproveourcancerarmamentariumintheimmediatefuture.DeclarationsAuthors’contributionsTheauthorsolelycontributedtothearticle.AvailabilityofdataandmaterialsNotapplicable.FinancialsupportandsponsorshipNotapplicable.ConflictsofinterestTheauthordeclaredthattherearenoconflictsofinterest.EthicalapprovalandconsenttoparticipateNotapplicable.ConsentforpublicationAwritteninformedconsentforpublicationwasprovided.Copyright©TheAuthor(s)2020.References1.Noble D.Atheoryofbiologicalrelativity:noprivilegedlevelofcausation.InterfaceFocus2012;2:55-64.DOIPubMedPMC2.Noble D.Abiologicalrelativityviewoftherelationshipsbetweengenomesandphenotypes.ProgBiophysMolBiol2013;111:59-65.DOIPubMed3.Noble D.Themusicoflife.Oxford;2006.4.Egeblad M,Nakasone ES,Werb Z.Tumorsasorgans:complextissuesthatinterfacewiththeentireorganism.DevCell2010;18:884-901.DOIPubMedPMC5.McAllister SS,Weinberg RA.Tumor-hostinteractions:afar-reachingrelationship.JClinOncol2010;28:4022-8.DOIPubMed6.Al-Zoughbi W,Huang J,Paramasivan GS,Till H,Pichler M,etal.Tumormacroenvironmentandmetabolism.SeminOncol2014;41:281-95.DOIPubMedPMC7.McAllister SS,Weinberg RA.Thetumour-inducedsystemicenvironmentasacriticalregulatorofcancerprogressionandmetastasis.NatCellBiol2014;16:717-27.DOIPubMedPMC8.Borniger JC.Centralregulationofbreastcancergrowthandmetastasis.JCancerMetastasisTreat2019;5.DOIPubMedPMC9.Borniger JC,Walker IiWH, Surbhi,Emmer KM,Zhang N,Zalenski AA,etal.Aroleforhypocretin/orexininmetabolicandsleepabnormalitiesinamousemodelofnon-metastaticbreastcancer.CellMetab2018;28:118-29.e5.DOIPubMedPMC10.Paul D.Cancerthebigpicture:seeingtheforestbeyondthetrees.Oncolog-Hematolog2015;1:28-30.11.Udrişte O.Genaancestralăşiorigineacancerului(inRomanian).Bucharest,Romania:Edituraştiinţificăşienciclopedică;1978.12.Arechaga J.Ontheboundarybetweendevelopmentandneoplasia.AninterviewwithProfessorG.BarryPierce.IntJDevBiol1993;37:5-16.PubMed13.Dongre A,Weinberg RA.Newinsightsintothemechanismsofepithelial-mesenchymaltransitionandimplicationsforcancer.NatRevMolCellBiol2019;20:69-84.DOIPubMed14.Gallik KL,Treffy RW,Nacke LM,Ahsan K,Rocha M,etal.Neuralcrestandcancer:divergenttravelersonsimilarpaths.MechDev2017;148:89-99.DOIPubMedPMC15.Vincent MD.Theanimalwithin:carcinogenesisandtheclonalevolutionofcancercellsarespeciationeventssensustricto.Evolution2010;64:1173-83.DOIPubMed16.Vincent MD.Cancer:beyondspeciation.AdvCancerRes2011;112:283-350.DOIPubMed17.Vincent M.Cancer:ade-repressionofadefaultsurvivalprogramcommontoallcells?alife-historyperspectiveonthenatureofcancer.Bioessays2012;34:72-82.DOIPubMed18.Hanahan D,Weinberg RA.Thehallmarksofcancer.Cell2000;100:57-70.DOIPubMed19.Hanahan D,Weinberg RA.Hallmarksofcancer:thenextgeneration.Cell2011;144:646-74.DOIPubMed20.Nguyen DX,Massague J.Geneticdeterminantsofcancermetastasis.NatRevGenet2007;8:341-52.DOIPubMed21.Chiang AC,Massague J.Molecularbasisofmetastasis.NEnglJMed2008;359:2814-23.DOIPubMedPMC22.Vogelstein B,Papadopoulos N,Velculescu VE,Zhou S,Diaz LAJr,etal.Cancergenomelandscapes.Science2013;339:1546-58.DOIPubMedPMC23.Paget S.Thedistributionofsecondarygrowthsincancerofthebreast.Lancet1889;1:571-3.DOI24.Sugarbaker EV.Cancermetastasis:aproductoftumor-hostinteractions.CurrProblCancer1979;3:1-59.DOIPubMed25.Fidler IJ,Kripke ML.Metastasisresultsfrompreexistingvariantcellswithinamalignanttumor.Science1977;197:893-5.DOIPubMed26.Price JE,Naito S,Fidler IJ.Growthinanorganmicroenvironmentasaselectiveprocessinmetastasis.ClinExpMetastasis1988;96:91-102.DOIPubMed27.McDonald OG,Li X,Saunders T,Tryggvadottir R,Mentch SJ,etal.Epigenomicreprogrammingduringpancreaticcancerprogressionlinksanabolicglucosemetabolismtodistantmetastasis.NatGenet2017;49:367-76.DOIPubMed28.Aytes A,Giacobbe A,Mitrofanova A,Ruggero K,Cyrta J,etal.NSD2isaconserveddriverofmetastaticprostatecancerprogression.NatCommun2018;9:5201.DOIPubMed29.Lambert AW,Pattabiraman DR,Weinberg RA.Emergingbiologicalprinciplesofmetastasis.Cell2017;168:670-91.DOIPubMedPMC30.Hendrix MJC,Seftor EA,Seftor REB,Kasemeier-Kulesa J,Kulesa PM,etal.Reprogrammingmetastatictumourcellswithembryonicmicroenvironments.NatRevCancer2007;7:246-55.DOIPubMed31.Telerman A,Amson R.Themolecularprogrammeoftumourreversion:thestepsbeyondmalignanttransformation.NatRevCancer2009;9:206-16.DOIPubMed32.Bissell MJ,Radisky D.Puttingtumoursincontext.NatRevCancer2001;1:46-54.DOIPubMedPMC33.Orimo A,Weinberg RA.Stromalfibroblastsincancer:anoveltumor-promotingcelltype.CellCycle2006;5:1597-601.DOIPubMed34.Caon I,Bartolini B,Parnigoni A,Carava E,Moretto P,etal.Revisitingthehallmarksofcancer:theroleofhyaluronan.SeminCancerBiol2020;62:9-19.DOIPubMed35.Amson R,Karp JE,Telerman A.Lessonsfromtumorreversionforcancertreatment.CurrOpinOncol2013;25:59-65.DOIPubMed36.Sun Y,Ma L.Theemergingmolecularmachineryandtherapeutictargetsofmetastasis.TrendsPharmacolSci2015;36:349-59.DOIPubMedPMC37.Scheel C,Onder T,Karnoub A,Weinber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Paul D.Thesystemichallmarksofcancer. JCancerMetastasisTreat 2020;6:29.http://dx.doi.org/10.20517/2394-4722.2020.63 Views14056Downloads2107Citations 8Comments07 DownloadandBookmark Download DownloadPDF AddtoBookmark ShareThisArticle ArticleAccessStatistics Full-TextViewsEachMonth PDFDownloadsEachMonth QuantitiesofCitationsEachYear *AllthedatacomefromCrossref Comments CommentsmustbewritteninEnglish.Spam,offensivecontent,impersonation,andprivateinformationwillnotbepermitted.IfanycommentisreportedandidentifiedasinappropriatecontentbyOAEstaff,thecommentwillberemovedwithoutnotice.Ifyouhaveanyqueriesorneedanyhelp,[email protected]. Post Login 0 Cancel Loginwith OAEMESAS tostartadiscussion! Tip× Ok Citation Paul D.Thesystemichallmarksofcancer. JCancerMetastasisTreat 2020;6:29.http://dx.doi.org/10.20517/2394-4722.2020.63 WelcometofollowOAE'sWeChatAccount!DownloadPDF2107downloadsDownloadXML11downloadsCiteThisArticle91clicksExportCitation49clicksCommentary0commentsLikeThisArticle7likesShareThisArticle ScantheQRcodeforreading!SeeUpdatesContentsFiguresRelatedFigure1ViewinarticleFigure2ViewinarticleFigure3ViewinarticleFigure4ViewinarticleFigure5ViewinarticleFigure6ViewinarticleFigure7ViewinarticleFigure8ViewinarticleFigure9ViewinarticleFigure10ViewinarticleFinalresultsofa2:1control-caseobservationalstudyusinginterferonbetaandinterleukin-2,inadditiontofirst-linehormonetherapy,inestrogenreceptor-positive,endocrine-responsivemetastaticbreastcancerpatientsAndreaNicolini, ... AngeloCarpiHowthe“seed”preparesthe“soil”:thebone/bonemarrowpre-metastaticnicheAntonioMaurizi, ... NadiaRucciStimulationofinvitroboneformationbycanineprostatecancerShiyuYuan, ... ThomasJ.RosolSurgicalresectionforpulmonaryrecurrenceofesophagealcanceraftercurativeesophagectomyMasaruMorita, ... YasushiTohBreast-to-brainmetastasis:afocusonthepre-metastaticnicheKathrynMalone, StellaE.TsirkaOsteolyticeffectsoftumoralestrogensignalinginanestrogenreceptor-positivebreastcancerbonemetastasismodelJuliaN.Cheng, ... JanetL.FunkAdvancesinmurinemodelsofbreastcancerbonediseasePenelopeD.Ottewell, MichelleA.LawsonMultiplexedbioluminescenceimagingofcancercellresponsetohypoxiaandinflammationinthecaudal-arteryinjectionmodelofbonemetastasisduringzoledronicacidtreatmentMisaMinegishi, ... ShinaeKizaka-KondohROR2regulatesthesurvivalofmurineosteosarcomacellsinlungcapillariesDiemThiPhuongTran, ... ShinaeKizaka-KondohIstherearoleforresectionofoligometastaticdiseaseinpancreaticductaladenocarcinoma?YanaPuckett, ... TimothyM.PawlikHotkeywords BiomarkerDiscovery AutophagyandCancer BreastCancerMetastasis BrainMetastases GastricCancerMetastasis LungCancer GeneticHeterogeneity ColorectalCancer ProstateCancer CancerImmunotherapy CirculatingTumorCells NeuroendocrineTumors SubmitaManuscript ManuscriptTemplates AimsandScope EditorialBoard DownloadPDFDownloadXMLCiteThisArticleExportCitationArticleAccessStatisticsViewed:14056Downloaded:2107Cited:8ShareThisArticle SeeUpdates ©2016-2022OAEPublishingInc.,exceptcertaincontentprovidedbythirdparties