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Mucin Gene Expression in Ovarian Cancers1

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Mucin Gene Expression in Ovarian Cancers1
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  1998;58:5546-5550. Cancer Res Robert L. Giuntoli II, Gustavo C. Rodriguez, Regina S. Whitaker, et al. Mucin Gene Expression in Ovarian Cancers   Updated version   http://cancerres.aacrjournals.org/content/58/23/5546Access 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 on March 11, 2014. © 1998 American Association for Cancer Research.cancerres.aacrjournals.org Downloaded from on March 11, 2014. © 1998 American Association for Cancer Research.cancerres.aacrjournals.org Downloaded from   (CANCERRESEARCH58.5546-5550.DecemberI,1998] MucinGeneExpressioninOvarianCancers1 RobertL.GiuntoliII,GustavoC.Rodriguez,ReginaS.Whitaker,RichardDodge,andJudithA.Voynow2 De/>anmentsafObstetricsandGynecology¡R.L.C.,G.C.R.,K.S.W.,R.D.IuntiPediatrics[J.A.V.l.DukeUniversityMedicalCenter.Durham,NorthCamlina277IO ABSTRACT Ovariancancer¡shighlylethaldiseasewithmétastasespresentinthemajorityofpatientsatthetimeofdiagnosis.Themolecularmechanismsunderlyingthemetastaticprocessofthiscancerarenotwellunderstood.Onefamilyofcell-associatedandsecretedglycoproteins,themucingly-coproteins,hasbeenimplicatedineventsleadingtometastasisofseveralepithelialcancersincludinggastrointestinalandlungcancers.Thepurposeofthisstudywastocharacterizemucingeneexpressioninovariancancersandrelateexpressiontotumorhistology,stage,andpatientsurvival.RNAwasisolatedfrom29epithelialovariancancers,1neuroendo-crinecarcinoma,3mixedmesoderma tumors,andtwotransformed,yetnonmalignant,ovarianepithelialcelllines.Theexpressionofmucingenes, MUCl 2 3 4 5ACandSB wasdeterminedbynorthernanalyses Epithelialovariancancersexpressedseveralmucinsincluding.\ll'('\.2,4,andSAC;MUC3andSBwererarelyexpressed.Incontrast,thetransformednonmalignantovarianepithelialcelllinesexpressedonlyMUClandSAC.Althoughtherewasnocorrelationofmucinexpressionwithtumorhistology,therewasasignificantdecreaseinexpressionofMUC3andl/f/4withincreasingcancerstage(/ <0.05).Inaddition,atrendtowardimprovedpatientsurvivaloccurredwithincreasedexpressionof MUC4 Theseobservationssuggestarelationshipbetweenmucingene expressionandthemetastaticprocessinepithelialovariancancers.AdditionalinvestigationofMUCÃŒndMUC4inovariancancersmayleadtonewapproachesforearlydetectionandtherapy. INTRODUCTION Ovariancancerisahighlylethaldisease.IntheUnitedStates,itranksfourthasacauseofcancer-relateddeathsamongfemalesandaccountsformoredeathsthanallothergynecologicalcancerscombined(1).Inthemajorityofpatients,metastaticdiseaseispresentatdiagnosis.Unfortunately,thelong-termsurvivalforwomenwiththisdiseaseremainspoor.Abetterunderstandingofthemolecularmechanismsunderlyingthemetastaticprocesswillhopefullyleadtonoveltherapiesthatcanmakeadramaticimpactonmortalityinthisdisease.Inepithelialcancers,themetastaticprocesshasbeenassociatedwithalterationsincellsurfaceandcell-associatedglycoproteinexpression(2).Specifically,mucinglycoproteinshavebeenimplicatedinthepathogenesisofepithelialcellmalignancies(3-5).Mucinglycoproteinsareeithermembrane-associatedandfunctionincell-cellinteractions(3,6),ortheyaresecretedandconstitutethemajormacromolecularcomponentsofmucusinthegastrointestinal,respiratory,andreproductivetracts(6,7).Mucinglycoproteinshavecharacteristicfeatures:(a)theirproteinbackbones(apoproteins)haverepetitivedomainsofpeptidesrichinserine,threonine,andproline,whicharethesitesforO-linkedglycosylation;and(b)theyhavemultiple,heterogeneousO-linkedoligosaccharidesthatcomposeupto50-80%oftheirmass.Aberrantlyglycosylatedmucinsareoverexpressedbytumorsandsecretedintothecirculationofcancerpatients.Theseoligosaccharides Received6/9/98:accepted10/5/98.Thecostsofpublicationofthisarticleweredefrayedinpartbythepaymentofpagecharges.Thisarticlemustthereforebeherebymarkedadvertisementinaccordancewith18U.S.C.Section1734solelytoindicatethisfact.1ThisworkwassupportedinpartbytheAmericanCancerSocietyClinicalOncologyCareerDevelopmentAward95-85-97to(G.C.R.)andbyNIHGrantR29HL50694(toJ.A.V).•owhomrequestsforreprintsshouldbeaddressed,atPediatriePulmonaryDiseases.Box2994.DukeUniversityMedicalCenter.Durham.NC27710. canbedetectedbyantibodiesinpatients'seraandserveastumormarkers(8).Ovariancancershaveseveraloligosaccharidetumormarkersincludingcancerantigen125,cancerantigen19-9,car-cinoembryonicantigen,Lewisyantigen(Fucal^>2Galßl—»4[Fucal^3]GlcNAcßl-*3Galßl^R),andTnantigen(GalNAcal-»O-Ser/Thr;Rets.9-12).Becauseofalteredglycosylation,mucinapoproteins(detectedbyanticancer-associatedserumantigenandantimammaryserumantigenantibodies)aremorereadilydetectedintheseraofbothovarianandbreastcancerpatientsthaninnormalsubjects(13).Theetiologyofalteredmucinglycosylationincancercellsisnotunderstood;changesinmucinglycosylationmaybeduetoalterationsinglycosyl-transferaseactivities(14)ortochangesinthespecificmucinapoproteinsthatareproducedandthenglycosylatedinthecancercells.Recently,bymoleculartechnology,atleast10differentmucingeneshavebeenidentifiedanddesignatedMUC\toMUC9(7,15).ByusingthecDNAsequencesreportedforthesegenes,severalstudieshavedemonstratedthatalterationsinmucingeneexpressionareassociatedwiththemetastaticprocessinepithelialcellcancers. MUC4mRNAandglycoproteinsarepresentinhighlevelsinpancre aticcancertissuesbutnotinbenignpancreatictissue(16,17).MUC2mRNAandproteinarepresentinnoninvasivepancreatictumorsbutnotininvasivecancer(18).MÕ/C5ACandMUC5BmRNAexpressioncorrelatewithearlierpostoperativerecurrenceoflungcancer(19).ThepresenceofMUC5ACglycoproteinalsocorrelateswithinvasivegastriccancer(20)andpancreaticadenocarcinoma(16).Thesereportssupporttheconceptthatchangesinmucinexpressionarerelatedtothemetastaticprocess.Severalovarianepithelialcancersmakemucinglycoproteinsbyhistologicalanalysis(21,22),yetonlytheexpressionofMUC2mRNA(23)andMUCl,2,and3glycoproteinshavebeencharacterizedinovariancancers(24,25).Thisreportdescribestheexpressionofsixmucingenesfoundinovariancancertissuesandcomparesthisexpressiontotransformednonmalignantovariancells.Mucinexpressionfromovariancancertissueswasalsorelatedtotumorhistology,stage,andpatientsurvival. MATERIALSANDMETHODS CancerTissuesandCellCultures.Thirty-oneovariancancertissuesam pleswereobtainedatthetimeofprimarysurgeryandtwoadditionalspecimenswereacquiredduringsurgeryfortumorrecurrence.Allofthetissueswerestoredat-70°CintheDukeUniversityMedicalCenterGynecologicalOncologytissuebank.Achartreviewwasperformedtorecordthetumorpathology,metastaticstage,therapies,andclinicaloutcomeforeachpatient.Somepatientsreceivedeitherradiationand/orchemotherapyinadditiontosurgery.Nopatientsreceivedendocrinological.immunological,orotheradjuvanttherapies.ThesedataarereviewedinTable1.Twenty-nineofthespecimensweretakenfrompatientswithepithelialovariancancer,including22serouscystadenocarcinomas.2mucinouscystadenocarcinomas,Iendo-metrioidadenocarcinoma.1clearcelladenocarcinoma.1primaryperitonealadenocarcinoma.and2poorlydifferentiatedcarcinomas.Inaddition,tumorsampleswereobtainedfromonepatientwithanovarianneuroendocrinecarcinomaandthreepatientswithmixedmesodermaltumorsoftheovary.Twospontaneouslytransformed,yetnonmalignant.ovarianepithelialcellculturesderivedfromnormalovarianepitheliumwerealsoevaluatedformucingeneexpression.Thesecultureshadbeenestablishedasdescribedpreviously(26.27).Theovariansurfaceepithelialcellsweremaintainedinmonolayercultureina1:1mixtureofMCDB105andM199media(SigmaChemicalCo.,  6 on March 11, 2014. © 1998 American Association for Cancer Research.cancerres.aacrjournals.org Downloaded from   MUCIN(il-.NI:EXPRESSIONINOVARIANEPITHELIALCANCER Table1Ovariancancerhistologyandstageandpatientclinicalprofiles Sample123456789101112131415161718192021222324252627282930313233Stage1 1ALMPIALMPIBIIC1IC1IBIIBIICLMPIICLMPn icmemeII LMPmemememeIM \mememememememeIVIVIVIVIVRECRECHistologyClear cell''MucinousSerousSerousEndometrioidSerousSerousSerousSerousSerousMMTovaryMMTovaryMMTovaryMucinousNeuroendocrinePrim,peritonealSerousPoorlydiff.SerousSerousSerousSerousSerousSerousSerousSerousPoorlydiff.SerousSerousSerousSerousSerousSerousRadiationNNNYYYNNNNNNNYNNNNKNNNNNNNNNYYNNNNChemotherapyNNNNYYYYNNYYYYNYYNKYYYYYYYYYYYYYYYSu TumorstagesaredescribedinRef.l.'Clearcell,clearcelladenocarcinoma;Mucinous.mucinouscysladenocarcinoma:Serous,serouscystadenocarcinoma:Endometrioid.endometrioidadenocarcinoma-.MMTovary,mixedmesodermaltumoroftheovary:Prim,peritoneal,primaryperitonealtumor:Poorlydiff..poorlydifferentiatedtumor:TumorsLMP.tumors,withlowmalignantpotentialbyhistologiegrade:Inonepatient,adjuvantNK.adjuvanttherapieswerenotknown:N.no:Y,yes:NED.noevidentdisease;AWD.alivewithdisease:DOD.deathduetodisease;LTF.losttofollow-up. St.Louis.MO)supplementedwith\(Wcheat-inactivatedfetalbovineserum(LifeTechnologies.Gaithersburg.MD).Themorphologyofthesecellsinculturewasconsistentwithepitheliumasverifiedbyimmunohistochemistrywithanticytokeratinantibodies(27).Twocontrolcelllines/tissueswereused:  a)CFPAC 28).agenerousgiftfromDr.RayFri/.zell Universityof Pittsburgh.Pittsburgh,PA),wasculturedinIscove'smodifiedDulbecco'smediumsupplementedwith10%fetalbovineserumandpenicillin/streptomycin:and(hinormalhumanskeletalmusclewasobtainedfromtheDepartmentofPathology.DukeUniversityMedicalCenter(Durham.NO. cDNAandOligonucleotideProbes.ProbesforMUC\,2.5ACand-yactin weresynthesizedfromcDNAclonesaswasdescribedpreviously(29).Insertsfromthesecloneswerelabeledwith['2P]dCTPusingarandomprimerlabelingkit(Prime-ItII.Stratagene,LaJolla,CA)toaspecificactivityof20XIO8cpm/fj.gcDNA.Synthetic48-bpoligonucleotideprobesforMUC3,4,and5Bcomplementarytothetandemrepeatdomains(30)weresynthesizedandlabeledtoaspecificactivityof20x10scpm/figwith['2P|dATPusingT4polynucleotidekinase(Promega.Madison,WI). NorthernAnalysis.TotalcellularRNAwasisolatedfromthetissuesam plesandcellculturesbythesingle-stepguanidineisothiocyanate-phenol-chloroformmethodusingTRIzolreagent(LifeTechnologies:Ref.31).RNAwasquantitatedbyspectrophotometry.Northernanalysiswasperformedasdescribedpreviously(29).Ten/xgoftotalRNAfromeachsamplewereelectrophoresedon1.2%agarose-formaldehydegelandtransferredtonylonmembrane(Nytran.SchleicherandSchuell.Keene.NH)bycapillaryblottinginlMammoniumacetate.Beforetransfer,thegelswerestainedwithethidiumbromidetoevaluateforRNAintegrityandloading.AfterUVcross-linking(Stratalinker,Stratagene,LaJolla,CA).themembraneswereprehybridi/.edin0.5Msodiumphosphatebufferandhybridi/edforatleast24hwith['2P1- 1Theabbreviationsusedare:CFPAC.pancreaticadenocarcinomacelllinefromacysticfibrosispatient:REC,recurrenttumor. labeledcDNAat62°CforMUC\.2,5AC.andyactin.andat58°CforMUtt,4.and5B.Theblotswerethenwashedtwicetor30minwith0.03Msodiumcitrate,0.3Msodiumchloride,and0.1%SDSatroomtemperatureandthenoncefor15minwith1.5m.Msodiumcitrate,15mMsodiumchloride,and0.1%SDSatthesametemperatureashybridization.ThefilterswerethenexposedonKodakX-Omatfilmat—0°CforIto4daysforautoradiography. StatisticalAnalysis.Todeterminemucinexpressionfromnorthernauto- radiographsforthesixMUCgenes,twoobservers—blindedtotheidentificationofthesamples—evaluatedwhethertherewasapositivesignalornosignalforeachsample.Mucingeneexpressionwasstratifiedbyhistologicalcelltypeandtumorstage.Thex2testfortrendwasusedtodeterminewhetherthereweresignificantdifferencesinthefrequencyofMUCexpressionbetweengroups.DifferenceswereconsideredsignificantifP<0.05.KaplanMeieranalysiswasusedtodetermineacorrelationbetweenmucingeneexpressionandpatientsurvival. RESULTSMucinGeneExpressioninOvarianCancerTissues.Northern analysesforMUC\.2,3,4,5AC,and5Bwereperformedforovariancancertissues.MostoftheMUCmRNAtranscriptshadapolydis-persepatternasdemonstratedbytheNorthernanalysisforMUC4(Fig.IA).Polydispersemucintranscriptsprobablyrepresentmultipletranscriptsizesexpressedbythetissues:thispatternhasbeenreportedpreviouslyinrespiratoryepithelialcells(32)andreproductivetractepithelium(33).IncontrasttoMUC4mRNA,MUClexpressionwasusuallypresentaseitheroneortwodiscretebandswiththemostcommontranscriptsizeof4.4kbasreportedpreviouslyinrespiratorytissues(Ref.34;Fig.Iß).ThepolydispersepatternwasnotduetomRNAdegradationinasmuchastheethidiumstainoftheNorthernagarosegelsshowedthatribosomalbandswereintact(Fig.ID)andtheNorthernfor-yactinrevealedintactmRNAbandsforeachsampleattheappropriatesize(Fig.1C).Whenthemucinexpressionwasstratifiedbytumorhistology,theserous,mucinous,andendometrioidtumorsexpressedtourtofiveofsixgeneswithallofthethreehistologicaltypesexpressingMUCl,2,4,and5AC(Table2).Incontrast,theclearcelltumorandmixedmesodermaltumorsexpressedonlytwotothreemucins(Table2). MucinGeneExpressioninNonmalignantOvarianCellLines. Normalovariesdonothavegobletcellsorglandshistologically.and,therefore,thenormaltissuewouldnotbeexpectedtoexpresssecretorymucingenes.Interestingly,thetransformed,nonmalignantovarianepithelialcelllinesexpressedbothMUC\(anepithelialcellsurfacemucin)andMUC5AC(asecretedmucin).Othermucingeneswerenotexpressed. MucinGeneExpressionwithAdvancingTumorStage.When mucingeneexpressionwascomparedtotumorstage,therewasasignificantdecreaseinexpressionofMUC3andMUC4asthetumorstageincreasedfromItoIV,forallofthehistologicaltypes(Fig.2).Whenthesubsetofserouscystadenocarcinomatumorswereanalyzed,asignificantdecreaseinMUC4expressionwithadvancingstagewaspersistent(P<0.05).Interestingly,thetwoRECsdidnotexpress MUC3orMUC4. MucinGeneExpressionandCancerSurvival.Theeffectof mucingeneexpressiononsurvivalwasexaminedusingKaplan-Meieranalysis.Althoughthedifferencesinthesurvivalcurveswerenotstatisticallysignificant,atrendtowardimprovedsurvivalwasnotedinpatientswhoseovariancancertissuesexpressedMUC4(Fig.3). DISCUSSION Toinvestigatethepotentialroleofmucinglycoproteinsinthemetastaticprocessofovariancancers,wedeterminedtheprofileof MUCgenesexpressedbyovariantumorsofdifferenthistological 5547 on March 11, 2014. © 1998 American Association for Cancer Research.cancerres.aacrjournals.org Downloaded from   MUCINGENEEXPRESSIONINOVARIANEPITHELIALCANCER   MUC4123456789101112131415161718123456789101112131415161718 MU 9.4-»4.4-»2.4-»  92 2 22232425262728293 3 32333435  92 2 22232425262728293 3 32333435 9 4 »4 4 »2 4 » 123456789101112131415161718  23456789 2 3 4 5 6 7 8 t-••§ » tff »  92 2 22232425262728293 3 3233 192021222324252627282930313233 Fig.I.NorthernanalysesofMUC4(A}.MUCl(B),andyactin(C)mRNAinovariancancertissuesamples.TotalRNA(10u,g),isolatedfromovariancancertissuesamples,CFPACcells,andmuscletissuebysingle-stepguanidineisothiocyanale-phenol-chlorofornimethodusingTRlzolreagent,wasblottedontonylonmembrane.RNAsampleswerearrangedinorderofadvancingstageoftheovariantumors(LanenumberscorrespondtoTableI).BecauseoflimitedRNAquantities,samples3,13and16werenotevaluatedforMUC4expressionandsample26wasnotevaluatedforMUC\expression.ThetwoovarianRECsareshowninLanes32-33.ThepositiveandnegativecontrolsareaCFPAC(Lane34)andnormalhumanskeletalmuscle(Lane35}.ArrowsinAandßndicateRNAstandards(kb);thearrowinCindicatesthe2.4-kbRNAmarker.DshowstheelhidiumstainsoftheNortherngelsforalloftheRNAsamples. typesandstages.Althoughtherewasnosignificantcorrelationbetweenspecificmucingenesandhistologicaltypes,apatternemergedrevealingthatendometrioidadenocarcinoma,mucinouscystadenocar-cinomas,andserouscystadenocarcinomasexpressedatleastfourtofivemucins,whereasthearrayofexpressionformixedmesodermaltumorsandclearcelladenocarcinomawaslimitedtotwotothreemucins.ThepatternofmucinexpressionreportedhereinconfirmspreviousreportsofMUCl,2,and3glycoproteinexpressioninnormalandmalignantovariancells.Hoelal.(25)determinedbyimmunohisto- Table2MucingeneexpressionbyhistologietypeNo.ofHistologysamplesMUC\MUC2 MUCiMUC4MUC5ACUC5BClear Cell 1+-I-+Endometrioid1++++Mucinous2+++++Serous20+++++MMToftheovary3---++ Clearcell,clearcelladenocarcinoma;Endometrioid,endometrioidadenocarcinoma;Mucinous,mucinouscystadenocarcinoma;Serous,serouscysladenocarcinoma;MMT,mixedniesodermaltumoroftheovary;+.MUCgeneexpressionispresentinatleastonesample;-,MUCgeneexpressionisabsent. chemistrythatalthoughnormalovariesdidnotexpressanyoftheMUCepitopes,themucinouscystadenocarcinomasexpressedthreemucinglycoproteins,MUCl,2,and3.ThispatternofexpressioncorrelatescloselywiththeexpressionofMi/Ci,2,and3mRNAbymucinouscystadenocarcinomasinourreport.Tashiroelal.(12)reportedthatonlyMUClglycoproteinwasproducedbythenormalovarywhilebothMUClandMUC2glycoproteinswereexpressedbyovariancancer.Dongetal.(24)reportedthathighlevelsofMUClglycoproteinattheapicalsurfaceofovariancancerscorrelatedwithapoorprognosiswhereasMUC2glycoproteinexpressionhadaninversecorrelationwithtumorgrade.Hanskietal.(23)demonstratedthatMUC2mRNAwasexpressedinovarianadenocarcinomas.Ourstudyfurtherexpandedthesefindingstodemonstratethatinadditionto intestinal mucins(MUCland3;Ref.35,36),theovariancancersalsoexpressedmucinsfoundinthenormalendocervix(MUC4,5AC,and5B:Ref.33).Thesedatasuggestthatovarianepithelialcancershavethecapacitytoproduceseveraldifferentmucinglycoproteinsduringthemetastaticprocess.Nonmalignantovarianepithelialcellsincultureexpressedtwomucingenes:MUC\and5AC.ThepresenceofmRNAforasecretorymucin,A/Õ/C5AC,wassurprisinginthesecellsbecausenormalovar- 5548 on March 11, 2014. © 1998 American Association for Cancer Research.cancerres.aacrjournals.org Downloaded from   MUCINOHNEEXPRESSIONINOVARIANEPITHELIALCANCER ianepitheliumcontainsasingleepithelialcelllayerwithoutsecretorycells.Itwillbeimportanttodeterminewhethernormalovariancellsproducemucinglycoproteins;iftheydo,mucinsmayfunctiontopreventnormalovariesfromadheringtoothertissues.Interestingly,thenonmalignantcellsdidnotexpresstheothermucinsthatwereexpressedbyovariancancercellsMUC2,3,4,and5B.Thechangefromnegativetopositiveexpressionofthesemucingenesinmalignantcellssuggeststhatnewonsetexpressionofsecretorymucingenesisassociatedwithmalignanttransformationoftheovarianepithelium.AmajorfindinginthisreportwasthedecreaseinA/Õ/C3and MUC4expressionwithadvancingstagesofcancer.Thereareseveral reportsofdecreasingMUCexpressionwithinvasiveormetastatictumors.Inpancreaticcancer,MUC2expressioncorrelatedwithnon-invasivebutnotwithinvasivetumors(18).GastriccancersexpressedMUC5ACglycoproteinwithearlyinvasionbutnotwithlateinvasivecancer(20).Finally,incoloncancer,althoughMUC\expressionincreasedwithmétastases(37),MUC2andMUC3expressiondecreasedwithmostformsofcoloncancer(38).MUC2and5AChaddecreasedlevelsofexpressioninhigh-graderectovillousadenomacomparedwithlow-gradeadenomaandwerenotpresentincolonadenocarcinoma(39).Thesestudiesindicatetheimportanceofmucinexpressionatspecifictimesduringthemetastaticprocess.Initially,mucingeneexpressionseemstoincreaseascancercellsdisseminatetodistantsites.Oncecancercellshavesuccessfullymetastasized,however,theyseemtolosethecapacitytomakemucinglycoprotein.Tometastasizetodistantsites,malignantcellsmustsuccessfullycompleteaseriesofstepsincluding:(a)dissociationfromtheprimarytumorsite;(b)localizedinvasion;(c)vascularandlymphaticspread;and(d)avidattachmenttodistantsites.Inaddition,malignantcellsmustescapeimmunesurveillance.Itislikelythatmucinsplayanimportantroleinallofthesesteps.Mucinglycoproteinsfunctionascell-celladhesionmolecules,therebymediatingadhesionandmigratorycapabilityofcells.Milkenselal.(3)demonstratedthatalterationsinmucinsmaydecreasetheabilityofneoplasticcellstoaggregate,therebyfacilitatingdissociationoftumorcellsfromtheprimarytumorsite.Mucinsthatbindtobasementmembraneproteins(40)andtoL-andP-selectins(41)mayplayaroleinadhesionandmigrationincoloncancer.Finally,alterationsinmucinglycoproteinsmayenhancetheabilityofcancercellstobindtotheendothelium(42).Ovariancancercellscanusesimilarmechanismstodisseminatethroughouttheperitoneum. MUCMUCMUCMUCMUCMUC 34SACSB Fig.2.BargraphdemonstralingmucingeneexpressionstratifiedbystageofdiseaseforalloftheovariancancertissuesamplesexceptRECs.Thenumberofsamplesforeachstagefollows:StageI,n=4(D);StageII,n=6(la);StageHI.n=16(D);andStageIV.n=5(•).EachbarrepresentsthepercenlageofsamplesposiliveformRNAexpressionoftheMUCgeneindicated(Mi/Ci,2.3.4,5AC.or5B).».ignificanttrendfordecreasinggeneexpressionwithincreasingstageinMUC3(P=0.04)andMUC4  P=0.03 .NostatisticallysignificanttrendsarenotedforMUC\,2.5AC,or5B. <D  _ 100 8 8 4020:......J.I  ears Fig.3.Kaplan-MeieranalysisofovariancancerpatientsurvivalstratifiedbyexpressionofMUC4.—,positivegeneexpressionofMUC4;,absenceofMUC4geneexpression:Xaxis(Years),survivalinyearsfromdaleofdiagnosis:Yaxis(Percent).percentageofpatientssurvivingattimeX.Althoughthereseemstobeabetlerlong-termsurvivalrateforpatientswhosetumorsexpressMUC4,thesedifferencesarenotsignificant(P=0.14). Mucinsmayplayanimportantroleinmodulatingimmunosup-pressiveresponsestotumors(43).Innudemice,squamouslungcarcinomacells,coveredbyamucingelexpressingLewisx(Gal/31-»4[Fucal-»3]GlcNAcßl-»3Gal/31-»R)antigens,evadeimmunerecognition(44).Theproductionofmucins—bothsecretoryandcellmembraneassociated—mayprotectovariancancercellsfromanimmuneresponse.Alloftheseinteractionssuggestplausiblemechanismsbywhichmucinsmayparticipatedirectlyinthemetastaticprocess.WehaveidentifiedMUC3andMUC4ascandidatesformucinsinvolvedinthesefunctions.FuturestudieswillfocusontheproductionoftheseMUCglycoproteinsandtheirglycosylationpatternsinovariancancerstodetermineastructure-functionrelationshipbetweenmucinsandinvasiveovariancancers. REFERENCES 1.DaSaia.P.J..andCreasman.W.T.Epithelialovariancancer.In:P.J.DaSaiaandW.T.Creasman(eds.).ClinicalGynecologicOncology.5lhéd..p.282-350.St.Louis:Mosby-YearBook.Inc..1997.2.Hakamori.S.I.Aberrantglycosylationintumorsandtumor-associatedcarbohydrateantigens.Adv.CancerRes.,52:257-331,1989.3.Milkens.J..Ligtenberg.M.J.,Vos.H.L.,andLitvinov.S.V.Cellmemhrane-associatcdmucinsandtheiradhesion-modulatingproperty.TrendsBiochem.Sci..17:359-363.1992.4.Bhavanandan.V.P.Cancer-associatedmucinsandmucin-typeglycoproteins.Gly-cobiology,/.•93-503,1991.5.Niv,Y.Mucinandcoloréela cancermetastasis.Am.J.Gaslroenterol..H9:665-669,1994.6.Slrous.G.J.,andDekker.J.Mucin-lypeglycoproleins.Crii.Rev.Biochem.Mol.Biol..27:57-92,1992.7.Gendler.S.J.,andSpicer.A.P.Epithelialmucingenes.Annu.Rev.Physiol.,57:607-634.1995.8.Feller,W.F..Henslee.J.G..Kinders.R.J..Manderino.G.L..Tornita.J.T.andRillenhouse.H.G.Mucinglycoproleinsastumormarkers.Immunol.Ser.53:631-72,1990.9.Koelhl.H..Schieder.K..Neunleufel.W..andBieglmayer,C.Acomparativestudyofmucin-likecarcinoma-associatedantigen(MCA).CA125,CA19-9andCEAinpatientswithovariancancer.Neoplasma(Bratisl.).36:473-478.1989.10.Yin.B.W..Finslad.C.L..Kitamura.K..Federici,M.G.,Welshinger,M.,Kudryashov,V.,Hoskins.W.J.,Well.S..andLloyd.K.O.Serologicalandimmu-nochemicalanalysisofLewisy(Ley)bloodgroupantigenexpressioninepithelialovariancancer.Im.J.Cancer.65:406-412.1996.11.Ghazizadeh.M..Ogawa.H..Sasaki.Y..Araki.T..andAihara.K.Mucincarbohydraleantigens(T.Tn,andSialyl-Tn)inhumanovariancarcinomas:relationshipwithhistopathologyandprognosis.Hum.Pathol..2K:960-966.1997.12.Tashiro.Y..Yone/awa.S..Kim.Y.S..andSato.E.Immunohistochemicalstudyofmucincarbohydratesandcoreproleinsinhumanovariantumors.Hum.Pathol.,25:364-372.1994.13.Devine.P.L..McGuckin.M.A..Ramm.L.E..Ward.B.G..Pee.D..andLong.S.ScrummucinantigensCASAandMSAinlumorsofIhebreast,ovary,lung,pancreas,bladder,colon,andprostale.Ablindtrialwith420patients.Cancer(Phila.l.72:2007-2015.1993. 5549 on March 11, 2014. © 1998 American Association for Cancer Research.cancerres.aacrjournals.org Downloaded from 
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