Altered Tumor-Cell Glycosylation Promotes Metastasis

Finally, glycan changes associated with cancer progression profoundly define the phenotype of cancer cells depending on interactions with ... ThisarticleispartoftheResearchTopic GLYCOBIOLOGYOFCANCER:CURRENTSTATUSANDFUTUREDIRECTIONS Viewall 10 Articles Articles Abstract Introduction TheProcessofMetastasis GeneralMechanismsforAlteredGlycosylationinCancer AlterationsofCancer-AssociatedO-LinkedGlycans FormationofT,Tn,andsTnAntigensduringCancerProgression Siglecs TheRoleofSiglecsinCancerProgression SiglecsasTargetofCancerTherapy Galectins Galectin-1 Galectin-3 Selectins SelectinLigandExpressionCorrelateswithCancerProgression P-Selectin L-Selectin E-Selectin CarcinomaMucinsasInitiatorsofCancer-RelatedProthromboticActivity SelectinsShapetheMetastaticMicroenvironment ConclusionandPerspectives ConflictofInterestStatement Acknowledgments References SuggestaResearchTopic> DownloadArticle DownloadPDF ReadCube EPUB XML(NLM) Supplementary Material Exportcitation EndNote ReferenceManager SimpleTEXTfile BibTex totalviews ViewArticleImpact SuggestaResearchTopic> SHAREON OpenSupplementalData REVIEWarticle Front.Oncol.,13February2014 |https://doi.org/10.3389/fonc.2014.00028 Alteredtumor-cellglycosylationpromotesmetastasis IrinaHäuselmannandLuborBorsig* ZürichCenterforIntegrativeHumanPhysiology,InstituteofPhysiology,UniversityofZürich,Zürich,Switzerland Malignanttransformationofcellsisassociatedwithaberrantglycosylationpresentedonthecell-surface.Commonlyobservedchangesinglycanstructuresduringmalignancyencompassaberrantexpressionandglycosylationofmucins;abnormalbranchingofN-glycans;andincreasedpresenceofsialicacidonproteinsandglycolipids.Accumulatingevidencesupportsthenotionthatthepresenceofcertainglycanstructurescorrelateswithcancerprogressionbyaffectingtumor-cellinvasiveness,abilitytodisseminatethroughthebloodcirculationandtometastasizeindistantorgans.Duringmetastasistumor-cell-derivedglycansenablebindingtocellsintheirmicroenvironmentincludingendotheliumandbloodconstituentsthroughglycan-bindingreceptors–lectins.Inthisreview,wewilldiscusscurrentconceptshowtumor-cell-derivedglycanscontributetometastasiswiththefocusonthreetypesoflectins:siglecs,galectins,andselectins.Siglecsarepresentonvirtuallyallhematopoieticcellsandusuallynegativelyregulateimmuneresponses.Galectinsaremostlyexpressedbytumorcellsandsupporttumor-cellsurvival.Selectinsarevascularadhesionreceptorsthatpromotetumor-celldissemination.Alllectinsfacilitateinteractionswithinthetumormicroenvironmentandtherebypromotecancerprogression.Theidentificationofmechanismshowtumorglycanscontributetometastasismayhelptoimprovediagnosis,prognosis,andaidtodevelopclinicalstrategiestopreventmetastasis. Introduction Themajorityofcancerdeathsareattributedtothemetastaticspreadofcancercellstovitalorgansratherthantotheprimarytumoroutgrowth.Duringmalignanttransformation,thegeneticalterationinthecellsresultsinmutationsofproto-oncogenesandtumorsuppressorgenes,whichasaresultgiverisetotumorcloneswithdifferentproperties(1).Malignantcellstherebyacquirecharacteristicsenablingthemdissociationfromtumors,degradationoftheextracellularmatrix,invasion,adhesion,andmetastasistodistantorgans.Alterationoftumor-cell-surfaceglycosylationisoneofthecharacteristictraitsassociatedwithenhancedmalignancy(2–4).Glycansareoligosaccharidestructuresthatarecovalentlyboundtoproteins,lipids,orpresentinafreeformintissuesortumors.GlycansareboundtotheproteineitherthroughAsn(N-linkedglycan)orthroughSerorThr(O-linkedglycan).Lectinsareafamilyofcarbohydrate-bindingproteinsthatspecificallyrecognizeglycans.Fundamentalprocessessuchascell–cellrecognition,celladhesion,mobility,andpathogen–hostinteractionarefacilitatedbylectinsinhealthyorganisms.Thecommonexpressionoflectinsonendothelialcells,immunecells,intheextracellularmatrixorassolubleadhesionmoleculesenablesthemtobindtotumor-cellglycansandtherebyaffecttumor-cellprogression(5).Subsequently,accumulatingevidencesupportstheinvolvementoftumor-cell-surfaceglycansintumor-cellmigration,adhesion,andmetastasis.Thisreviewaddressestheroleofcancer-associatedglycansduringmetastasiswiththefocusonendogenouslectininteractionswithinthetumormicroenvironment. TheProcessofMetastasis Hematogenousmetastasisisamultistepprocessduringwhichmalignantcellsdetachfromtheprimarytumors,degradetheextracellularmatrix,invadethesurroundingtissue,enterthebloodorlymphaticvessels,andextravasatetoformmetastaticlesions.Tumorcellsthroughthecell-surfaceglycanscanengagewithavarietyofendogenouslectinsbothattheprimarysiteofatumorandinthecirculation.Tumorcelluponreachingthebloodcirculationinducesmicrothrombi,theformationofwhichisfacilitatedbyplateletP-selectinbindingtotumor-cell-surfaceglycans(6,7).Tumor-cellemboliformationcontributestomechanicallodginginthemicrovasculatureand/oradhesiontotheendotheliumtherebypromotingtumor-cellextravasationandmetastasis(8).Thereisaccumulatingevidencethatvascularlectins–selectinsfacilitatetumor-cellinteractionswithallbloodconstituents,platelets,leukocytes,andendothelialcells,andtherebycontributetometastasis(3,9,10).Inaddition,recruitmentofimmunecellstothemetastaticmicroenvironmentisdependentonselectins(11–13). Specificglycanstructuresoncolonicepitheliumprovideimmune-modulatoryactivitytotissuemacrophagesthroughsialicacid-bindinglectins–siglecs(14,15).Inaddition,galactose-bindinglectins–galectinswereshowntobeinvolvedinimmune-suppressionandmetastasis(16).Consequently,alteredglycosylationmaybothinduceinflammatoryreactionsandpromoteimmune-suppression,however;itisdependentonthecellularcontextwithinthetissue.Finally,glycanchangesassociatedwithcancerprogressionprofoundlydefinethephenotypeofcancercellsdependingoninteractionswithendogenouslectinsbothintumorandmetastaticenvironments. GeneralMechanismsforAlteredGlycosylationinCancer Cancerprogressionrequiresarangeofalterationsinextracellularandintercellularsignalingthatpromotescellproliferation,emergenceofinvasivesubsets,dissociationfromthetumor,intravasation,andadhesiveinteractionswithinthecirculationthatfinallyfacilitatemetastasis.Withinthetumorenvironmentchangesinglycosylationallowmalignantcellstopromotecellmobility,celladhesion,andevenreceptoractivation,andtherebycontributingtotheinvasivephenotype(3–5).Malignanttransformationleadstoexpressionofoncofetalantigens,epitopesthatarepresentonembryonictissuesandtumorcells,butaregenerallyabsentinhealthyadultcells.Neo-synthesisandincompletesynthesisarethetwomajormechanismsforgenerationofcancer-specificglycans(2). AlteredglycosylationofN-linkedglycansincanceristypicallyassociatedwithenhancedβ1,6-branching(Table1)thatisfacilitatedbyβ1,6-N-acetylglucosaminyltransferase-5(GnT5)(17,18).IncreasedactivityofGnT5isassociatedwithincreasedpolylactosaminicsequences,andtheinhibitionofGnT5resultedinattenuationofmetastasis(19,20).GnT5deficiency(Mgat5-deficientmice)resultedinreducedtumorgrowthandmetastasis(21).However,thefunctionalroleofbranchedN-glycosylationincancerwaslatershowntobedependentongalectinbindingandtherebyalteringthephenotypeofthecell(22). TABLE1 Table1.Commonglycanalterationsoncarcinomacellsandtheireffectonlectinrecognition. Virtuallyineverycancertypeupregulationofglycosyltransferaseshasbeendetected,leadingtoexpressionofcommontumor-cellepitopessuchassialyl-Lewisxandsialyl-Lewisa(sLex/sLea),Thomsen-nouvelleantigen(Tn),andsialyl-Tn(sTn)(3–5,23,24).Hypoxiahasbeenidentifiedasoneofthefactorsleadingtoincreasedexpressionofglycosyltransferases(25,26).Forinstance,increasedexpressionofα1,3-fucosyltransferase-7(FUT7)andα2,3-sialyltransferaseST3Gal1,enzymesinvolvedinsynthesisofsLex/ahasbeendetected(27).Thegeneralincreaseinsialylationhasbeendetectedbothinclinicalsettingsandexperimentalmodelsthatisassociatedwithametastaticcellphenotype(25,28,29).Anincreaseinα2,6-sialylationintumorsisusuallyattributedtotheupregulationofST6Gal1sialyltransferasethatisprimarilyactiveonN-linkedglycans(30–32),orST6GalNAcfamilyofsialyltransferases,whichareactiveonO-linkedglycansorglycolipids(33).Accordingly,overexpressionofNeu1sialidaseincoloncancercellsledtoreducedlivermetastasisinmiceduetoincreaseddesialylationofβ4integrinwhereassilencingofNeu1sialidaseincreasedcellmigration,invasion,andadhesioninvitro(34). SynthesisofshorterglycanstructureslikeThomsen–Friedenreich(TForT),Tn,andsTnepitopeshasbeenobservedinanumberofcarcinomas(35–39).OneofthefactorsaffectingthesynthesisofincompleteglycanstructuresisthefrequentmutationoftheCosmcchaperonethatisrequiredforthegalactosyltransferaseactivitythatmodifiesO-linkedglycans(40).Anotherexampleofshortenedglycansynthesisisthereducedexpressionofdisialyl-Lewisa(di-sLea)andsialyl6-sulfoLewisxstructuresinepithelialcancer.Disialyl-Lewisx(di-sLex)structureissynthesizedwiththeα2,6-sialyltransferaseST6GalNAc6,anditsexpressionisdownregulatedbyepigeneticsilencinginmalignantepithelium(41,42).Similarly,repressedexpressionofsulfotransferaseresponsiblefor6-sulfoLexwasdetectedincancercellsbutnotinnormalepithelialcells(26). Gangliosidesaresialicacid-containingglycolipids,whichexpressionisoftendysregulatedduringmalignanttransformation(2).Apartfromglycolipidspecificglycanstructurescontainingdisialicacidinaα2,8-linkage(e.g.,GD3),changesinglycosyltransferasespromoteexpressionofsLexepitopes(43).OverexpressionofsialidaseNeu2ledtoreducedmetastasis,whileNeu2wasfoundtobedownregulatedinhighlymetastaticvariantsofcoloncarcinoma(44). Despitemanypossibilitiesfortheformationofglycans(linkageandsequenceofmonosaccharideunits)thereisarathersmallnumberofstructurescommonlydetectedincancer.Furthermore,terminalglycanstructuresexposedonthecellsurfacesoftumorcellscanberecognizedthroughendogenouslectinsandtherebymodulatecancerprogression. AlterationsofCancer-AssociatedO-LinkedGlycans MucinsarehighmolecularweightglycoproteinsexhibitingarodlikeconformationduetoheavyglycosylationwithO-linkedglycans(3,45).O-linkedglycosylation,whichisbasedonGalNAcboundtotheSer/Throfaprotein,isfurthermodifiedbygalactose(core1structure)orGlcNAc(core3structure)innormalmucins(Figure1).Duringmalignanttransformationmucinsofintestine,colon,liver,andpancreashavereducedcore1andcore3structuresthatcorrelatewithenhancedsialylationofTnandTantigens(24,46,47).Core3-derivedglycansareamajortypeexpressedbynormalepithelialcellsofthegastrointestinaltract,whicharedownregulatedduringmalignancyduetolossoffunctionalβ3-N-acetylglucosaminyltransferase-6(core3synthase)expression(48,49).Consequently,overexpressionofcore3synthaseinpancreaticcellswasassociatedwithdecreasedpresenceofTnantigensandresultedinareducedtumorigenicityandmetastasisuponorthotopicinjection.Inaddition,enhancedexpressionofthecore2β1,6-N-acetylglucosaminyltransferase(C2GnT1)responsibleforthecore2synthesiswasdetectedincolorectalandlungcarcinomas,whichcorrelatedwithhighlevelsofsLexonO-glycansandthereforestrongbindingtoE-selectinandmetastasiscomparedtonormaltissues(50–52).MucinsofnormalmammaryepithelialcellscontainamixtureofO-glycansandthemajorityiscore2-basedstructures(53,54).ReducedexpressionofC2GnT1inmammarycancerisassociatedwithenhancedpresenceofTnandsTn(53–56).However,despitereducedcore2structuresonbreastcancercells,increasedpresenceofsLexepitopeshasbeenobserved,whichlikelyisaresultofincreasedfucosylation(57). FIGURE1 Figure1.BiosynthesisofO-glycans.O-glycansynthesisisinitiatedbylinkingofGalNActotheproteinatSerorThrresidue.ThesimplestO-glycanTnantigencanbefurtherconvertedtocore1structure(Tantigen)byβ1,3galactoseextension;core3structurebyadditionofβ1,3-GlcNAc.Duringcancerincreasedexpression(greenarrow)ofsialyltransferaseswithconcomitantreducedexpression(redarrow)ofcore1GalTandcore3GlcNAcTleadstoincreasedformationofsialyl-Tnandsialyl-Tantigens.Core1structureisfurtherbranchedbyC2GnT1toformcore2thatcanbefurthermodifiedtopoly-N-acetyllactosaminestructurescarryingsialyl-Lewisx/a[modifiedfromRef.(23)]. FormationofT,Tn,andsTnAntigensduringCancerProgression Inhealthytissues,core1-basedTandTnepitopesarealmostabsenthowever;inabout90%ofallhumancarcinomastheseprecursorstructuresaredetected(36,39).UnsubstitutedTnepitopesoccurinhumancancersofcolon,breast,bladder,prostate,liver,ovary,andstomach;andtheirpresencecorrelatewithcancerprogressionandmetastasis(35–37,58–63).Similarly,sialylatedTandTnantigenscorrelatewithprogressionofepithelialcancerandpoorclinicalprognosisofmanycarcinomas(25,28,39,64–66).ST6GalNAc1-mediatedα2,6-linkedsialylationofGalNAcoftheprecursorTnantigenresultsinformationofthesTnantigen(25,67–69).ThesialylationsteppreventsfurtherglycanextensionandthereforeleadstotruncationofO-linkedglycans(47,70). SeveralmechanismshavebeendescribedtoenableincreasedTn,sTn,orTexpressionincancer(Table1)(33,46).(1)Decreasedactivityofcore2C2GnT1enzymeleadstoaccumulationofTantigen(describedabove)thatisfurthersialylatedbyST6GalNAc1andST6GalNAc2enzymes(71,72).(2)EnhancedavailabilityofthenucleotidesugarsubstrateUDP-galactoseappearstopromoteincreasedTantigenbiosynthesisthroughcore1β1,3-galactosyltransferase(73).ColoncancertissuesexpressedincreasedlevelsoftheUDP-Galactosetransporter,whichbringsthesugardonorintotheGolgiapparatuscomparedtonon-malignantmucosa.(3)Activityofβ1,3-galactosyltransferase(Tsynthase)requiresthepresenceofthemolecularchaperonproteinCosmc,whichisresponsibleforfoldingandstabilityoftheenzyme(40,74).TheabsenceofCosmcleadstoβ1,3-galactosyltransferasedegradation.MutationinCosmcchaperoneisassociatedwithincreasedTnexpressionincoloncarcinomaandmelanomacelllinesandalsoincreasedsTnexpression(40,75).Accordingly,down-regulationofT-synthaseresultedinamarkedincreaseofT,Tn,andparticularlysTnincoloncarcinomacells(76).(4)GenerationofsTnisfacilitatedbythesialyltransferaseST6GalNAc1andST6GalNAc2(71,72).HumangastriccancercellswithenhancedST6GalNAc1expressionshowedhigherintraperitonealmetastasiscomparedtosTn-negativetumorcells.Similarly,overexpressionofST6GalNAc1,therebysTnepitope,inhumanbreastcancercellsledtoincreasedtumorgrowthinimmunodeficientmice(68,77).Inaddition,enhancedsialylationofTantigeninbreastcancercorrelatedwithhigherlevelsofα2,3-sialyltransferase(ST3Gal1)(72,78).OverexpressionofST3Gal1underthehumanMUC1promoterinaspontaneousmurinebreastcancermodelresultedinsignificantlydecreasedtumorlatencycomparedtomicewithoutST3Gal1overexpression(79).Furthermore,thesialyltransferaseexpressionalonewasresponsibleforenhancedtumorigenesisindicatingthatthisenzymeperseactsasatumorpromoter(79). OnlyfewglycoproteinsareknowntopresentTn,T,orsTnandsialyl-T(sT)antigensinmalignanttissues(66).MucinMUC1andCD44v6displaysTnandsTantigensincolon,gastric,andbreastcancers(80–83).MUC2isamajorcarrierofshortenedglycansingastriccancer(84).EnhancedsTnexpressioninbreastandgastriccancerisassociatedwithoverexpressionofMUC1,CD44,andST6GalNAc1(68,77).AlthoughCD44v6isexpressedinsometypesofhealthyepithelia,higherexpressionisobservedinsquamouscellcarcinomasandadenocarcinomasincludingbreast,lung,colon,andpancreaticcarcinomas(85–87).Interestingly,serumlevelsofosteopontin,aCD44ligand,thatitselfisasTncarrier,havebeendetectedincancerpatientsandcorrelatewithpoorprognosis(87). TheenhancedexpressionofTn,sTn,andTantigensonMUC1,osteopontin,andCD44isassociatedwithhighmetastaticpotentialandpoorprognosis(84,88,89).However,thereislittleevidenceforthefunctionalconsequenceofthisaberrantglycosylationduringcancerprogression.Inhumanbreastcancercells,expressionofsTnonMUC1wasassociatedwithreducedcelladhesionandincreasedcellmigration(77).Inaddition,β1integrinscarryaberrantformsofO-glycansthatisassociatedwithmetastasis(90).EnhancedexpressionofST6GalNAc1inmurinecarcinomacellsledtoanincreaseinsTnexpressiononβ1integrinsubunitassociatedwithmorphologicalchangesincludinglossofepithelialappearance,disorganizationofactinstressfibers,andreducedabilitytomigrateonfibronectin.ArecentstudyshowedthathighexpressionoftheppGalNAcT13,whichinitiatesO-glycansynthesisbyaddingthefirstGalNActoSer/Thr,inducedhighmetastaticpotentialofLewislungcarcinomabygeneratingtrimericTnantigens(GalNAc1-Ser/Thr)3onsyndecan1(91).ThecomplexformationoftrimericTnantigensonSyndecan1togetherwithα5β1integrinandMMP-9resultedinenhancedinvasionandmetastasis.Recentfindingsprovideevidencethatcell-surfacemucinsareinvolvedinsignaltransductionevents[reviewedinRef.(24,45)].DecreasedsTnexpressiononneuroblastomaachievedbyextensionofcore1structurewithB3GNT3expressionreducedactivationoffocaladhesionkinaseandtherebypartiallysuppressedmalignantphenotype(92).Aberrantglycosylationincancerdoesnotaffectonlythetumor-cellphenotypebehavior(e.g.,proliferation,differentiation,andadhesion),butalsocontributetothecontrolofthelocalmicroenvironment,immuneresponses,andmetastasis.Therefore,theseglycansserveasligandsforcellsinthetumormicroenvironmentthroughendogenouslectins. Siglecs Sialicacid-bindingimmunoglobulinsuperfamilylectins(siglecs)arethelargestfamilyofsialic-acid-bindingmolecules(93–95).Siglecsareexpressedonspecificsubpopulationsofhematopoieticcellswheretheyexerttheirimmune-regulatoryfunction.Manysiglecscontainintracellulartyrosinemotifs,whichincludeoneormoremembrane-proximalimmunoreceptortyrosine-basedinhibitorymotif(ITIM)andamembrane-distalITIM-likemotif(93,94).Thesemotifsareinvolvedininhibitorysignaltransduction.Basedonbothsequencesimilarityandconservationbetweenmammalianspeciessiglecsaredividedintwomajorsubgroups.ThefirstgroupcomprisesSiglec-1(sialoadhesin,CD169),Siglec-2(CD22),Siglec-4(myeloid-associatedglycoprotein),andSiglec-15.ThesecondsubfamilyofCD33/Siglec-3relatedsiglecsconsistsof10humanmembers(Siglec-3,-5,-6,-7,-8,-9,-10,-11,-14,and-16)and5rodentmembers(Siglec-3,-E,-F,-G,and-H)(93,95).Thefirstsubgroupwithitsevolutionaryconservedmembershasrestrictedexpressionpatterns.ForinstanceSiglec-1isspecificallyexpressedonmacrophages,Siglec-2onB-cellsandSiglec-4onoligodendrocytesandSchwanncellsinthenervoussystem(96).Ontheotherhand,CD33-relatedsiglecsdisplayamoredivergentexpressionpatterndependentondevelopmentalstageofimmunecells(93,95).Thehighsialicacidconcentrationonthecell-surfaceofsiglec-expressingcellsoftenleadstobindingtothecellglycans(incis)oradjacentcells(intrans).Siglecscanbeaffectedbyvariousstimuliincludingcytokines,toll-likereceptoractivation,andviralandbacterialinfections,thebiologyofsiglecsisthereforerathercomplex(96).Thebindingspecificityofsiglecsdependsonthedistincttypes,linkages(α2,3,α2,6,andα2,8),arrangementsofsialicacids,theirwayofpresentationondifferentcells,organs,andorganisms.Siglecbindingtoligandsmodulatescell–cellinteractions,cellproliferation,celldeath,andendocytosis(96–99). TheRoleofSiglecsinCancerProgression Accumulatingevidenceindicatesthattheinteractionbetweentumor-specificglycansandlectinsonimmunecellsareinvolvedinmodulationofthetumormicroenvironment(100).Theinhibitorynatureofsiglecuponbindingofspecificglycanmayleadtodampeningofimmuneresponsesandtherebyescapeofimmunesurveillanceandclearance.Whethersiglecscontributetocancerprogressionthroughrecognitionofdistinctcancer-specificglycanstructuresiscurrentlyunderinvestigation.Non-malignantcolonepithelialcellsexpressdi-sLeaepitopesthatserveasligandsforbothSiglec-7and-9(15).Theexpressionofsiglecligandswasdecreaseduponmalignanttransformation,whichwasassociatedwithenhancedexpressionofsLexandsLeaepitopes(26).ExpressionofST6GalNAc6,whichsynthesizesdi-sLeainhumancoloncancercellsresultedinincreaseddi-sLea,lossofsLeaepitopes,andincreasedbindingtoSiglec-7(41).MainlyresidentmacrophageswerefoundtocarrySiglec-7and-9inacoloniclaminapropriaandSiglec-7/9ligationcouldsuppressmacrophage-mediatedcyclooxygenase-2(COX2)andprostaglandinE2expressionandtherebypreventinflammatorydamageofthecolonicmucosa(15).Siglec-15,whichpreferentiallyrecognizessTnantigen,isexpressedintumor-associatedmacrophages(TAMs)invarioushumancarcinomatissuesincludinglung,liver,andrectum(101).BindingofmyeloidcellsthroughSiglec-15tosTnontumorcellsresultedinincreasedTGF-βsecretionintothetumormicroenvironmentthatisassociatedwithcancerprogression.Interestingly,Siglec-15expressionwasinducedbyM-CSF,whichusuallypolarizesmacrophagestoM2phenotypecommonlydetectedinthetumormicroenvironment. Siglec-1isexpressedinasubsetofmacrophagesthatareinvolvedinthepathophysiologyofcancer(102).ClinicalobservationshowedthatincreasedSiglec-1ispresentinsplenicmarginalcelllymphomaaswellasinmacrophageinfiltratesofMUC1-positivebreastcancers(103,104).Siglec-1positivemacrophageswerefoundtoinfiltrateintoratxenografttumorsinaCCL2-dependentmanner(105).Oncontrary,recentstudydemonstratedthatSiglec-1positivemacrophagesinregionallymphnodesofcolorectalcarcinomapatientspromoteCD8+T-cellmediatedanti-tumorimmunityandareassociatedwithabetterprognosisforthesepatients(106). Siglec-9,asurfacereceptoronNKcells,B-cells,andmonocytes,hasbeenidentifiedasareceptorformucinMUC16(14).Cell-surfaceboundaswellassolubleMUC16isoverexpressedinhumanovariantumorcellsanddetectedinperitonealfluidofcancerpatients(107).EngagementofSiglec-9onmonocytesalsoinducedsecretionofimmunosuppressivecytokineIL-10(108).Similarimmune-suppressionmediatedbySiglec-7onNKcellswasobservedinrenalcellcarcinomaexpressingdisialosylglobopentaosylceramide(DSGb5)asamajorganglioside(109).RecentstudyfromC.Bertozzigroupprovidedstrongevidencethatsiglec-7-mediatedcytotoxicityofNKcellscanbemodulatedbythealterationofglycansoncellsurfaces(110).Presentationofsialylatedligandsontumorcellsrecognizedbysiglec-7resultedinenhancedphosphorylationofcytoplasmictyrosineresidues,causingdampeningofcytolyticactivity. TheassociationbetweenSiglec-9positiveimmunecellsandMUC1-positivetumorcellshasbeendetectedintissuesofhumancolon,pancreas,andbreastcancer.Interestingly,Siglec-9bindingtoMUC1expressingtumorcellswasshowntoinducerecruitmentofβ-cateninintumorcellsresultinginpromotionofcellgrowthinvitro(111).ThesefindingssuggestthatSiglec-9engagementofcarcinomamucinMUC1maybeinvolvedintumorgrowth,however;thenatureofSiglec-9ligandsaswellasthecellularcontextinvivoremainstobedefined. Takentogether,thecurrentevidenceislargelybasedonclinicalcorrelationofcancer–glycanexpressionandseveralexperimentsshowingSiglec-cancer–glycaninteractioninvitro.Whethertheseinteractionsindeedfunctionallymodulateimmunecellresponsesinthetumormicroenvironmentandtherebyaffectcancerprogressioninvivorequiresexperimentalvalidation. SiglecsasTargetofCancerTherapy TheidentificationofSiglec-2andSiglec-3asmarkersofacutemyeloidleukemia(AML)andB-celllymphomasraisedinterestinpotentialimmunotherapy(112–114).Anti-Siglec-2andsiglec-3specificantibodieswereconjugatedwithvarietyoftoxinsandsuchimmunotoxinshavebeentargetedinseveralautoimmunediseasesandhematologicalmalignancies[reviewedinRef.(93,94,115)].Inthemajorityofacutelymphoblasticleukemias(ALL)Siglec-2(CD22)wasidentifiedasausefultargetforcell-depletiontherapy(116).InotuzumabozogamicinisanimmunotoxincomprisedofahumanizedIgG4monoclonalantibodycovalentlylinkedtocalecheamicin(CMC-544).CMC-544wasactiveagainstB-celltumorsinpreclinicalmodelsandhasbeenevaluatedinphaseIstudyforpatientswithB-celllineageALL(117).Inotuzumabozogamicinusedasasingletherapyinpatientswithrefractory-relapsedALLshowedpositiveresults. Theimmunotoxingemetuzumabozogamicin(OG,Mylotarg;Wyeth,Madison,NJ,USA),whichconsistsofahumanizedanti-CD33(siglec-3)murineantibodylinkedtocalicheamicin,wasapprovedbytheFDAfortreatmentofCD33+AMLpatients.BindingandendocytosisoftheconjugateresultedintheintracellularreleaseofthetoxincausingcelldeathofCD33+cells(94,115).Howeverthedrugisoffthemarketsince2010becausethekeyphaseIIItrial(SouthWestOncologyGroupStudyS0106)inwhichGOwascombinedwithinductionchemotherapyfailedtoimprovedisease-freesurvivalandcausedhigherfatalinductiontoxicityratecomparedtochemotherapyalone(118).RecentstudiesusinglowerorfractionateddoseofGOsuggestthatGOmaystillimprovesurvivalofdistinctsubsetsofAMLpatients,particularlypatientswithfavorablecytogenetics(119).NewapproacheswithhumanizedCD33antibodyconjugatedtosyntheticDNAcross-linkingpyrrolobenzodiazepine(SGN-CD33A)havebeendevelopedandrevealedpromisingeffectivenessinanimalmodels(120).SGN-CD33AisnowcurrentlybeingtestedinaphaseItrial(ClinicalTrials.gov:NCT01902329). Galectins Incontrasttosiglecsandselectins,whicharemostlycell-surface-boundreceptors,galectinsaresolubleimmunomodulatorylectins(121).Galectinsbindtogalactosethatiseitherβ1,3-orβ1,4-linkedtoN-acetylglucosamine,acommondisaccharidefoundbothonN-andO-linkedglycansandglycolipids.Galectinsactbothintracellularlybymodulatingsignalingpathwaysandextracellularlyasregulatoryreceptors(100).Uptodatethegalectinfamilyconsistsof15members,whichareclassifiedintothreegroupsbasedonstructuraldifferences:prototypegalectins(Galectin-1,-2,-5,-7,-10,-11,-13,-14,and-15)havingonecarbohydraterecognitiondomain(CRD),tandemrepeat-typegalectins(Galectin-4,-6,-8,-9,and-12)havingtwoCRDs,andthesinglememberGalectin-3,whichhasoneCRDconnectedtoanon-lectinN-terminalregionresponsibleforoligomerization(100).Galectinsareexpressedbyvariouscelltypesincludingepithelialandimmunecells,buttheirexpressionisalteredduringprogressionofcolon,breast,lung,pancreatic,headandneck,andcervicalcancers(16,122).Manystudiesindicatethatcancer-associatedgalectinscouldregulatecancercellproliferation,signaling,adhesion,invasion,andmetastasis(122–124).Galectin-1andGalectin-3weremostintensivelystudiedincontextofcancer. Galectin-1 Accumulatingevidenceindicatethattumor-derivedGalectin-1contributestoimmunosuppressiveactivityindifferenttumors,includinglungandpancreaticcarcinoma,melanoma,andneuroblastoma(16,125–127).IthasbeenshownthatGalectin-1bindingtoT-cellsthroughN-andO-linkedglycansonCD43orCD45mucinsinducesapoptosisofactivatedT-cells(128,129).Galectin-1expressionbymelanomacellsinducedapoptosisoftumor-specificeffectorT-cells,andGalectin-1inhibitionallowedgenerationofatumor-specificT1response(126).Modificationofcell-surfaceglycosylationaffectsglycanpatternonT-cellsandtherebychangesGalectin-1binding.Enhancedexpressionofα2,6-sialyltransferase-1(ST6Gal1)selectivelymodifiedN-glycansonCD45andtherebyinhibitedGalectin-1binding(130).HowGalectin-1contributestoimmune-suppressionintumorshasbeendelineatedinlungcancer(131).HighexpressionofGalectin-1inlungcancercelllines,aswellasinhumantumortissues,altersthephenotypeofmonocyte-deriveddendriticcellsandimpairsT-cellresponse,concomitantwithincreasedpresenceofregulatoryT-cells(Tregs).TheregulatoryeffectofGalectin-1ismediatedbyincreasedexpressionofIL-10inmonocytestherebyinducingaTh2-dominantcytokineprofile.TheenhancedinfiltrationofCD11c+dendriticcellsinhumanlungcancersampleshasbeenrecapitulatedinamousemodel,whichwascompletelyomittedaftertransplantationofGalectin-1silencedtumorcells.Inanotherstudy,theamountofGalectin-1positivecellscorrelatedwiththetumorgradeinhumanbreastcancer(132).SilencingofGalectin-1inametastaticmurinemammarytumorledtoareductionoftumorgrowthandlungmetastasiswithaconcomitantreductionininfiltratingregulatoryT-cells. ExperimentalevidencealsosuggeststhatGalectin-1expressedonvarioustumor-celltypesincludinghepatocellularcarcinoma,melanoma,ovarian,andprostatecancercellsmediatestumor-celladhesiontotheextracellularmatrix(133,134).Inaddition,Galectin-1mediatedattachmentofcancercellstotheextracellularmatrixandendothelialcellsthroughbindingtoCD44andCD326onmurinebreastandcoloncancercells(16).Galectin-1mightalsobeinvolvedinformationofplatelet-cancercellcomplexessinceitwasshowntoactivateplatelets(135).Murinebreast,colon,andLewislungcancercellswithsilencedGalectin-1showeddecreasedlungmetastasis,whichwasassociatedwithincreasedT-cellnumbersandreducedangiogenesis(16,125).Takentogether,tumor-derivedGalectin-1exertsitsimmunosuppressivefunctionthroughbindingtoendogenous(non-tumor-derived)glycansandtherebycontributestocancerprogression. Galectin-3 Thereisaccumulatingevidencethatthecancer-associatedT,Tn,andsTnstructurespromotemetastasisthroughbindingtoGalectin-3.Galectin-3expressionisalsoincreasedinpatientseraofseveralcancertypesandassociatedwithincreasedriskofmetastasis(136,137).Forinstance,Tantigenexpressionbybreastandprostatecancercellsfacilitatedinteractionswithcancer-associatedGalectin-3orwithendothelialassociatedGalectin-3(66,138–140).Theseinteractionsleadtohomotypicaggregationofcancercells,whichprotectscancercellsfromapoptosisinducedbythelackofadhesiontotheextracellularmatrix(139).Inaddition,cancercell-associatedTantigenscaninduceGalectin-3expressionontheendothelium,whichenabledcancer-endotheliumadhesion(140).Anotherstudyhasshownthatlysosomal-associatedmembraneprotein-1(LAMP-1)onhighlymetastaticmelanomacellscarriesN-acetyllactosaminylstructures,whicharerecognizedbyGalectin-3onlungendothelialcellssuggestingthatlungendothelialgalectin-3canserveasanchorforLAMP-1expressingtumorcellsinthecirculation(141). Acharacteristicfeatureofgalectinsistheinductionofcomplexformationbycross-linkingglycoproteins,whichcanformmultimers“lattice”microdomain(121).ComplexN-glycansareformedbyGnT5modificationofN-glycansthataretheligandsforGalectin-3(142).ExpressionofGnT5haslongbeenimplicatedintumorprogressionandmetastasis(17).Inparticular,theabsenceofGnT5delayedtumorformationandsuppressedmetastasis(21).Accordingly,up-regulatedGnT5expressionhasbeenobservedinvarioushumancancers(18,143);andtheectopicexpressionoftheGnT-Vinmultipleepithelialcellsresultedinincreasedcellmotility,tumorformation,andenhancedmetastasis(144,145).Furthermore,GnT5-dependentmodificationsoftyrosinekinasereceptorssuchasEGF,TGF-β,IGFR,andPDGFenhancedaffinitytogalectin-3andtherebyprolongedtheircell-surfaceexpression(22,146).Galectin-3-inducedlatticeformationpreventedthesurfaceclearanceofreceptorsbyclathrin-dependentendocytosisandenabledinteractionwithinhibitorycaveolin-1domains. BranchedO-glycanswithpoly-N-acetyllactosaminestructuresarerecognizedbyGalectin-3(147).InC2GnT1-expressingbladdertumorcellscore2O-glycanspresentonMHCclassI-relatedchainAareboundtoGalectin-3thatreducedtheaffinityfortheactivatingNKcellreceptorsNKG2D,therebyimpairingNKcellfunctionandanti-tumoractivity. RecentfindingssuggestthatGalectin-3alsoregulatesdynamicsofN-cadherinandthelipidraftmarkergangliosideGM1(148).AccumulationofN-cadherinandGM1atcell–celljunctionsdestabilizedcell–celljunctionsandtherebypromotedtumor-cellmigration.N-glycansonα5β1integrinareimportantfortheirproperbindingtofibronectin(149,150).IncreasedGnT5mediatedβ1,6-branchingreducescell-surfaceclusteringofα5β1integrin,specificallyoftheβ1subunit,resultinginalessadhesivephenotypeduetoreducedadhesiontofibronectinandmodulatesfibronectinmatrixremodelingintumors(20,151).Thus,Galectin-3latticeformationprovidesanothermechanismhowalteredglycosylationcontributestothemalignantandinvasivephenotypeoftumorcells(148). Selectins SelectinsarevascularcelladhesionmoleculesthatbelongtoafamilyofC-typelectins,whichfacilitatetheinitialattachmentofleukocytestotheendotheliumduringtheprocessofleukocyteextravasation.TheselectinfamilyconsistsofL-,E-,andP-selectin,whichsharearound50%sequencehomologyintheirC-typelectindomain(152).L-selectin(LECAM-1andCD62L)isconstitutivelyexpressedonalmostallhematopoieticcelltypesincludingmyeloidcells,naïve,andsomeactivatedmemoryT-cells(152)andenablesadhesionofleukocytestotheactivatedendotheliumorinhighendothelialvenulesoftheperipherallymphnodes(153,154).E-selectin(ELAM-1andCD62E)isexclusivelydisplayedonendothelialcells,whichrequiresdenovoexpressioninresponsetoinflammatorystimulisuchasTNF-αandIl-1β.However,skinandpartsofthebonemarrowmicrovasculaturehavebeenshowntoconstitutivelyexpresscertainE-selectinlevels(155).Oncontrary,P-selectin(PADGEMandCD62P)isstoredinalpha-granulesofplateletsaswellasinWeibel–Palladebodiesofendothelialcellsandcanberapidlymobilizedtothecell-surfaceuponactivationofplateletsortheendothelia.E-andP-selectinbindtoligandsonmyeloidcells(156),certaintypesoflymphocytes(152)butalsotoseveraltypesoftumorcells(157–159).Selectinsarethemost-studiedlectinsincancerbiology,whichpromotecell–cellinteractionwithtumorcellsandtheirmicroenvironment(9).Allthreeselectinshavebeenshowntocontributetotumordisseminationandspecificallyfacilitateprocesseswhenthetumorcellsareinthecirculation. SelectinLigandExpressionCorrelateswithCancerProgression ThereiscompellingclinicalandexperimentalevidencethatoverexpressionoftetrasaccharidessLexandsLeacorrelateswithpoorprognosisduetoenhancedmetastaticphenotypeinanumberofcancertypes,includingcolon,gastric,prostate,renal,pancreatic,andlungcancer(89,160–165).EnhancedexpressionofsLex/aoncancercellscorrelatedwithincreasedabilitytoadheretoE-selectinortotheactivatedendothelialcellsandstromalcellsinvitro(157,166–168).Furthermore,highcell-surfaceexpressionlevelsofsLexwerelinkedtoenhancedmetastaticactivityinvariousexperimentalmetastasismodelsusinghumancarcinomacellscomparedtolowerorminimalsLexexpression(169–171). TheminimalrecognitionmotifforallthreeselectinsaretetrasaccharidessLex/a(Figure2)(172).SLexareterminalstructuresofN-orO-linkedglycansattachedtoglycoproteinsandglycolipidsdisplayedbymostcirculatingleukocytesandendothelialcellswhereassLeaisdetectedonsomeepithelialcellsbutmostlyonvarioustumorcells(3,4,173).ThefourglycosyltransferasesN-acetylglucosaminyltransferase,β1,4-galactosyltransferase,α2,3-sialyltransferase,andα1,3-fucosyltransferase-7areresponsibleforsynthesisofsialyl-Lewisa/xstructuresoncellsofthehematopoieticsystem(172,174).Efficientselectinbindingtocarbohydratesusuallyrequiresaglycoproteinscaffoldthatfacilitatesthepresentationofselectinligandsinclusters(175).OneofthebestcharacterizedligandsforallthreeselectinsistheP-selectinglycoproteinligand-1(PSGL-1),whichisconcentratedonthetipsofmicrovillionleukocytesurface(176).TothemostcommonmucinscarryingselectinligandsthatareassociatedwithcancerprogressionbelongMUC1,MUC2,MUC4,andMUC16(35,45,177,178).Apartfrommucins,severalotherselectinligandcarriersontumorcellshavebeenidentifiedthatincludesCD24,CD44,death-receptor3,E-selectinligand-1,PSGL-1,andpodocalyxin-likeproteinandthislistisbyfarnotcomplete(179–183).Severaloftheseligandsarealsoexpressedontumorcellsandareassociatedwithcancerprogression.Forinstance,CD44glycoproteinsexistinseveralisoformsandareexpressedonepithelialandendothelialcellsaswellasonmultiplecancercelltypessuchasgastric,colorectal,pancreatic,andlungcancer(184–186).TheaberrantexpressionofCD44incolorectalcarcinomacellscorrelatedwithincreasedmetastaticpotentialinvivo(187,188).Basedonflow-basedadhesionassaysinvitro,CD44vonhumancoloncarcinomacellsbindstoP-,E-,andL-selectin(189,190).Themajorityofselectinligandsarepresentedonmucins,buttheycanbefoundequallyfunctionalalsoonN-linkedglycansorglycolipids.Finally,P-andL-selectinsalsobindtoheparin,heparansulfate,andsulfatedglycolipids,whichalsoindicatescertainflexibilityinligandrecognition(9,175).Inaddition,chondroitinsulfateglycosaminoglycans(CS-GAGs)onbreastcancercellswereidentifiedtoserveasaP-selectinligandthatisassociatedwithbreastcancermetastasis(191).Despitethelargevarietyofglycans,tumorcellsexpresssialylatedandfucosylatedmolecules,mostlyonmucinswhicharealsorecognizedbyselectins(158,159,167,192,193). FIGURE2 Figure2.FormationofLewisantigens.TerminalGlcNAcresidues,particularlyoncore2structures,arefurtherextendedbyadditionofβ1,4galactose,forLewisxepitope,andβ1,3galactose,forLewisaepitope.Thisisfurtherfollowedbytheadditionofα2,3-linkedsialicacidtoGalbyST3Galenzymesandfinalizedbytheadditionofα1,3-linkedfucoseforsLexandα1,4-linkedfucoseforthesLeaantigen.FUT3finalizedthesynthesisofLeaantigen,whileFUT6andFUT7wereshowntofinalizeLexepitopes. IncreasedexpressionofsLex/aintumorcellshasbeenattributedtoelevatedlevelsofα1,3-fucosyltransferase-7(FUT7),whichhasalsobeenshowntocorrespondwithincreasedmalignancyinlungcancerpatients(161).Inaddition,overexpressionofα1,3-fucosyltransferase-3and-6inmetastaticprostatecancercellscorrelatedwithhighersLexlevelsandmoremetastasisthatwasdependentonE-selectin-mediatedrecruitmenttodistantsites(169,194).GenesencodingforFUT3,FUT4,andST3GAL6enzymesthatareinvolvedinsLexsynthesisweresignificantlyincreasedinbreastcancersandcorrelatedwithmetastasistothebonewheresLexreceptorE-selectinisconstitutivelyexpressed(195).InflammatorycytokinesmightalsobeinvolvedinsLexproduction.TNF-αenhancedmotilityandinvasionpropertiesofprostaticcancercellswereassociatedwithselectiveupregulationofgenesrelatedtosLexsynthesis(196).StudiesanalyzingprostateandpancreaticcancercellhomingintoboneshowedthatE-selectin-mediatedadhesionisdependentonenhancedα1,3-fucosyltransferase,FUT3,FUT6,andFUT7activity(197,198).Consequently,down-regulationofα1,3-fucosyltransferaseactivitydramaticallyreducedprostatecancerincidence.However,thereisalsothepossibilitythatselectin-mediatedactivationofeithertumorcellsorthetumormicroenvironmentfurtherpromoteinflammationthatisahallmarkofcancerprogression. P-Selectin Theassociationbetweencirculatingcancercells,platelets,andformationoftumormicroemboliiswidelyaccepted(199–202).Manystudiesshowedthatplateletsenhancehematogenousdissemination,intravasculartumor-cellsurvival,andmetastasis(203–206).However,themajormechanismofplatelet-adhesiontotumorcellshasbeenfoundtobemediatedbyplateletP-selectin(6).Platelet-tumorcellinteractionsweresignificantlyreducedinP-selectindeficientmice,andconsequentlyattenuationofmetastasiswasobserved.EnzymaticremovalofcarcinomamucinscarryingselectinligandsfromtumorcellspriortotailveininjectionresultedinattenuatedmetastasiscomparabletotheabsenceofP-selectin(158,203).Inaddition,endothelialP-selectin-mediatedinteractionsalsocontributedtometastasisindicatingthatbothplateletandendothelialP-selectinpromoteearlyeventsduringtissuescolonization(11,207).AnotherstudyshowsthatplateletspromotelungmetastasisofB16F1melanomaand4T1.2breastcancercells(208).PlateletdepletionresultedinasignificantreductionoflungmetastasiswhencomparedtoNKcelldepletedanimals,indicatinganadditionalpro-metastaticfunctionofplatelets.Thesefindingsareinagreementwithadirecteffectofplatelet–tumor-cellinteractionsthatpromotesthemetastaticbehavioroftumorcells(209).Takentogether,P-selectin-mediatedinteractionssignificantlycontributetotheearlystepsofmetastasiswhentumorcellsareincirculation. L-Selectin L-selectinbindstoavarietyoftumorcellsandcontributestometastasis(167,210).IntravenousinjectionofhumanandmurinetumorcellsinL-selectindeficientmiceresultedinreducedrecruitmentofleukocytesandsubsequentlyattenuatedmetastasisthatconfirmedtheactiveroleofL-selectin-mediatedinteractioninthisprocess(11,13).MetastasiswasfurtherattenuatedinP-andL-selectindoubledeficientmiceprovidingevidencethatbothselectinssynergisticallycontributetometastasis(11).Inaddition,theenhancedexpressionofselectinligandsaroundthemetastatictumorcellswasdetectedwithL-selectinchimera,whichcorrelatedwiththerecruitmentofleukocytes(13).ThesefindingsindicatedthatL-selectiniseitherresponsibleforrecruitmentofleukocytesortheirinteractionswithinthemetastaticmicroenvironment.Enhancedpresenceofinflammatorycells,primarilymyeloid-derivedcells,inthetumormicroenvironmentisusuallyassociatedwithtumorgrowthandmetastaticdissemination(211,212).Thus,L-selectinrepresentsapotentialfacilitatorofmyeloidcellrecruitmenttometastaticsitesandtherebypromotesearlystepsofmetastasis,e.g.,tumor-cellextravasation(13,213).Duringinflammation,leukocyteinteractionwiththeendotheliumresultsininducedvascularpermeability.However,whetherL-selectinpromotesmetastasisthroughadirectengagementwithselectinligandsontumorcellsorrathermimicsinflammatory-likereactionaccompanyingtheprocessoftumor-cellseedingindistantorgansremainstobedetermined. E-Selectin E-selectinhasbeenthefirstselectinintensivelystudiedincontextofmetastasis(9,10).TheoriginalhypothesiswasthatE-selectinmediatesmetastaticdisseminationtodistantorgansthroughbindingtoligandsontumorcells,similarlytoleukocyteadhesionduringinflammation(3).Numerousstudiesprovidedevidencethattumorcellsexpressingselectinligandsadheretoactivatedendotheliumunderflowconditioninvitro(157,168,181).WhiledifferentE-selectinligandswerelinkedtoenhancedmetastasis,themajorityofthembelongtothemucintypemolecules.Despitetheobservationofincreasedprimarytumorgrowthinselectindeficientmice,whichseemstobelinkedtoreducedanti-tumorigenicinfiltrationofimmunecells(214),thereisaccumulatingevidencethatE-selectinpromotescancermetastasisinanimalmodels.EnhancedE-selectinexpressionwasobservedintheliverduringmetastaticcolonizationandthedown-regulationofE-selectinresultedinattenuationofmetastasis(215,216).MetastasiswasredirectedtotheE-selectinoverexpressingliverusingexperimentallungmetastasismodel,whichprovideddirectevidenceforinvolvementofE-selectininfacilitationoftumor-cellseeding(217).Accordingly,experimentallivermetastasisofhumancoloncarcinomacellswasalsoE-selectin-dependent(218).However,experimentallungmetastasisofhumancolonadenocarcinomacellsremainedunchangedinE-selectindeficientmice(219).Oncontrary,spontaneousmetastasisofhumanbreastcancercellstothelungswassignificantlyattenuatedinE-selectin-deficientmice(220).Interestingly,Hiratsukaetal.showedthatfactorssecretedfromprimarytumorscanactivateendothelialfocaladhesionkinaseandE-selectinexpressioninthelungvasculatureandtherebyinducetheformationofpermissiblesitesformetastasis(221).Enhancedhomingofmetastatictumorcellstothesesiteswasobservedandwasassociatedwithmetastasis.Theseobservationsindicatethatprimarytumorscanactivelyformadistantmetastaticnicheandupregulateexpressionofcelladhesionmoleculesinvolvedintumorcell-endothelialinteractions.Inconclusion,thereisconvincingevidencethatendothelialE-selectinfacilitatesmetastasisbyenablingtumor-celladhesiontovasculature.Nevertheless,theexactmechanismofE-selectinfacilitationofmetastasisremainstobedefined. CarcinomaMucinsasInitiatorsofCancer-RelatedProthromboticActivity Alteredcancerglycosylationisnotreflectedonlyoncell-surfacemolecules,butaberrantlyglycosylatedproteinsaredetectedinthecirculation(26).Antibodiesraisedagainsttumorcells,wereshowntospecificallyrecognizeglycanstructures,e.g.,sLea,whicharecurrentlyusedforcancerdiagnostics(45).Thepresenceofcarcinomamucins(e.g.,CA-125,CA19-9),whicharesheddedfromtumors,areroutinelyusedasserumtumormarkersindiagnosisofcancer.Besides,efficientbindingofrecombinantsolubleselectintocarcinomamucinshasbeenobserved(158,222).Increasedthromboembolismisarecognizedcomplicationinvariouscarcinomas,particularlymucinouscarcinomas,however;thereareseveralpathologicmechanismslikelytobeinvolved(7).Idiopathicthromboembolism,whichisfrequentlyassociatedwithoccultcarcinomas,belongstotheTrousseausyndrome.Recentstudiesprovidedevidencethatintravenousinjectionofcarcinomamucinscarryingselectinligandsintomiceresultedingenerationofplatelet-richmicrothrombi(222).ThispathologywasmarkedlydiminishedinP-selectinorL-selectindeficientmice.Interestingly,carcinomamucinscouldnotactivateplateletsandtherebycouldnotgeneratemicrothrombiinmicelackingPSGL-1(223).CarcinomamucinsinitiatedthrombosisonlyinthepresenceofplateletsthatinducedreleaseofcathepsinGfromneutrophilsthroughaselectin-dependent,reciprocalactivationofneutrophilsandplatelets.Takentogether,carcinomamucinscarryingselectinligandsinbloodcirculationmayserveasinitiatorsofthrombiformationobservedincancerpatients. SelectinsShapetheMetastaticMicroenvironment Thereisaccumulatingevidencethatselectinsfacilitateheterotypicinteractionsbetweentumorcellsandbloodcomponents,includingtheendotheliumandtherebypromotetumor-cellseeding,survivalandextravasation(8,9,224).Whencirculatingtumorcellsarrestinthemicrovasculatureofdistantorgans,earlyonmarkersofendothelialcellactivationandinflammation,includingE-selectin,wereupregulatedinexperimentallungandlivermetastasismodels(219,225–228).EnhancedE-selectinexpressionwasdetectedalsointhemetastaticlungsusingaspontaneousmetastaticmodelwithLewislungcarcinoma(219,221).Consequently,inhibitionofendothelialactivationand/orE-selectinfunctionattenuatedmetastasis(227,229).Endothelialactivationcausedbyfactorsderivedfromprimarytumororfromarrestedtumorsinthevasculaturepromotedselectin-mediatedinteractionsandformationofapermissivemicroenvironmentwithinthevasculaturepriortotumor-cellextravasation(11,13,213).Tumor-cellglycan-inducedandP-selectin-dependentendothelialactivationresultedinenhancedexpressionofE-selectinandvascularcelladhesionmolecule1(VCAM-1)andpromotedlungcolonizationandmetastasis(213).Inaddition,elevatedproductionofchemokineCCL5contributedtotherecruitmentofmonocytes.Accordingly,endothelialVCAM-1expressionwasinducedbytumor-cellembolusthatresultedinincreasedrecruitmentofmyeloidcellssupportingmetastasis(225).Recruitmentofinflammatorycells,especiallymyeloid-derivedcells,isstronglyassociatedwithenhancedmetastaticcolonizationthatisatleastpartiallydependentonL-selectin(12,13,213,230–232).Takentogether,theselectin-mediatedinteractionsplayacriticalroleduringtheestablishmentofmetastasisthatisco-initiatedbyaberrantglycansontumorcellsincirculation.Whethertumorglycansonlyinitiatetheinflammatory-likecascadeleadingtometastasisorhavefurtherfunctioninshapingthisprocessremainstobedefined. ConclusionandPerspectives Cancer-associatedaberrantglycosylationhasbeenidentifiedinvirtuallyeverytypeofcancer.Expressionofcancer-specificglycanepitopesrepresentsagreatopportunitytoexplorethemfordiagnosticsandpotentiallyspecifictargetingoftumors.Consideringthatgenesonlyindirectlyregulateglycanformation,itisstillpuzzlingthatglycanepitopeshavebeenconsistentlyvalidatedascancermarkers.Basedonthebroadexpressionandhighspecificityforcancertissues,Tantigeniscurrentlyexploredasapotentialtargetforthedevelopmentofcancerdiagnosticsandimmunotherapeutics(16,233).SincetheexpressionofsTnantigensonthemajorityoftumorscorrelatedwithpoorprognosis,thesTnantigenhasbecomeatargetforcancervaccine(58,61).AdministrationofsTndisaccharideconjugatetohighlyimmunogenicproteininducedantibodiesagainstsTnandshowedprotectiveeffectsinamousemodelofbreastcancer(234).AlthougharandomizedphaseIIIclinicaltrialusingthesamesTnvaccinedidnotimproveoverallsurvival,patientswithhightiteragainstthesTnhadsignificantlyprolongedoverallsurvival(235). Theaccumulatingknowledgeaboutthefunctionoflectin–tumor-cellglycaninteractionsincancerwillopenwaysfornewapproachestointerferewithcancerprogression.However,theexploitationofsuchtherapeuticopportunitiesrequiresacomprehensiveknowledgeabouttheunderlyingmechanismsoflectin-mediatedinteractions.Nevertheless,theroleofselectinsincancerprogressionhasbeenextensivelyinvestigatedinnumberofpreclinicalmodelsandthemechanismatleastpartiallycharacterized(9).Clearly,furtherstudiesintheexactmechanismofactionarestillrequired,butselectininhibitionincancerhasbeeninadvertentlyclinicallytestedincancerpatientstreatedwithantithrombotictherapies(236).UnfractionatedheparinaswellaslowmolecularweightheparinhasastrongP-andL-selectininhibitoryactivityatclinicallyrelevantconcentrations.Retrospectiveanalysisofclinicalstudiesrevealedthatapartfromantithromboticactivity,heparinimprovedsurvivalofcancerpatientsespeciallyinpatientswithearlystagedisease.Still,prospectiveandwell-designedclinicalstudyremainstobeperformed.Similarly,developmentofhighlyspecificligandprobesforsiglecs(e.g.,Siglec-2)revealedtheabilitytotargetsiglec-expressingcells(94).Furtherinvestigationsarerequiredfordecidingwhetherglycan-specifictargetingoflectinsinvolvedincancermodulation(e.g.,siglec,selectins,orgalectins)orratherdevelopmentofglycan-specifictargetingoftumorcellsrepresentstherightapproachforthetreatmentofcancer.Thecell-surfacepresentationofuniqueglycanepitopesmakestheman“ideal”candidatefortargetingsincetheyarebothspecificandtherapeuticallyaccessible.Futurestudiesneedtovalidatethetherapeuticpotentialinclinicallyrelevantexperimentalmodelspriortoclinicalevaluation. ConflictofInterestStatement Theauthorsdeclarethattheresearchwasconductedintheabsenceofanycommercialorfinancialrelationshipsthatcouldbeconstruedasapotentialconflictofinterest. Acknowledgments ThisworkwassupportedbyagrantfromSwissNationalFoundation#31003A-133025toLuborBorsig. 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Keywords:glycosylation,cancer,metastasis,glycanligands,mucins,siglecs,galectins,selectins Citation:HäuselmannIandBorsigL(2014)Alteredtumor-cellglycosylationpromotesmetastasis.Front.Oncol.4:28.doi:10.3389/fonc.2014.00028 Received:13December2013;Accepted:29January2014;Publishedonline:13February2014. Editedby: RogerChammas,UniversidadedeSãoPaulo,Brazil Reviewedby: StephanVonGunten,UniversityofBern,SwitzerlandShoukatDedhar,UniversityofBritishColumbia,Canada Copyright:©2014HäuselmannandBorsig.Thisisanopen-accessarticledistributedunderthetermsoftheCreativeCommonsAttributionLicense(CCBY).Theuse,distributionorreproductioninotherforumsispermitted,providedtheoriginalauthor(s)orlicensorarecreditedandthattheoriginalpublicationinthisjournaliscited,inaccordancewithacceptedacademicpractice.Nouse,distributionorreproductionispermittedwhichdoesnotcomplywiththeseterms. *Correspondence:LuborBorsig,ZürichCenterforIntegrativeHumanPhysiology,InstituteofPhysiology,UniversityofZurich,Winterthurerstrasse190,ZurichCH-8057,Switzerlande-mail:[email protected] COMMENTARY ORIGINALARTICLE Peoplealsolookedat SuggestaResearchTopic>