Interleukin 1-induced Augmentation of Experimental Métastases from a Human Melanoma in Nude Mice1

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Interleukin 1-induced Augmentation of Experimental Métastases from a Human Melanoma in Nude Mice1

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  1990;50:4771-4775. Cancer Res Raffaella Giavazzi, Angela Garofalo, Maria Rosa Bani, et al. from a Human Melanoma in Nude MiceInterleukin 1-induced Augmentation of Experimental Metastases   Updated version   http://cancerres.aacrjournals.org/content/50/15/4771Access the most recent version of this article at:   E-mail alerts  related to this article or journal.Sign up to receive free email-alerts   SubscriptionsReprints and .pubs@aacr.orgDepartment atTo order reprints of this article or to subscribe to the journal, contact the AACR Publications   Permissions  .permissions@aacr.orgDepartment atTo request permission to re-use all or part of this article, contact the AACR Publications Research. on November 21, 2013. © 1990 American Association for Cancercancerres.aacrjournals.org Downloaded from  Research. on November 21, 2013. © 1990 American Association for Cancercancerres.aacrjournals.org Downloaded from   [CANCERRESEARCH50 4771-4775 August1.1990 Interleukin1-inducedAugmentationofExperimentalMétastasesfromaHumanMelanomainNudeMice1 RalladlaGiavazzi,2AngelaGarofalo,MariaRosaBani,MauroAbbate,PietroGhezzi,DianaBoraschi,AlbertoMantovani,andElisabettaDejana MarioNegriInstituteforPharmacologicalResearch ViaGava::eni11 24100Bergamo[R.G. A.G. M.R.B. M.A.] andViaEritrea62 20157Milano[P.G. A.M. E.£>./ ndSciavoResearchCenter 53100Siena[D.B.] Italy ABSTRACT Thisstudyhasexaminedtheeffectofthecytokineinterleukin1(IL-1)onmetastasisformationbythehumanmelanomaA375Minnudemice.WehavefoundthathumanrecombinantIL-1/3(asingleinjection>((.() ngpermousei.v.givenbeforetumorcells)inducedanaugmentationofexperimentallungmétastasesfromtheA375Mtumorcellsinnudemice.Thiseffectwasrapidlyinducedandreversiblewithin24hafterII.-1injection.AsimilareffectwasinducedbyhumanrecombinantIL-laandhumanrecombinanttumornecrosisfactor,butnotbyhumanrecombinantinterleukin6.5-[' I]Iodo-2'-deoxyuridine-radiolabeledA375Mtumorcellsinjectedi.v.remainedatahigherlevelinthelungsofnudemicereceiving11-1thanincontrolmice.Inaddition,II-Iinjected1h,butnot24h,aftertumorcellsenhancedlungcolonizationaswell,thussuggestinganeffectofIL-1onthevasculartransitoftumorcells.Thesefindingsmayexplaintheobservationofenhancedsecondarylocalizationoftumorcellsatinflammatorysitesandsuggestthatmodulationofsecondaryspreadshouldbecarefullyconsideredwhenassessingtheabilityofthiscytokinetocomplementcytoreductivetherapies. INTRODUCTIONIL-13isapleiotropiccytokineinvolvedininflammatoryandimmunologicalcircuitsandinthegenerationofacutephaseresponses(1).Itinducesawidespectrumofbiologicalresponseswithsystemicandlocaltissuechanges(2).RecentlyithasbeenshownthatIL-1stimulateshematopoieticprecursors,hasra-dioprotectiveactivity,andcounteractsthemyelotoxicityofcancerchemotherapyagents(3-6).Thesefindingssuggestthatthiscytokinemayhavepotentialclinicalapplicationduringradiotherapyandchemotherapyorinthecontextofbonemarrowtransplantation.InadditionithasbeensuggestedthatIL-1canhaveantitumoractivityinvitro(7)andinvivo(8),dependentontheexperimentalmodelused.However,inarecentworknotherapeuticactivitywasobservedwhenIL-1wasgivenasasingleagentforthetreatmentofmetastaticdisease(6).AmajortargetoftheactionofIL-1istheendothelialliningofbloodvessels,whosefunctionalstatusisreprogrammedbythiscytokine(9,10).InthecontextofstudiesontheeffectofIL-1onECfunctionrecently,ourgroupandothershavefoundthatIL-1treatmentofhumanumbilicalveinendothelialculturesincreasedtheiradhesivitytodifferenthumantumorcells(11,12).Toinvestigatetherelevanceofthisphenomenoninvivo,weexaminedtheeffectofIL-1onexperimentalmetastasisformationinthelungsofnudemicegivenahumanmelanomacellline. Received9/25/89;revised1/29/90.Thecostsofpublicationofthisarticleweredefrayedinpartbythepaymentofpagecharges.Thisarticlemustthereforebeherebymarkedadvertisementinaccordancewith18U.S.C.Section1734solelytoindicatethisfact.'Researchsponsoredbygrant(s)fromtheItalianAssociationforCancerResearch,Milan,Italy.2Towhomrequestsforreprintsshouldbeaddressed,atIstitutodiRicercheFarmacologicheMarioNegri,ViaGavazzeni,11,24100Bergamo,Italy. 3Theabbreviationsusedare:IL 1 interleukin1;hurIL 1 humanrecombinant interleukin1;IL-6,interleukin6;hurIL-6,humanrecombinantinterleukin6;TNF,tumornecrosisfactor;hurTNF,humanrecombinanttumornecrosisfactor;EC,endothelialcells;HBSS,Ca2*-andMg2*-freeHanks balancedsaltsolution. MATERIALSANDMETHODS Animals.Six-to8-wk-oldmaleNCr-wu/w«micewereobtainedfromtheNationalCancerInstituteAnimalProgram,Frederick,MD.Micewerehousedthroughouttheexperimentsinalaminarflowcabinetunderspecific-pathogen-freeconditions.Inaccordancewithinstitutionalguidelinesmicedidnotsufferunnecessarydiscomfort,pain,orinjuryandreceivedpropercareandmaintenance.TumorLine.A375M,ahumanmelanomalineselectedinvivoforhighlungcolonizationcapacity(13),wasmaintainedonplasticinEagle'sminimalessentialmediumsupplementedwith10%fetalbovineserum,sodiumpyruvate,nonessentialaminoacids,L-glutamine,and2-foldvitaminsolution(Gibco,Paisley,Scotland).CultureswereroutinelyverifiedasMycoplasmafree.Thehumanoriginofthetumorlinewasconfirmedbythehumanláclatedehydrogenaseisoenzymepattern(ISO-LAD;ChemetronChimica,Milan,Italy).A375Mtumorcellsfrommid-logphaseculturewereharvestedbyexposureto0.25%trypsin-0.02%EDTAsolution,washedtwice,andresuspendedinHBSSattheconcentrationindicatedforinjection.Cytokines.HighlypurifiedhurIL-10(Escherichiacoli117-269)wasfromSciavo,Siena,andDeBiDivision,CassinaDePecchi,Italy.ThehurIL-1/3preparationusedhadaspecificactivityofIO7units/mgofprotein,anditcontained<0.5pgofendotoxin//ig(LALchromogenicassay;WhittakerBioproducts,Walkersville,MD).LyophilizedhurlL-1/3wasreconstitutedto100ug/m\inpyrogen-free,sterile,phosphate-bufferedsalinesolution;sterilizedbymicrofiltrationin0.2^m;andstoredfrozenin10-^galiquots.HurIL-1«(specificactivity,3xIO8units/mg)wasprovidedbyHoffman-LaRoche,Nutley,NJ.HurIL-6(50xIO3units/ml;lesscellline)waskindlysuppliedbyDr.S.Gillis(ImmunexCorporation,Seattle,WA),andhurTNF-a(specificactivity,8.1xIO6units/mg)wasfromDr.E.Schlick(Basf-Knoll,WestGermany).Workingconcentrationsofcytokinesweredilutedin0.9%NaClsolutionbeforeinjectionandgiveni.v.1hbeforetumorcellsunlessotherwiseindicated.Controlmicereceivedvehiclealone.ExperimentalMetastasisAssay.Singlecellsuspensions(>95%viabilitybytrypanblueexclusion)atconcentrationsfrom5xIO5to10xIO5in0.2mlofHBSS,asdetailedin Results, wereinjectedinthelateraltailveinofnudemice.Micewereautopsied8wklater,lungswereremovedandfixedinBouin'ssolution,andthenumberoflungcolonieswascountedunderadissectingmicroscopeaccordingtothestandardtechnique.Extrapulmonarymétastaseswerecheckedforallanimals.DifferencesinthenumbersoflungcolonieswereanalyzedusingtheMann-WhitneyUtest.Resultsarerepresentativeofatleasttwodifferentexperiments.OrganDistributionAnalysis.CulturesofA375Mmelanomacellsinmid-logphasewereprelabeledwith5-['25I]iodo-2'-deoxyuridine(Amer-shamInternational,Buckinghamshire,UnitedKingdom)(specificactivity,5Ci/mg)at0.3uC\permlofmediumfor24h(14).Thecellmonolayerwasthenrinsedtwicetoremovenonboundradioiodineandharvestedasdescribedabove.Thecellsuspensionwaswashedandresuspendedatafinalconcentrationof5xIO5cells/0.2mlofHBSSfori.v.injection.Labeledtumorcellswereinjectedintonudemicetreated1hearlierwithhurIL-1/3(1Mg/0.2ml)or0.2mlof0.9%NaClsolution.Atthetimeindicatedaftertumorcellinjection,nudemicewereautopsied;lungs,liver,spleen,andkidneyswerecollectedfromeachmouseandwashedinthreechangesof70%ethanolovera72-hperiodtoremovefreelabel(14).Radioactivityinallorganswasthencountedinagammacounter.ElectronMicroscopyAnalysis.Lungsfromnudemicewereremoved4771 Research. on November 21, 2013. © 1990 American Association for Cancercancerres.aacrjournals.org Downloaded from   AUGMENTATION.OFEXPERIMENTALMETASTASESBYIL-I atdifferenttimesafterhurIL-1/3injection(3lungs/timegroupfrom1to24h).Piecesoflungswererandomlychosenandfixedin2.5%glutaraldeydein0.1Mcocodylatebuffer(pH7.4),postfixedin1%osmiumtetroxideincocodylatebuffer,dehydratedinethanol,andembeddedinEpon.ThinsectionswerestainedwithuranylacetateandleadcitrateandexaminedwithaZeissModelEM109electronmicroscope. RESULTSEffectofIL-1onLungColonyFormationbyA375M.Thei.v.injectionof1yugofhurIL-1/3intonudemice1hbeforeA375Mhumanmelanomacellsgiveni.v.resultsinadramaticincreaseoftumorcoloniesinthelungsofmiceautopsied8wklater(Fig.1).Table1showstheresultsrepresentativeofseveralexperimentsruninthecourseofthisstudy.AsimilareffectwasobservedwhenhurIL-10-pretreatednudemiceweregiveninjectionsofatumorcellnumberrangingfrom5x10sto10xIO5(Table1).Thenumberoflungcolonieswasslightlyhigherinanimalsreceiving0.01figofhurIL-1ßmediannumberoflungcolonies,17),andtheincreasewassignificantinmicereceivinghigherdoses(mediannumberoflungcolonies,respectively,61,68,and95innudemicereceiving0.1,1,or10/ug)comparedwithmicereceivingvehicle(mediannumberoflungcolonies,6.5)(Table2).ThekineticsofIL-1augmentationofexperimentalmétastaseswasexaminedbyinjectinghurIL-lßi.v.atadoseof1pgpermouseatvarioustimesbeforeandaftertumorcellinjectionandcountingthenumberoflungcolonies8wklater(Fig.2).Asignificantaugmentation(P<0.005)oflungcolonieswasobservedwhenhurIL-1/3wasgivenfrom5minto4hbeforeA375Mtumorcells(mediannumberoflungcolonies,199,187,and126inmicepretreatedat5min,lh,and4h).HurIL-1/3givenlhaftertumorcellsincreasedthenumberoflungcoloniesaswell(mediannumberoflungcolonies,190)(Fig.2).Incontrast,hurIL-lßtreatment24hbeforeoraftertumorcellinjectiondidnotsignificantlyinfluencelungcolonyformation(mediannumberoflungcolonies,respectively,28and10)comparedwithcontrolmice(mediannumberoflungcolonies,25)(Fig.2).Toinvestigatewhethertheobservedphenomenonwasduetoadirecteffectontumorcells,A375Mtumorcellswereharvestedfromtissueculture,incubatedforlhat37 CwithhurIL-1/3(1xIO6cellswithl^gofhurIL-l/iin0.2ml),washedrepeatedly,andtheninjectedi.v.intonudemice.Atautopsy,8wklater,thenumberoflungcoloniesfrommicegiveninjectionsoftumorcellsexposedtohurIL-1/3wasnotsignificantlydifferent(median,25;range,6to62)frommicethatweregivencontroltumorcells(mediannumberoflungcolonies,31;range,2to57).SpecificityofIL-1-inducedLungColonyAugmentation.Weexaminedwhethertheaugmentationoflungtumorcolonieswas,infact,becauseoftheIL-1moleculeitselfandwhetherfunctionallyrelatedcytokinesshowedthesameproperty.Firstofall,heatingthehurIL-1/3preparation(100°Cfor15min)completelyabolisheditsabilitytoincreasemétastases,thusexcludingaroleofpossibleendotoxincontaminationoftherecombinantcytokine(Table3).Similarlypreincubation(20hat4°C)withappropriatespecificantibodiesabolishedthestimulatoryeffectofhurIL-1/3onmetastasisformation(datanotshown).Table3showsthatunderthesameexperimentalcondition,similarresultswereobtainedwiththe«andßpeciesofIL-1.WethenexaminedtheeffectofthecytokinesIL-6andTNFwhich,thoughmolecularlydistinctandactingthroughdistinctreceptors,shareseveralbiologicalpropertieswithIL-1(2,15).Interestingly,hurIL-6didnotaffectmetastasisformationbyA375Mmelanomainnudemice,whereashurTNF«significantlyaugmentedlungcolonyformationcomparedwithcontrolmice(Table3).OrganDistributionandArrestofA375MCells.ToinvestigatethemechanismsresponsiblefortheIL-1-mediatedincreaseofexperimentalmétastases,weexaminedtheorgandistributionandarrestofradiolabeledA375MtumorcellsinhurIL-10-or0.9%NaClsolution-pretreatednudemicefrom10minto72h(Fig.3).Afteri.v.injection,radiolabeledtumorcellsrapidlylocalizedinthelung,andnodifferencewasobservedbetweenthetwogroupsofanimalsinthefirsthour.Thelevelofretentionwashigher4haftertumorcellinjectioninhurlL-10-treatedmice(52%versus35%).Thisratioincreasedpro- Fig.1.IncreaseofexperimentallungmetastasisinnudemicegiveninjectionsofIL-I.Tenx10'A375Mtumorcellswereinjectedi.v.intonudemicetreatedlhearlierwith1*igofhuilll.i.andlungcolonieswerecounted8wklater.LungsfromnudemicepretreatedwithhurIL-1/îbottom)showanextensivetumorburden,whilethosefrommicepretreatedwith0.9%NaClsolution(top)showfewertumorcolonies. 4772 Research. on November 21, 2013. © 1990 American Association for Cancercancerres.aacrjournals.org Downloaded from   AUGMENTATIONOFEXPERIMENTALMETASTASESBYIL-I gressivelyoverthe72-hobservationperiod(Fig.3).Thelossofcell-associatedcpmfromthelungswasrapidbetween4and24h,asdescribed(14),butat24htheretentionwassignificantlyhigherinthelungsoftreatedmicethanincontrolmice(5% versus0.4 ).By72h,lessthan0.2 oftheinjectedcellswere detectableinthelungsofcontrolmice,whilehurIL-1/Ã-treatedmiceshowed3%tumorcellretention.Cell-associatedradioactivityinthevisceralorgans(spleen,kidneys,liver)didnotdifferinthetwogroups(datanotshown).ThisdistributionpatternsuggeststhatIL-1doesnotinterferewiththeabilityoftumorcellstoreachthelung,butwiththeirretentioninthesecondary-organ.Lungsfromnudemicewerecollectedat1,4,and24hafterhurIL-10treatment,andsectionswereexaminedbyelectronmicroscopy.Althoughatthisstagewedidnotperformaquan- Table1EffectofIL-1onlungcolonyformationbyA375Mmelanomainjected intonudemice Table3Lungcolonyformationinnudemicegiveninjectionsofdifferent cytokinepreparations No.oftumorcells5x10'7.5x0'10x10sTreatment VehicleHuIL-1/3VehicleHuIL-lfiVehicleHurIL-1/JNo.oficewithlungcolonies/no,receivinginjection6/87/88/88/89/99/9Medianno.oflungolonies3(0-25) 450-125)f16.5(1-45)85(28-133)''30(14-60)225(162-293)'' Nudemiceweregiveninjectionsi.v.of1^gofhurIL-l/iorvehicle1hbeforetumorcells.*Numbersinparentheses,range.  P<0.01comparedwithmicereceivingvehicle. 'Ps0.001. Table2LungcolonyformationbyA375Mmelanomainnudemicegiren injectionsofdifferentconcentrationsofIL-1 HuIL-10(ng/mouse)°Vehicle0.0010.010.1110Mediano.oflungcolonies*6.5517616895Range1-122-341-931-1153-12058-98f0.50.110.010.010.002°Nudemiceweregiveninjectionsi.v.ofdifferentconcentrationsofhurIL-lrf1hbefore5x10'tumorcells.Controlmicereceivedthesamevolumeofvehicle.*n=8.Allmicepresentedlungcoloniesatautopsy. cProbabilityofnodifferencefromcontrolmice. Oo) 3oE ai Q.  />0)O o 300• 200-100- -24h-4h-1h-5min TimeofIL-1injection Fig.2.KineticsofIL-1lungcolonyinduction.HurIL-l/i(1fig/mousei.v.)wasgivenatdifferenttimesbeforeorafteri.v.injectionof10x10'A375Mtumorcells.Resultsateachtimepointareexpressedasthenumberofcoloniesforeachlung(n=8).C(n=16).untreatedcontrolmice.Horizontalbars,medianforeachgroup.No.ofumorcells10X0'5x10'Treatment VehicleHeatedhuIL-10HurlL-li?HurTNFnrHurlLVVehicleHurIL-l,.rHurTNFtt'Micewithlungcolonies/total8/88/88/88/88/87/88/88/8Medianno.flungcolonies79(10-97)*75(36-96)224(207-251)''191(33-224)'86(15-98)5.5(0-40)139(15-134)''68(50-285)''°Cytokinesin0.2mlof0.9%NaCIsolutionweregiveni.V.Mcells.Resultsarefromtwoindependentexperiments.*Numbersinparentheses,range. cOneMgpermouse.dP<0.001comparedwithvehicle-treatedmice. P<0.0\. thousandunitspermouse. 10* Sio1 i i10° 10 hbeforeA375 —10min  h h 24h72hTimeaftertumorcellinjection Fig.3.OrgandistributionandfateofA375McellsinnudemicegiveninjectionsofIL-1.5-[' I]Iodo-2'-deoxyuridine-labeledtumorcellswereinjectedi.V..andlungswerecollectedatvarioustimesafterinjection.ThepercentageofradioactivityoftheoriginallyinjectedcellsremaininginthelungsofnudemicereceivinghurlL-ti(Q)andinthelungsofmicereceiving0.9%NaCIsolution(*). Points,mean;ban.SD(n=4).Inputofinjectedcells=69.309±3,180cpm. titativemorphometricassessmentofenhancedretentionoftumorcellsinthelungs,noobviousalterationofECwasobservedatanytimeinnudemicereceivinghurIL-1/icomparedwithcontrolmice.Therewasnoevidenceofpolymorphonuclearcellinfiltration,plateletaccumulation,andfibrindeposition.DISCUSSIONInthisstudywefoundthathurIL-1/3increasedtheformationoftumorcoloniesfromthehumanA375Mmelanomainthelungsofnudemice.Theeffectwasconcentrationdependent,timedependent,andshortlived.TheincreaseinexperimentalmétastaseswasobservedwithintherangeofIL-1concentrationsthathavemanybiologicalactivities,includingprotectionagainstmyelosuppressionbyradiationandchemotherapy(3-6).TheenhancementoflungcolonizationwasseenwithhurIL-1/3administeredbeforetumorcellinjection,thusimplyinganindirecthost-mediatedeffect.Infurthersupportofthishypothesis,wefoundtheexposureofA375MmelanomacellstohurIL-lßbeforeinjection(followedbywashing)didnotchangetheirlung-colonizingability.TNFpossessesmanyoftheactivitiesdescribedforIL-1,includingECactivation(2,9,10),soitisnotsurprisingthathurTNF«showedaneffectsimilartothatobservedwithhurIL-1/3.ThepossibilitythatTNFactsbyinducingIL-1needstobetakenintoconsideration(16). 4773 Research. on November 21, 2013. © 1990 American Association for Cancercancerres.aacrjournals.org Downloaded from   AUGMENTATIONOFEXPERIMENTALMETASTASESBYIL-1 IL-1hasbeensuggestedtoexertseveralofitsactivitiesthroughinductionofIL-6(17);thelackofactivityofhurIL-6suggeststhatIL-1affectsmetastasisformationeitherperseorthroughintermediatecytokinesotherthanIL-6.ItisofinterestthatIL-6,unlikeIL-1andTNF,doesnotaffectotherendothe-lialfunctions(18),includingadhesiveproperties,4thusfurthersuggestingthattheeffectsofcytokinesonendothelialliningsareanimportantcomponentinthemodulationofthemet-astaticprocess.AvarietyofmechanismscanbepostulatedtoexplainIL-l'spromotinglungcolonization.Metastasisformationisacomplexprocessinvolvingseveralsequentialstepsthattumorcellshavetocompleteaftertheirreleasefromtheprimarytumor(19).Physiologicalsystemicorlocalalterationscaninfluencethetumorcells'abilitytodisseminateandmetastasize.Theorgandistributionandarrestofradiolabeledtumorcells(14)havebeenoftenusedasanexperimentaltoolforfollowingthedisseminationoftumorcells.ThedistributionpatternofA375Mcells(Fig.3),showinghigherretentioninthelungsofhurIL-l/3-injectedmice,suggestsamorespecificeffectatthelevelofthetargetorgan.Morphologicalstudiesontheintra-vasculararrestofcirculatingtumorcellsindicateaninitialarrestoftumorcellscharacterizedbyatumor-ECcontactduringthefirsthour,followedbypenetrationofthetumorcellsthroughvascularendotheliumafter4handthecompleteextravasationbyabout24h(20).WefoundthathurIL-1/3given1h,butnot24h,aftertumorcellsinducedanaugmentationoflungcoloniesaswell.MoreoverhigherlevelsofradiolabeledtumorcellswerefoundinthelungsofhurIL-lß-treatedmicefrom4to72haftertheirinoculation.TheseresultssupportthehypothesisthattheIL-1treatmentinterfereswiththeretentionand/orinitialextravasationofcirculatingtumorcellsinthesecondaryorgansbutdoesnotaffectthetumorcells'intrinsiccapabilitytogrowandformmétastases.Theintravasculartransitofmalignantcellsmayperhapsbeoneofthemostimportantstepsinmetastasis(21).IL-1inducesacascadeofcellularandbiochemicaleventsonEC(2,9,10)thatleadstovascularcongestion,clotformation,andcellularinfiltration(22,23),whichcouldthenaffecttumorcellarrestandextravasation.However,inourstudywefoundthattheeffectofhurIL-l/3-inducedaugmentationoflungcolonieswasnotpreventedinnudemiceunderwarfarinanticoagulanttreatment(datanotshown).Moreover,treatmentwithhurIL-10attheconcentrationsandschedulesusedinourstudydidnotcauseareductionofcirculatingplatelets(datanotshown).Finally,wedidnotobservefibrindepositionoraccumulationofneutrophilsandplateletsonthesurfaceofECthatappearedtobeintactbyelectronmicroscopyanalysis.Inadditionthetreatmentofnudemicewithibuprofen,anonsteroidantiinflam-matoryinhibitorofcyclooxygenase,describedtoprotectagainsthemodynamiceffectsinducedbyIL-1,includingvasculardamage(24),didnotpreventIL-l'slungcolonyaugmentation(datanotshown).Inthisregarditispossiblethatothers'inflammatorymediatorsproducedviathelipoxygenasepathwayofthearachidonicacidmetabolism(i.e.,leukotrienes),whichspecificallyboundtoEC,canregulatetumorcell-endothelialcellinteraction(25).Takentogethertheseobservationssuggestthatmechanism(s)otherthanmicrovascularinjuryorintravascularclottingareresponsibleformetastasisaugmentation.SeveralreportshaveshownthatIL-1stimulatesleukocyteadhesiontoECandthatthisprocessismediatedbytheinductionofadhesivemoleculesontheECmembrane(26-28).Our 4E.Dejana,unpublishedobservation. groupandothershaveshownthatdifferenttumorcelllines,includingA375Mmelanoma,adheremoreefficientlytoIL-1-activatedEC(11,12).RecentlyRiceandBevilacqua(29)haveidentifiedanoveladhesionstructureresponsibleforIL-1-augmentedadhesionofmelanomacells,thusmakingthehypothesisthatIL-1-inducedaugmentationoflungtumorcoloniesresultsfromamodificationofECsurfacepropertiesquiteattractive.IL-l'seffectinvivoisalreadypresentwhenthiscytokineisinjected1horevenlessbeforetumorcells.Invitro,theIL-1-inducedincreaseintumorcelladhesiontoECrequiresatleast2hofincubation(11,12).Thisdiscrepancycanbeexplainedbytheobservationmentionedearlierthattumorcellscantakeafewhourstointeractwithandpenetratevascularendothelium(20),atimecompatiblewiththemodulationofECpropertiesbyIL-1.Inaddition,itisworthnotingtheothereffectsbyIL-1,likeprostaglandin-mediatedfeverresponsethatappearsasearlyas30minafterIL-1injection,whileinvitrotheproductionofprostaglandinErequiresseveralhours(30).FurtherandmoredirectstudiesareunderwaytodefinetheroleofIL-1-inducedECactivationintheincreasedincidenceoflungcolonies.TheobservationsreportedhereareofinterestinthecontextofthepathogenesisofmetastasisandconsideringthatIL-1isproposedincombinationwithantineoplastictherapy.Macrophages,themajorproducersofIL-1,canexertacomplexdualinfluenceintheregulationoftumorprogressionandmetastasis(31).Augmentedsecondarylocalizationofcancerhasbeendocumentedatsitesinfiltratedbyinflammatorymacrophages(32),andIL-1couldbeamajormediatorunderthesecircumstances.Moreover,nonhematopoietictumorlines,includingmelanomas,havebeenshowntoproduceIL-1(33,34).Inlightofthepresentobservations,IL-1productioncouldrepresentacontributingelementinthemalignantbehavioroftumors,byfavoringtheimplantationofneoplasticcellsatsecondarysites.IL-1stimulateshematopoieticprecursors,hasradioprotec-tiveactivity,andcounteractsoramelioratesmyelosuppressioninducedbycancerchemotherapy(3-6).TheconcernsraisedbytheobservationreportedhereshouldnotpreventtrialsinanimalsandhumansdesignedtoassesstheefficacyofIL-1incombinationwithcytoreductivetherapy.Theseresultsshould,however,servetoheightenawarenessthatanoverallassessmentofthepotentialofthiscytokineandproposedagonistsshouldincludecarefulevaluationoftheirinfluenceonthesecondaryspreadofneoplasia.ACKNOWLEDGMENTS WethankJ.D.BaggottforstyleeditingandL.Piccolifortypingthemanuscript. REFERENCES 1.Dinarello.C.A.Interleukin-1andthepathogenesisoftheacute-phaseresponse.N.Engl.J.Med..311:1413-1418,1984.2.Dinarello,C.A.IL-1anditsbiologicalrelatedcytokines.Adv.luminimi.44:153-205,1989.3.Neta,R.,Douches.S.,andOppenheim.J.J.Interleukin1isaradioprotector.J.Immunol..136:2483-2485.1986.4.Morrissey.P.,Charrier,K.,Bressler,L.,andAlpert,A.TheinfluenceofIL-1treatmentonthereconstitutionofthehcmopoicticandimmunesystemsaftersublethalradiation.J.Immunol..140:4204-4210,1988.5.Moore,M.A.S.,andWarren,D.J.Synergyofinterleukin1andgranulocytecolony-stimulatingfactor:invivostimulationofstem-cellrecoveryandhematopoieticregenerationfollowing5-fluorouraciltreatmentofmice.Proc.Nati.Acad.Sci.USA.84:7134-7138,1987.6.Castelli,M.P..Black.P.L..Schneider,M.,Pennington,R.,Abe,F.,andTalmadge,J.E.Protective,restorative,andtherapeuticpropertiesofrecombinanthumanIL-1inrodentmodels.J.Immunol..140:3830-3837,1988.7.Onozaki,K.,Matsushima.K..Aggarwal.B.B.,andOppenheim.J.J.Human 4774 Research. on November 21, 2013. © 1990 American Association for Cancercancerres.aacrjournals.org Downloaded from 
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