Uterine DCs are essential for pregnancy
Transcript of Uterine DCs are essential for pregnancy
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Uterine DCs are essential for pregnancyJeffrey W. Pollard
Department of Developmental and Molecular Biology, Department of Obstetrics and Gynecology and Womenâs Health, Center for the Study of Reproductive Biology and Womenâs Health, Albert Einstein College of Medicine, New York, New York, USA.
Successfulembryoimplantationrequirescomplexinteractionsbetweentheuterusandembryo,includingtheestablishmentofmaternalimmuno-logictoleranceoffetalmaterial.Thematernal-fetalinterfaceisdynamicallypopulatedbyawidevarietyofinnateimmunecells;however,therelevanceofuterineDCs(uDCs)withinthedeciduatothesuccessofimplantationhasremainedunclear.InthisissueoftheJCI,Plaksetal.show,inatrans-genicmousemodel,thatuDCsareessentialforpregnancy,astheirablationresultsinafailureofdecidualization,impairedimplantation,andembry-onicresorption(seetherelatedarticle,doi:10.1172/JCI36682).DepletionofuDCsaltereddecidualangiogenesis,suggestingthatuDCscontributetosuc-cessfulimplantationviatheireffectsondecidualtissueremodeling,includ-ingangiogenesis,andindependentoftheiranticipatedroleintheestablish-mentofmaternal-fetaltolerance.
Nonstandardabbreviationsused:âDT,âdiphtheriaâtoxin;âsFLT1,âsolubleâFMS-likeâtyrosineâkinaseâ1;âuDC,âuterineâDC;âuNKâcell,âuterineâNKâcell.
Conflictofinterest:âTheâauthorâhasâdeclaredâthatânoâconflictâofâinterestâexists.
Citationforthisarticle:âJ. Clin. Invest.âdoi:10.1172/JCI37733.
Placentalâviviparity,âaâmodeâofâreproduc-tionâduringâwhichânutrientsâareâsuppliedâtoâtheâembryoâdirectlyâfromâtheâmotherâviaâtheâplacenta,âposesâaânumberâofâchallenges.âTheâfirstâisâtheârequirementâforâcoordinatedâdevelopmentâofâmaternalâandâfetalâtissue,âwhileâtheâsecond,âinâmammals,âdemandsâmaternalâ immunologicâ toleranceâ ofâ theâfetus,âwhichâexpressesâforeignâtransplanta-tionâantigens.âThisâlatterârequirementâposesâaâ significantâ immunologicalâ challenge,â
becauseâ mechanismsâ ofâ graftâ rejectionâneedâtoâbeâsuppressedâsoâasâtoâavoidâfetalâloss,âwhileâatâtheâsameâtime,âanâadequateâdefenseâagainstâpathogensâmustâbeâmain-tained.âOriginalâproposalsâregardingâhowâthisâbalanceâisâachievedâsuggestedâthatâtheâfetusâisâimmunologicallyâinertâ(1).âButâthisâcontentionâwasâsoonâshownâtoâbeâincorrect,âandâitâisânowâappreciatedâthatâpregnancyâinvolvesâcomplexâimmuneâregulationâsoâasâtoâpreventâcytotoxicâTâcellsâfromârespond-ingâtoâfetalâantigens,âwhileâsimultaneouslyâmaintainingâimmunityâatâtheâmaternal-fetalâinterfaceâ(1).âInâfact,âearlyâobservationsâthatâtheâuterineâenvironmentâisârichâinâhema-topoieticâgrowthâfactors/cytokinesâ(whoseâexpressionâinâmanyâcasesâisâregulatedâbyâtheâovarianâsexâsteroidâhormonesâ17β-estradiolâ
andâprogesterone),âcoupledâwithâtheâobser-vationâofâtheâdynamicârecruitmentâofâdiverseâinnateâimmuneâcells,âledâtoâtheâproposalâthatâtheseâimmuneâcellsâplayâanâimportantâroleâinâdecidualâandâplacentalâdevelopmentâ(2,â3).âAmongâtheâearliestâgrowthâfactorsâexpressedâinâtheâuterusâareâGM-CSFâandâCSF-1,âwhichâregulateâtheâmyeloidâsystemâ(4,â5).âLevelsâofâCSF-1âsynthesizedâbyâtheâuterineâepitheliumâareâelevatedâatâtheâtimeâofâ implantationâ andâ continueâ toâ climbâdramaticallyâ throughoutâ theâ processâ ofâplacentationâ(4).âCSF-1âhasâbeenâfoundâinâallâmammalianâspeciesâtestedâ(3),âandâthisâgrowthâfactorâisâtheâmajorâregulatorâofâtheâmononuclearâphagocyticâlineageâandâcon-trolsâmacrophageâproliferation,âmigration,âviability,â andâ functionâasâwellâ asâhavingâaâsignificantâroleâinâDCâdevelopmentâ(6).âMacrophagesâandâDCsâbothâaccumulateâafterâimplantationâaroundâtheâdeciduaâandâinâtheâuterusâthroughoutâpregnancyâ(7,â8).âTheseâantigen-presentingâcellsâcouldâbeâdet-rimentalâifâtheyâwereâtoâpresentâfetalâanti-gensâtoâTâcells,âsoâtheâprevailingâviewâisâthatâtheseâantigen-presentingâcellsâareâtrophicâand/orâtolerogenicâ(9).
Ablation of uterine DCs blocks decidualizationTheâstudyâbyâPlaksâetâal.â(7)âinâthisâissueâofâtheâJCIâreportsâthatâuterineâDCsâ(uDCs)âareâ
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commentaries
TheJournalofClinicalInvestigationâ â â http://www.jci.orgâ
requiredâforâsuccessfulâembryoâimplanta-tionâandâdecidualizationâinâmiceâ(Figureâ1).âTheâauthorsâusedâaâsuicideâgeneâablationâapproachâtoâspecificallyâdeleteâuDCsâdur-ingâembryoâimplantationâinâtheseâanimals.âAsâpartâofâthisâapproach,âtheâhumanâdiph-theriaâtoxinâreceptorâ(DTR)âwasâexpressedâfromâtheâCD11câpromoter,âwhichâmadeâcellsâexpressingâtheâreceptorâuniquelyâsen-sitiveâ toâdiphtheriaâ toxinâ (DT);âmiceâdoânotâhaveâtheâDTRâandâareâtherebyâresistantâtoâDT.âSinceâCD11câisârestrictedâtoâDCs,âtheseâcellsâwereârapidlyâablatedâwithâlittleâtoânoâablationâofâotherâhematologicâcells.âTheâablationâofâuDCsâduringâimplantationâresultedâinâaâfailureâofâdecidualizationâandâembryoâ resorption.â Thisâ effectâ wasâ spe-cificâtoâtheâuterusâandâdidânotâinvolveâtheâembryo,âsinceâuDCâablationâalsoâblockedâdecidualizationâinâanâartificiallyâinducedâmodelâofâdecidualizationâinâtheâabsenceâofâ theâ embryo.â Furthermore,â thisâ wasâ aâlocalâeffectâandânotâsecondaryâtoâaâsystemicâeffect,âasâadministrationâofâDTâtoâoneâuter-ineâhornâresultedâinâretardedâdecidualiza-tion,âwhileâtheâcontralateralâcontrolâhornâ
wasâunaffected.âInâaddition,âuDCâablationâresultedâinâfailedâdecidualizationâinâbothâallogeneicâ andâ syngeneicâ pregnancies.âTheseâdataâindicateâthatâuDCsâareâessentialâtoâimplantationâandâdecidualization,âandâthisârequirementâdidânotâhaveâanâimmuno-logicalâcomponent,âbutâratherârepresentedâtrophicâactivitiesâofâuDCs.
Decidual angiogenesis is regulated by uDCsTheseâstudiesâraiseâtheâquestion,âByâwhatâmechanismsâdoâDCsâaffectâdecidualization?âOneâofâtheâearliestâeventsâinâtheâdecidualâresponseâisâanâincreaseâinâvascularâperme-ability,âinducedâbyâtheârapidâexpressionâofâtheâangiogenicâfactorâVEGFâuponâembryoâattachmentâtoâaâsuitablyâhormone-primedâuterus.âThisâisâinâfactâtheâbasisâforâtheâearli-estâtestâofâimplantation,âcalledâblue spotting,âwhichâisâtheâresultâofâextravasationâofâi.v.âadministeredâpontamineâblueâdyeâatâtheseâsitesâofâvascularâpermeabilityâimmediatelyâbelowâ theâ attachedâ blastocyst.â Afterâ thisâincreaseâinâvascularâpermeability,âthereâisârapidâdecidualâcellâproliferationâandâdecidu-
alâtransformationâofâtheâunderlyingâstroma,âgivingâriseâtoâepithelioid-typeâcellsâthatâsur-roundâtheâinvadingâblastocyst.âTheseâcellsâformâtheâprimaryâdecidualâzone,âwhichâisâinâturnâsurroundedâbyâaâdiploidâsecondaryâdecidualâzoneâ(Figureâ1).âAfterâtheâdeciduaâisâformed,âthereâisâextensiveâvascularizationâviaâsproutingâofâtheâuterineâarteryâatâtheâmeso-metrialâsideâ(siteâofâfutureâplacenta),âwhichâresultsâinâtheâformationâofâveryâdilatedâves-selsâandâtheâbathingâofâtheâ implantationânoduleâwithâmaternalâblood.âUsingâsophis-ticatedâdynamicâmacromolecularâcontrast-enhancedâMRIâassistedâstudiesâfollowingâpartialâ uDCâ ablationâ thatâ allowedâ someâdecidualâresponseâcomparedâwithâcontrols,âPlaksâetâal.âshowâthatâtheseâearlyâvascularâeventsâwereâsignificantlyâperturbedâfollowingâuDCâablationâ(7).âIndeed,âtheâdataâsuggestâthatâuDCâdepletionâdelayedâtheâangiogenicâresponse,âincreasedâvascularâpermeability,âandâinhibitedâbloodâvesselâmaturation.
Inâmice,âuDCsâareârestrictedâtoâtheâouterâdecidualâ zonesâ (Figureâ 1)â andâ areâ oftenâfoundâassociatedâwithâbloodâvessels,âcon-sistentâwithâaâroleâinâangiogenesis.âTakingâaâ
Figure 1uDCs regulate decidualization. At the beginning of pregnancy, the ovarian steroid hormones 17β-estradiol (E2) and progesterone (P4) stimulate synthesis of growth factors from the uterine epithelium, including CSF-1 and leukemia inhibitor factor (LIF). LIF, acting on the luminal epithelium, is essential for blastocyst implantation and subsequent decidualization. CSF-1 recruits and regulates uterine macrophages, while also influencing the biology of uDCs. In addition, CSF-1 acts on decidual cells and trophoblastic cells (not shown). Macrophages play a largely immune role at this stage, while, as Plaks et al. (7) show in their current study in this issue of the JCI, uDCs are required for efficient decidualization. This decidualiza-tion process involves transformation of stromal cells into epithelioid-type cells at the site of blastocyst implantation on the antimesometrial side of the uterus. The decidual cells grow in an arc, via rapid proliferation and transformation, to surround the implanting embryo. After implantation is complete, the blastocyst is entirely surrounded by a primary decidual zone of polyploid cells and a secondary diploid decidual zone. Vasculariza-tion commences on the mesometrial side of the uterus via the growth of vascular sprouts from the uterine artery into the decidua, which results in vessels with large, dilated lumens through which maternal blood bathes the decidual nodule. As Plaks et al. report, uDCs located in the outer layers of the decidua regulate this vascularization in part through their synthesis of TGF-β1 and sFLT1. Ablation of uDCs results in a failure of decidual growth and resorption of the embryo, showing that uDCs are essential for a successful pregnancy.
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commentaries
TheJournalofClinicalInvestigationâ â â http://www.jci.org
targetedâgeneâapproach,âtheâauthorsâfoundâthatâ solubleâ FMS-likeâ tyrosineâ kinaseâ 1â(sFLT1)âââaâsolubleâformâofâVEGFR1âââwasâexpressedâbyâuDCsâ(7).âThisâmolecule,âbyâact-ingâasâaâtrap,âopposesâtheâactionsâofâVEGF,âandâPlaksâetâal.âsuggestâthatâtheâabsenceâofâsFLT1âresultsâinâexcessiveâVEGFâactionâandâaâdisruptionâtoâtheâfine-tuningâofâangiogen-esis.âSuchâanâinterpretation,âalthoughânotâtestedâexperimentallyâinâtheâcurrentâstudyâbyâPlaksâetâal.,âisâconsistentâwithâtheâresultsâobtainedâfollowingâinhibitionâofâVEGFâbyâneutralizingâ antibodies,â whichâ wasâ alsoâshownâtoâpreventâdecidualizationâandâpreg-nancyâinârodentsâ(10).âTheseâauthorsâalsoâshowedâthatâuDCsâexpressâTGF-β1âandâthatâthisâmoleculeâwasâdepletedâfollowingâuDCâablationâ (7).â Amongâ itsâ manyâ activities,âTGF-β1âisâinvolvedâinâendothelialâcellâsurviv-alâandâvascularâmaturation.âSuchâfunctionsâareâfurtherâconsistentâwithâaâroleâofâuDCsâinâangiogenesis.âInterestingly,âinâotherâcon-texts,âDCsâsynthesizeâandâsequesterâTGF-β1ââonâÎąvβ8â integrinâ andâ asâ aâ consequenceâsuppressâTâcellâresponsesâandâpromoteâtheâdevelopmentâofâTregsâ(11).âTregsâareâcentralâtoâtheâestablishmentâandâmaintenanceâofâmaternalâimmuneâtoleranceâduringâpreg-nancy,âasâtheirâablationâresultsâ inâlossâofâallogeneicâpregnanciesâ(12).âThisâactionâmayâ
thusâcoupleâtheâroleâofâuDCsâinâdecidualâformationâthroughâtheirâactionâonâangio-genesisâ(7)âwithâtheirâtolerogenicâroleâinâpre-ventingâimmuneârejectionâofâtheâfetus,âthusâresultingâ inâsuccessfulâ implantationâfreeâfromâimmuneâattackâ(Figureâ2).
Placentation is regulated by the interplay of innate immune cellsTheâ uteroplacentalâ unitâ ofâ miceâ andâhumansâisârichlyâpopulatedâwithâhemato-poieticâcellsâsuchâasâmacrophages,âuterineâNKâ(uNK)âcells,âandâuDCs.âTheseâcellsâareâdynamicâinâtheirârecruitmentâandâlocationâandâareâregulatedâbyâtheâlocalâsynthesisâofâhematopoieticâcytokinesâsuchâasâGM-CSF,âCSF-1,â IL-11,â IL-15,â andâ TNF-Îą,â oftenâunderâtheâcontrolâofâestrogenâandâproges-terone.âWhileâtheseâcellsâhaveârolesâinâtheâimmuneâ response,â theâcurrentâ studyâ (7)âasâwellâasâpreviousâonesâ(13,â14)âestablishâthatâtheyâareâalsoâtrophic,âinâthatâallâthreeâcellâtypesâplayâimportantârolesâinâregulat-ingâpregnancy.âMacrophages,âforâexample,âregulatedâbyâCSF-1,âplayâaâmajorâroleâinâtheâimmuneâresponseâagainstâpathogensâinâtheâdeciduaâ(15)âandâareâalsoâinvolvedâinâtheârip-eningâofâtheâcervixâduringâparturitionâ(14).âIL-11ârecruitsâimmatureâuNKâcells,âwhileâatâtheâsameâtimeâthisâcytokineâalsoâregulatesâ
Figure 2Proposed roles of uDCs in the regulation of angiogenesis and T cell action at the maternal-fetal interface. During pregnancy, monocytes are recruited to the uterus, where they differentiate into mature tolerogenic cells such as uDCs, under the influence of CSF-1, GM-CSF, and other cytokines (usually IL-4, although this cytokine has not been found in the uterus). uDCs produce sFLT1 and TGF-β1, which act to maintain the intricate balance of vascular development: sFLT1 modulates the actions of VEGF, and TGF-β1 influences endothelial cell viability and vascular maturation. This fine-tuning of angiogenesis is required for decidualization and embryo implanta-tion. In addition, other studies have shown that TGF-β1 is presented by DCs at their surface on ιvβ8 integrin. TGF-β1 suppresses cytotoxic CD8+ T cell function and promotes the development of Tregs. These data suggest that in addition to their role in decidual development, as shown in the present study by Plaks et al (7), uDCs also play a role in immunoregulation. Together, these dual functions of uDCs contribute to successful implantation and the progression of an allogeneic pregnancy. This whole process is further coordinated during implantation and decidualization by the uterine synthesis of the growth factors VEGF and CSF-1 under the control of the ovarian hormones E2 and P4 (see Figure 1), which are the master regulators of pregnancy.
theâdevelopmentâofâtheâmesometrialâdecid-uaâ(16,â17).âIL-15,âexpressedâlater,âregulatesâtheâmaturationâofâuNKâcellsâthatâremodelâtheâspiralâarteriesâandâareâinvolvedâinâpla-centalâangiogenesis,âevenâthoughâtheseâcellsâareânotâessentialâforâpregnancy,âatâleastâinâmiceâ(13,â18,â19).âTheâcurrentâstudyâbyâPlaksâetâal.âidentifiesâuDCsâasâanotherâessentialâcellâtypeâinâpregnancyâbyâshowingâthatâtheyâareânecessaryâ forâdecidualâ formation,â inâpartâthroughâtheirâeffectsâonâvasculariza-tionâbutâalsoâprobablyâotherâactionsâdirect-lyâonâdecidualâcells.âTheseâtrophicârolesâforârecruitedâhematopoieticâcellsâinâdecidualâandâplacentalâdevelopmentâfurtherârein-forceâtheâviewâthatâaâmajorâroleâofâmigratoryâhematopoieticâcellsâofâtheâinnateâimmuneâsystemâisâinâtissueâdevelopmentâandâtheseâtrophicâfunctionsâareâoftenâsequesteredâinâpathologicalâcontextsâsuchâasâcancerâ(20).
GivenâtheseâprofoundâeffectsâofâuDCâabla-tionâonâdecidualâangiogenesisâ(7),âitâisâpossi-bleâthatâperturbationsâinânormalâuDCâactiv-ityâcouldâreduceâtheâfitnessâofâtheâfetus,âforâexampleâinâsuchâconditionsâasâpreeclampsia,âaâmajorâcauseâofâlowâfetalâbirthâweightâasâwellâasâmaternalâandâfetalâmorbidityâinâwomen.âThisâconditionâisâthoughtâtoâresultâfromâlim-itedâtrophoblasticâinvasionâandâpoorâdecid-ualâandâplacentalâvascularizationâandâtoâbeâinitiatedâearlyâinâfetalâdevelopment.âIndeed,âratiosâofâcirculatingâangiogenicâandâantian-giogenicâfactorsâareâpredictiveâofâtheâonsetâofâpreeclampsia,âwithâtheâserumâconcentrationâofâsFLT1âbeingâanâimportantâdeterminingâfactorâthatâpredictsâtheâpreeclampticâcondi-tionâ(21).âTheânewâdataâreportedâinâtheâstudyâbyâPlaksâetâal.â(7)âindicatingâthatâuDCsâareâaâmajorâcontributorâtoâsFLT1âsynthesisâatâtheâuteroplacentalâinterfaceâwillânowâfocusâfur-therâresearchâonâtheâfunctionâofâtheseâcellsâandâtheirâpossibleâinvolvementâinâtheâetiol-ogyâofâpreeclampsia.
AcknowledgmentsTheâauthorâisâtheâLouisâGoldsteinâSwanâChairâinâWomenâsâCancerâResearch,âandâhisâresearchâisâsupportedâbyâNIHâgrantsâHD30820,â HD050614,â CA131270,â andâCA100324âandâbyâaâgrantâtoâtheâCancerâCenterâfromâtheâNationalâCancerâInstituteâ(P30-13330).
Addressâcorrespondenceâto:âJeffreyâW.âPol-lard,âDepartmentâofâDevelopmentalâandâMolecularâBiology,âAlbertâEinsteinâCollegeâofâ Medicine,â 1300â Morrisâ Parkâ Avenue,âChaninâ607,âBronx,âNewâYorkâ10461,âUSA.âPhone:â (718)â 430-2090;â Fax:â (718)â 430-8972;âE-mail:â[email protected].
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Tumor metabolism: cancer cells give and take lactate
Gregg L. Semenza
Vascular Program, Institute for Cell Engineering, Departments of Pediatrics, Medicine, Oncology, and Radiation Oncology, and McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Tumorscontainwell-oxygenated(aerobic)andpoorlyoxygenated(hypoxic)regions,whichwerethoughttoutilizeglucoseforoxidativeandglycolyticmetabolism,respectively.InthisissueoftheJCI,Sonveauxetal.showthathumancancercellsculturedunderhypoxicconditionsconvertglucosetolactateandextrudeit,whereasaerobiccancercellstakeuplactateviamono-carboxylatetransporter1(MCT1)andutilizeitforoxidativephosphoryla-tion(seetherelatedarticle,doi:10.1172/JCI36843).WhenMCT1isinhibited,aerobiccancercellstakeupglucoseratherthanlactate,andhypoxiccancercellsdieduetoglucosedeprivation.Treatmentoftumor-bearingmicewithaninhibitorofMCT1retardedtumorgrowth.MCT1expressionwasdetect-edexclusivelyinnonhypoxicregionsofhumancancerbiopsysamples,andincombination,thesedatasuggestthatMCT1inhibitionholdspotentialasanovelcancertherapy.
Nonstandardabbreviationsused:âLDH,âlactateâdehy-drogenase;âMCT,âmonocarboxylateâtransporter.
Conflictofinterest:âTheâauthorâhasâdeclaredâthatânoâconflictâofâinterestâexists.
Citationforthisarticle:âJ. Clin. Invest.âdoi:10.1172/JCI37373.
TheâpioneeringâworkâofâPeterâVaupelâandâhisâcolleaguesâestablishedâthatâtheâpartialâpressureâofâoxygenâ(pO2)âwithinâhumanâcancersâisâfrequentlyâmuchâlowerâthanâthatâofâtheâsurroundingânormalâtissueâandâthatâintratumoralâhypoxiaâisâassociatedâwithâanâincreasedâriskâofâlocalâspread,âmetastasis,âandâpatientâmortalityâ (1).âRakeshâJainâsâ
laboratoryâdemonstratedâthatâ inâmouseâtumorâxenografts,âtheâmeanâpO2âandâpHâdeclinedâ asâ distanceâ fromâ theâ nearestâbloodâvesselâincreasedâ(2),âreflectingâtheâswitchâfromâoxidativeâtoâglycolyticâmetab-olismâthatâoccursâinâresponseâtoâreducedâO2âavailability.
Thisâmetabolicâreprogrammingâisâorches-tratedâbyâHIF-1âthroughâtheâtranscriptionalâactivationâofâkeyâgenesâencodingâmetabolicâenzymes,âincluding:âLDHA,âencodingâlac-tateâdehydrogenaseâA,âwhichâconvertsâpyru-vateâtoâlactateâ(3);âPDK1,âencodingâpyruvateâdehydrogenaseâkinaseâ1,âwhichâinactivatesâ
theâenzymeâresponsibleâforâconversionâofâpyruvateâ toâ acetyl-CoA,â therebyâ shunt-ingâpyruvateâawayâfromâtheâmitochondriaââ(4,â5);âandâBNIP3,âwhichâencodesâaâmemberâofâtheâBCL2âfamilyâthatâtriggersâselectiveâmitochondrialâautophagyâ (6)â (Figureâ1).âInâaddition,âHIF-1âtransactivatesâGLUT1â(7)âââwhichâencodesâaâglucoseâtransporterâthatâincreasesâglucoseâuptakeâtoâcompen-sateâforâtheâfactâthat,âcomparedâwithâoxida-tiveâphosphorylation,âglycolysisâgeneratesâapproximatelyâ19-foldâlessâATPâperâmoleâofâglucoseâââandâgenesâencodingâtheâglycolyticâenzymesâthatâconvertâglucoseâtoâpyruvateâ(3).âTheâextracellularâacidosisâassociatedâwithâhypoxicâ tumorâcellsâ isâdueâ toâbothâincreasedâH+âproductionâandâincreasedâH+âeffluxâthroughâtheâHIF-1âmediatedâtrans-activationâof:âCA9,âwhichâencodesâcarbonicâanhydraseâ IXâ (8);â MCT4,â whichâ encodesâmonocarboxylateâ transporterâ 4â (9);â andâNHE1,âwhichâencodesâ sodium-hydrogenâexchangerâ1â(10).
Metabolic symbiosisInâthisâissueâofâtheâJCI,âtheâelegantâarticleâbyâSonveaux,âDewhirst,âetâal.âmakesâaâmajorâcon-tributionâtoâtheâfieldâofâcancerâbiologyâ(11).ââ