SpecialIssue:CellCommunicationReviewMetabolicInteractionsintheTumorMicroenvironmentCostasA.Lyssiotis1,2,*andAlecC.Kimmelman3,*Tumorsaredynamicpseudoorgansthatcontainnumerouscelltypesinteract-ingtocreateauniquephysiology.Withinthisnetwork,themalignantcellsencountermanychallengesandrewiretheirmetabolicpropertiesaccordingly.Suchchangescanbeexperiencedandexecutedautonomouslyorthroughinteractionwithothercellsinthetumor.Thefocusofthisreviewisontheremodelingofthetumormicroenvironmentthatleadstopathophysiologicinteractionsthatareinfluencedandshapedbymetabolism.Theyincludesymbioticnutrientsharing,nutrientcompetition,andtheroleofmetabolitesassignalingmolecules.Examplesofsuchprocessesaboundinnormalorgan-ismalphysiology,andsuchheterocellularmetabolicinteractionsarerepur-posedtosupporttumormetabolismandgrowth.Theimportanceandubiquityoftheseprocessesarejustbeginningtoberealized,andinsightsintotheirroleintumordevelopmentandprogressionarebeingusedtodesignnewdrugtargetsandcancertherapies.FeaturesoftheTumorMicroenvironmentThatAffectMetabolismInnormalorganphysiology,parenchymalcellsformtheorgananddefineitsfunction.Thesecellsaresupportedbytheconnectivetissue,whichmaintainsthestructuralframeworkandintegratesorgansystems.Cellsoftheimmunesystemfunctiontoprotectagainstinfectionandtosupporttissuerepairfollowinginjury.Solidtumorsarehighlydisorganizedversionsofnormalorganspopulatedwithnumerouscelltypesincludingendothelialcells(e.g.,bloodvessels),stromalfibroblasts,immunecells,andmalignantcancercells[1].Transformationandgrowthoforgan-residentparenchymalcellsleadtothedevelopmentofmalignantsubtypeswithinatumor.Clonaldiversityisachievedastransformedcellsaccumulatemutations.Thisleadstochangesinsignaltransduction,theepigenome,andgeneexpression,whichendowaspectrumofdifferentiation,metabolic,andproliferativestatesacrossthecancercellpopulationsinthetumor[2,3].Thesefeaturesencompasstheintrinsicmetabolicpropertiesofthecancercells[4–6].Clonalheterogeneityisfurtherdiversifiedthroughinteractionswithoth...
