Hallmarks of cancer: the next generationThe hallmarks of cancer metabolism: still emergingWarburg effectAerobic glycolysis cancerTargeting metabolism for cancer therapyFundamentals of cancer metabolismFrontiers | Shedding New Light on Cancer Metabolism
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In addition to oncogene-driven metabolic reprogramming, the oncometabolites themselves alter cell signaling and are responsible for ... Articles CappelloAnnaRita UniversityofCalabria,Italy DomenicaScumaci DepartmentofClinicalandExperimentalMedicine,MagnaGræciaUniversityofCatanzaro,Italy AlessandraFerramosca UniversityofSalento,Italy Theeditorandreviewers'affiliationsarethelatestprovidedontheirLoopresearchprofilesandmaynotreflecttheirsituationatthetimeofreview. Abstract MetabolisminCancer ReprogrammedMetabolismasaCauseofCancerDevelopment TheInfluenceofTumorMicroenvironmentonEarlyMalignancy,Full-BlownTumor,andCancerStemCells TheMetabolismofCancerCellMetastasis TherapeuticImplicationsoftheMetabolicFlexibilityoftheTumorandItsCancerStemCells Conclusion AuthorContributions ConflictofInterest References SuggestaResearchTopic> DownloadArticle DownloadPDF ReadCube EPUB XML(NLM) Supplementary Material Exportcitation EndNote ReferenceManager SimpleTEXTfile BibTex totalviews ViewArticleImpact SuggestaResearchTopic> SHAREON OpenSupplementalData REVIEWarticle Front.Oncol.,31March2020 |https://doi.org/10.3389/fonc.2020.00409 SheddingNewLightonCancerMetabolism:AMetabolicTightropeBetweenLifeandDeath MatthiasLäsche,GünterEmonsandCarstenGründker* DepartmentofGynecologyandObstetrics,UniversityMedicineGöttingen,Göttingen,Germany SincetheearliestfindingsofOttoWarburg,whodiscoveredthefirstmetabolicdifferencesbetweenlactateproductionofcancercellsandnon-malignanttissuesinthe1920s,muchtimehaspassed.Heexplainedtheincreasedlactatelevelswithdysfunctionalmitochondriaandaerobicglycolysisdespiteadequateoxygenation.Meanwhile,wecametoknowthatmitochondriaremaininsteadfunctionalincancercells;hence,metabolicdrift,ratherthanbeinglinkedtodysfunctionalmitochondria,wasfoundtobeanactiveactofdirectresponseofcancercellstocellproliferationandsurvivalsignals.ThismetabolicdriftbeginswiththeuseofsugarsandthefulloxidativephosphorylationviathemitochondrialrespiratorychaintoformCO2,anditthenleadstotheformationoflacticacidviapartialoxidation.Inadditiontooncogene-drivenmetabolicreprogramming,theoncometabolitesthemselvesaltercellsignalingandareresponsiblefordifferentiationandmetastasisofcancercells.Theaberrantmetabolismisnowconsideredamajorcharacteristicofcancerwithinthepast15years.However,theproliferatinganabolicgrowthofatumoranditsspreadtodistalsitesofthebodyisnotexplainablebyalteredglucosemetabolismalone.Sinceatumorconsistsofmalignantcellsanditstumormicroenvironment,itwasimportantforustounderstandthebilateralinteractionsbetweentheprimarytumoranditsmicroenvironmentandtheprocessesunderlyingitssuccessfulmetastasis.Weheredescribethemainmetabolicpathwaysandtheirimplicationsintumorprogressionandmetastasis.Wealsoportraythatmetabolicflexibilitydeterminesthefateofthecancercellandultimatelythepatient.Thisflexibilitymustbetakenintoaccountwhendecidingonatherapy,sincesingularcancertherapiesonlyshiftthemetabolismtoadifferentalternativepathandcreateresistancetothemedicationused.AswithOttoWarburginhisdays,weprimarilyfocusedonthemetabolismofmitochondriawhendealingwiththisscientificquestion. MetabolisminCancer Themetabolicplasticityandcontext-dependentdiversityofitsphenotypecharacterizecanceranditsdevelopmentintotumorsandmetastases.Inthiscontext,sixhallmarksofcancermetabolismhavebeendescribed(1,2),whichinclude:(1)increaseduptakeofglucoseandaminoacidsfromtumormicroenvironmentandconcomitantdeliveryoflactateandprotonstotumorcells;(2)increaseoftheglycolysispathway,thepentosephosphatepathway(PPP),andthetricarboxylicacid(TCA)cycleintermediatestobuildandsustaintheaberrantproliferationofcancercells;(3)amoremechanicaluptakeofnutrientsviaphagocytosis,entosis,andmicro-andmacropinocytosis;(4)increasedneedandutilityofnitrogenderivativesandtheirconversiontonucleotides(pyrimidines,purines),non-essentialaminoacids,andpolyamines;(5)changesinmetabolite-drivengeneregulationby,forinstance,methylation,acetylationandsuccinylation;and(6)bilateralmetabolicinteractionthroughtheexchangeofnutrientsandaminoacidsortheinfluenceofgrowthfactorsorenvironmentalconditions,suchashypoxiaorredoxstressonthemicroenvironmentortheirinfluenceonmetabolismandthedifferentsignalinglevelsofcancercells.Becauseofthecomplexity,thecancermetabolismcharacteristicsmentionedaboveoccurinvaryingdegreesandcontextsofmanydifferenttypesofcancer;therefore,theycanbeonlyroughlydefinedandarenotconclusiveintheirnumberorform. Nearly100yearsago,OttoWarburg(3–5)discoveredthefirstmetabolicdifferencesbetweennormalandcancercells.Sincethen,theknowledgeofthecorrelationsofmetabolismofcancercellsassociatedwiththeirenvironmentalhealthytissueandtheimpactofthesecorrelationsonthedegreeofcelltumorgrowthandmetastaticspreadinghasgrownconstantlyandhasadoptedanunimaginedcompleximageoverthelast15years.Warburgandhisfollowingscientificcolleaguesstartedfromthenowrefutedassumptionthatthechangeinglucoseconsumptionandtheaggravatedincreaseinacidifyingthetumor-microenvironmentwereduetoirreversiblemitochondrialdamage(4).Todayweknowthatcancercells,duetotherequirementsforexaggeratedproliferationandtheresultingincreasedneedformetabolites,activelyputforwardadvancingthepathofglycolysis,usuallyassociatedwiththepathwayofoxidativecitratecyclecatabolism(6).However,why,allofasudden,docancercells“changetheirmind”?Whyaretheyusingaerobicglycolysis,andwhyaretheynotalsousingthecitricacidcycle,giventhatthelatter,whencomparedtoglycolysis,whichproducesonlytwomoleculesofATPpermoleculeofglucose,resultsin36or38moleculesofATPandGTP,respectivelythroughtheelectrontransportchain(ETC)? Oneexplanationisgivenbythefactthatitiswrong,unlikeOttoWarburgunderstood,thatcancerdependsonaerobicglycolysisonlyasit,nexttoglycolysis,treadtheoxidativepathofmitochondriaacrossETCforabout5–15%oftheglucoseflow.Ontheonehand,itiscorrecttosaythatneoplasiacanariseasacauseofdysfunctionalmitochondria;otherwise,thismeansnotthatoncogenicdevelopmentissolelyglycolysis-dependent(1);rather,themetabolicdrifttoaerobicglycolysisisduetotherapidlyproliferatingneoplasiameetingitsmetaboliclimits.Hypoxiaincreasesinthecoreofthedevelopingtumor(Figure1).Hypoxiaup-regulatesthetranscriptionoftargetgenesrelatedtothehypoxiaresponseelement(HRE)(likegenescodingforerythropoiesis,glycolysis,andangiogenesis)throughthestabilizedhypoxia-induciblefactor1-alpha(HIF-1α),translocatingtothenucleusandbindingHIF-1βtoanactivecomplex.Thisoccursviathecell'soxygensensor,thehypoxia-inducibleprolylhydroxylaseprotein2(PHD2),leadingtohigherexpressionlevelsofglycolyticenzymeswhichisresponsiblefortheuptakeofnutrients,essentiallyglucose(Figure2A).Enzymesfortheapparent“waste”productlactate—thelactatetransporterproteinsMCTs,whichacceleratethereleaseoftheglycolysisproduct(7,8)—showhigherexpressionlevelsaswell(Figure2B).Theseenzymesinclude,forinstance,hexokinase2(HK2),phosphofructokinase1(PFK1),aldolaseA(ALDOA),phosphoglyceratekinase1(PGK1),pyruvatekinase(PK),andlactatedehydrogenaseA(LDH-A).Inaddition,tumorigenesisshowsamuchhigherutilizationofdifferentmetabolitesnexttoglucose,whichisduetothestrongcellgrowthanddivision.Augmentedaerobicglycolysisgivesthedevelopingtumortheopportunitytoquicklygeneratethemetabolicbricksrequiredforcellassemblyanddivision.Energy,nucleotides(non-essential),andessentialaminoacids,polyamines,fattyacids,andreductiveequivalents(Figure2C)aresupportingcellproliferationanditsneedforphospholipidsfortheconstructionofmembranes,mitochondria,lysosomes,andsoon.Thisproductionworksthroughvariousways,whichwewilldiscussinmoredetailinthelatercontextofthisreview(9–13). FIGURE1 Figure1.Phenotypicevolutioninhypoxia/hypoglycemia-exposedmetastaticcancerandtheaccompanyingdriftinenergymetabolism.(A)Inthestateofnormoxia/normoglycemia,theconditionthatresemblestheenvironmentintumorsclosetothevascularsystemandlinedbyouterproliferatingtissue(C),ATPisproducedthroughthecommonlyusedenergymetabolismpaths,withthemajorpartofATPsuppliedbyoxidativephosphorylation(OxPhos).Enzymes,whicharerelatedtometastasisarelowexpressed;andthereisonlyasmalltendencyofcellstoinvadethesurroundingtissue.(B)Inthestateofhypoxia/hypoglycemia,theconditionwhichresemblestheenvironmentintumorsdistanttothevascularsystemandsurroundedbyrestingtissue(C),oxidativephosphorylation(OxPhos),reducedbyalowerproteincontent(possiblyinducedasaresultofastrongdownregulationoftranscription),isgreatlydiminishedandautophagyfullyactivated.ATPispredominantlyproducedthroughglycolysis.Enzymes,whicharerelatedtometastasis,showahighexpressionlevel;andthereisahightendencytoinvadethesurroundingtissue.AMPK,AMP-activatedproteinkinase;ATP,adenosinetriphosphate;BCAA's,branched-chainaminoacids;EAA's,essentialaminoacids;EMT,epithelial-mesenchymaltransition;GLUT's,glucosetransporters;OxPhos,oxidativephosphorylation;TCA,tricarboxylicacidcycle. FIGURE2 Figure2.Metabolic-regulatoryrelationshipsincancercells.Relationshipsbetweeninfluxesandeffluentsofmetabolitesincancercells,individualmetabolicpathwaysofenergyproductionandproductionofprecursormoleculesforbiosynthesisoflipids,nucleotides,andmacromoleculesformembranesandorganelles,NADPHforproductionofreducingequivalentsandthecontrolofalltheseinteractionsbyappropriatesignalingpathways.Signalingmoleculesaremarkedgreen,participatingenzymesblueandmaincatabolicandanabolicpathwaysred.Signalingmolecules:AKT,proteinkinaseB;AMPK,AMP-activatedproteinkinase;β-catenin,cadherin-associatedprotein;c-Myc,MYC;HIF-1α,hypoxia-induciblefactor,subunit1α;mTOR,Mammaliantargetofrapamycin;p53,tumorsuppressorp53;PI3K,phosphoinositide3-kinase;PTEN:phosphataseandtensinhomolog;ROS:reactiveoxygenspecies;ULK1,Unc-51-likeautophagy-activatingkinase;VEGF:vascularendothelialgrowthfactor.Metabolicenzymes:α-KG-DH,α-ketoglutaratedehydrogenase;CPT-1/2,carnitinepalmitoyltransferase1/2;FH,fumaratedehydrogenase;G6PD(H),glucose-6-phosphatedehydrogenase;GDH,glutamatedehydrogenase;GLS,glutaminase;GSH,glutathione(reducedform);GSSG,glutathione(oxidizedform);GSSG-R,GSSG-reductase;HK,hexokinase;IDH1/2,isocitratedehydrogenase1/2;LACS,long-chainacyl-coenzymeA(CoA)synthetase;LDHA/B,lactatedehydrogenaseA/B;ME1,malicenzyme1;NADP+/NADPH,nicotinamideadeninedinucleotidephosphate(oxidized/reducedform);PDH,pyruvatedehydrogenase;PD(H)K,pyruvatedehydrogenasekinase;PEPCK,phosphoenolpyruvatecarboxykinase[GTP-dependent];PFK1/2,phosphofructokinase1/2;PHDs,Prolyl4-hydroxylasedioxygenases;PKM2,pyruvatekinasetypeM2;SDH,succinatedehydrogenase.Transporterproteins:ASCT2/SN2,glutaminetransporter;Glut-1,glucosetransportertype1,alsoerythrocyte/brainhexosefacilitator(gene:SLC2A1);Glut-2,glucosetransportertype2(gene:SLC2A2);MCT1/4,monocarboxylatetransporter1/4(gene:SLC16A1/3).Metabolites:α-KG,α-ketoglutarate;BCAA's,branched-chainaminoacids;EAA's,essentialaminoacids;OAA,oxaloacetate;PEP,phosphoenolpyruvate.Others:HRE,hypoxia-response-element.CharactersA–U:(A)glycolyticenzymesup-regulatedbyhypoxia;(B)lactateefflux;(C)synthesispathwaysbranchedofffromglycolysispath;(D)NADPHproducingpathways;(E)PFK2activitystimulatedbyVEGF;(F)autophagyregulation;(G)extracellularuptakeofnutrientsviamacropinocytosis;(H)glucoseuptake;(I)glutaminemetabolism;(J)oxidativephosphorylation;(K)reductiveNADPHproduction;(L)citrateascentralmetabolite;(M)citratereductiontoacetyl-CoA;(N)acetatederivedacetyl-CoAsynthesis;(O)proteinglycosylationviahexosaminesynthesis;(P)glycolysisfluxcontrollingPKM2activity;(Q)oftenmutatedenzymesandtheresultingoncometabolitesintheTCAcycle;(R)stabilizationofHIF-α;(S)NADPHproductionthroughoxidativedecarboxylationcatalyzedbyME1;(T)ROS-mediatedPTENinactivationandHIF-αstabilization;(U)suppressionofPDHviaPDHKleadingtotheshiftfromOXPHOStoglycolysis. Furthermore,concerningATPasanenergycarrier,theunfinishedglucoseoxidationwithlactateastheend-productoffersadecisivegrowthbenefit.Althoughglycolysisproducesonly6%oftheATPpermolglucosewhencomparingittotheoutcomethroughtheKrebscycleandETC,itisabouttwoordersofmagnitudesfasterasaresultofthemuchfasterchemicalreaction(14,15).Whilenotefficientlyenoughinutilizingthesugar,itisquiteworthyfortheaberrantproliferation,anditproducesfastenergy. Glycolysisandtheresultingmetabolismpathways,likepentosephosphatepathway(PPP)orone-carbon(folate)cycle(Figure2D),offerthebenefitofproducingsufficientreductiveforceswithNAD(P)Handglutathionetoneutralizereactiveoxygenspecies(ROS).ROSare,forexample,thehyperoxideanion(O2·−),thehydroxylradical(HO·),orthehydrogenperoxide(H2O2),resultingfromtherapidmetabolism,whichwould,ifnoteliminated,depolarizethemitochondrialmembraneandleadtoapoptosis.However,thesesameROSarecriticallyimportantintheinitiationphaseoftumorigenesisastheyprovidethesomaticorgermlinemutations,likeinthefumaratehydratase(FH),succinatedehydrogenase(SDH),orisocitratedehydrogenase(IDH1/2)genes,necessarytopromotetumorigenesis(16). Furthermore,glucoseuptakeregulation,lactateexcretion,andincreasedtumormicroenvironmentacidificationthroughthemonocarboxylatetransporters(MCTs)(Figure2B)alsoareresponsiblefortumorsurvival(17–19).Thetumordevelopmentisthereforedependentoninfluencingthemicroenvironmenttoprovidetheneededsignalingandmetabolicfueltokeeptheaberrantmetabolismgoing,contributingtotheevasionofthesurveillingimmunesystem.Onlyrecently,thetumormicroenvironmentresearchhasbecomemoreattentivetotheirgreatvalue.Theinfluenceofthedevelopingtumoronitsmicroenvironmentorviceversaisarelationshipcharacterizedessentiallybytheaggressivenessoftumordevelopmentanditsabilitytopromotemetastasis.Forthetumortomakeitswaythroughthebodyandtoproliferatewithoutbeingaffectedbytheimmunesystem,itiscrucialforittobecapableoffurthergrowthdespiteadverseconditionsinitsdevelopment,suchasincreasinghypoxia,glucosedeprivation,lackofaminoandfattyacids,andfatalhyper-acidification.Asresearchhasrecentlyrevealed,cancercells,intheirentiredevelopment,alwaysmoveonanarrowmetabolicridgebetweenlifeanddeath,whichiscrucialforapatient'ssurvival. Depletedfromoxygenandglucosesupplyduringitsgrowthandwiththediffusioncoefficientofglucosebeingfargreaterthanthatofoxygen,theinnercoreofthedevelopingtumorgetsincreasinglyhypoxicandhypoglycemic.Essentialnutrients,too,likeglutamine,importantforthenitrogencontainingmoleculesderivedfromthem,significantlydecreaseinthenutrientbalance(Figure1B).However,thetumorescapestheselimitingconditionsbystimulatingthemicroenvironmenttodeveloptheso-calledtumormicro-vascularizationorneo-vascularization.Theendothelialdevelopmentneedsthestimulusofthevascularendothelialgrowthfactor(VEGF)toformanddiversifynewbloodvesselsthatgrowtowardthetumorandprovideitwiththenecessarybuildingmaterials(Figure1C).Inductionbyanimportantenzymeoftheenergymetabolism,thephosphofructokinase-2/fructose-2,6-bisphosphatase3(PFKFB3)thatcatalyzesphosphorylationoffructose-6-phosphatetoformfructose-2,6-bisphosphatestimulatedbyVEGF(Figure2E),drivesangiogenesisandthemigrationoftheendotheliabyregulatingthevasculatureofstressfibers(20,21).IncreasinglactatesecretionbyenhancedglycolysispromotesangiogenesisthroughHIF1αactivationandVEGFreceptor2(VEGFR-2)up-regulation(22). Lacticacidosis,ahighlactateconcentrationatacidicpH,rescuesthecancerouscellsfromcelldeaththreatenedbyglucosewithdrawal(18).NoglucosemeansnoglycolysisandnoPPP.Fattyandaminoacidssustainenergymetabolism,buttheyarenotabletosustainPPP,essentialfortumorsurvival.Cancercellschangetoasleepingmode.MaybeitcomestoaG0/G1phasearrest,possiblyviatheup-regulationandstabilizationoftheG1/Stransitioninhibitorp27andthedown-regulationanddestabilizationofSkp2.Skp2isamemberoftheSCFcomplex.P27recognizesit,andafteritispoly-ubiquitinatedandproteolysed.Thereby,lacticacidosisactivatesautophagy[(18,23,24);Figures1B,2F].Autophagy,namelythebreakdownandutilizationofcell-derivedproteinsandorganelles,providesthetumorwithmetabolitesforsurvivalindeprivedglucoseconditions.Ifre-vascularizationofthetumorissuccessful,thecellsofthetumorbud,precedingtheproliferativetipofthetumor,mayinvolveatransitiontoincreasedmigrationandinvasion,assumingmesenchymalstructuresinitiatingtheso-called“metastaticcascade”orepithelial-mesenchymaltransition(EMT). Theresultingphenotypicandmetabolicplasticityofdevelopingmalignanciesrequiresfunctionalinteractionwiththenon-malignantconstituentsofthemicroenvironmentofthetumor.Amongothers,cancerstemcells(CSCs)existwithaself-renewingpotentialresponsibleforthelocalprogressionandresurgenceofthetumor.Theyshow,exceptforthoseofovariantumors,apredominantlyglycolyticmetabolism.Themicroenvironmentofthetumor—specifically,thatoftheso-calledtumor-associatedfibroblasts(TAFs)—isreprogrammedforglycolysisandthussupportMCT-4transporter-drivenlactatesecretionintothetumormilieuand,viatheMCT-1transporter-driveningestionoflactate,thetransporttotheoxidativemetabolismwithinthemitochondriaofthemalignantcells.ManyothertumorsinduceautophagywithintheTAFsandthusexploitthegeneratedalanineavailabilitythroughtheextracellularuptakeofproteinsviaso-calledmacropinocytosis(Figure2G)—abehaviorsimilartoparasitism.Metaboliccompetitionwithimmuneeffectorcellsfornutrients,withdeprivedavailability,isalsooneofthereasonsforinadequateimmunesurveillanceoftumorprogressionbyimmunesystemeffectorcellsthatresemblecancercellsintheirmetabolism. Metabolicrewiringpromotestumorigenesis,ontheonehandbytheincreaseduptakeofglucose(Figures1A,B,2H),ontheotherhandviatheglutaminemetabolism(Figures1A,B,2I).Thiscontributes,inanoxidativemanner,totheenergyproductioninthecitratecycleandsubsequentETC(Figures1A,B,2J)or,inareductiveway,tofattyacidandcholesterolsynthesisviatheproductionofNADPH(Figure2K),maintainingredoxhomeostasis(25–28).Themetabolicallyflexibleuseofothercarbonsources,suchaslactate,glycine,serine,oracetate,ortheflexiblechangeofuseofglycolysis,OxPhos,andfattyacidoxidationasanenergysourcedemonstratetheimmenseplasticityoftheresponseofcancercellstotheever-changingenvironmentalconditionswithintheirtumormicroenvironment(29–33).ReversibilityoftheTCAcycleandvariousmitochondrialanapleroticcircuitsprovidetherequiredadaptationofmetabolism(34,35).CitrateisoneoftheseimportantcentralmetabolitesthatisoxidativelyconvertedinTCAasafuel(Figure2L)andreductivelybytransferringanacetylresiduefromthecitratetocoenzymeAbymeansofATPcitratelyase(ACLY)andtoacetyl-coenzymeA(acetyl-CoA)(Figure2M).TheenzymeACLYusedhereisspecificofcancercellsandisnotexpressedbynormalcellproliferation.Theacetylatingreactionsareusingacetyl-CoA,regulatingtranscriptionandcytoplasmicprocesses,suchasautophagy,inadditiontoitsuseinfattyacidandcholesterolsynthesis(35–40).α2-macroglobulin(α2M*),onceactivated,forexample,signalsthroughtheglycoprotein78(GRP78)viathetumorand,inadditiontoactivatingtheAKTpathway,regulatesglucose-dependentACLYandacetate-dependentacetyl-CoAsynthetase(ACSS2),theacetyl-CoAsynthesis(Figure2N),andsubsequenthistoneacetylationtoinducetumorgrowth(41). Thehexosaminebiosynthesispathway(HBP)isattheinterfaceofmanyprocessesincancerdevelopment.Itisverymuchdependentonthenutritionalstatusofcancercells,especiallytheglucoseandglutaminesupply,aswellasothermetabolitesofothermetabolicpathwayssuchasfattyacid(acetyl-CoA)ornucleotide(UTP)metabolism.TheHBPbranchesofffromtheglycolyticpathwayattheleveloffructose-6-phosphate,anditsmetabolicendproducturidinediphosphateN-acetylglucosamine(UDP-GlcNAc)mediatesmanydownstreamglycosylationstepsviaitsdownstreamproteinO-GlcNAc-transferase(OGT)andthestructuralchangesoftheproteinsandlipidsthatareinvolvedinprocessesthataffectcellsignaling,generegulation,andEMT(Figure2O).TheresultingprocessesaresovariedandcomplexthatwerefertoAkellaetal.(42)foranextensivesummary. Theso-calleduronicacidorglucuronatepathwaybranchesofffromtheglycolyticpathwayatthelevelofglucose-6-phosphateviaglucose-1-phosphatewithitskeyenzyme—UDP-glucose-6-dehydrogenase(UGDH)—transformingUDP-glucosetoUDP-glucuronicacidthroughactivatedEGFRsignaling.ThecancercellneedsUDP-glucuronicacidtoproducepolysaccharides,likehyaluronicacid—anextracellularmatrixcomponentinepithelialtissues.HyaluronicacidactivatescellsurfacereceptorstriggeringEMT,beingresponsibleforthepoorclinicaloutcome(43,44).pUGDHreactswithhumanantigenR(HuR),transformingUDP-glucose(UDP-Glc)toUDP-glucuronicacid(UDP-GlcUA);attenuationofUDP-glucose-derivedinhibitionofHuRassociatingwithSNAI1mRNAincreasestheSNAI1mRNA-stability.AugmentedSNAILdrivesepithelial-mesenchymaltransition,tumorcellmigrationandlungcancermetastaticdissemination.Tyrosine473phosphorylationofUGDHgoesinhandwithmetastasisandadevastatingprognosisforpatientswithlungcancer(45).Unlikemetabolitesaccumulatingbecauseofcancer-causinggeneticalterationsinmetabolicenzymes,normallypromotingtumorprogression,UDP-Glcislimitingtumorigenesis(46,47). Movingfromneoplasia,throughmalignancytodistantmetastasisandrestingcancerstemcells,thecancercellre-orientsitsmetabolismanditsassociatedphenotypicde-differentiationseveraltimestosurviveintheever-changingmicroenvironmentandmaintainsteadyproliferationor,inthecaseofcancerstemcells,survivetransientsenescencetore-metastasizeandproliferateinthepresenceofadequatemicro-environmentalconditions.Withmetastaticseeding(dissemination)causedbytheepithelial-mesenchymaltransition(EMT),thecancercellsgainanincreasedmigratoryandinvasivepotentialandassociatedcytoskeletalmodificationsfortherequiredmotilityofthespreadingtumor. Thecancercellregulatesevolutionarilyhighlyconservedgenes,suchastheeukaryotictranslationinitiationfactors5Bor2[eIF5B(2)](48),orthedimericisoform2ofpyruvatekinase(PKM2)[(49);Figure2P],whicharewidelyneededinhumanembryogenesis.Theyareobligatoryforde-differentiationfromthetumor'scelloforiginandthereorganizationofcentralcarbonmetabolism. ReprogrammedMetabolismasaCauseofCancerDevelopment Neoplasia,ormalignantprecursorcell,developsfromacellthathaslostitsnormaldifferentiationcharacterandinvolvementinthesurroundingmicroenvironmentofitshostorgan.Variousfactorscanleadtocancer. Researchonthebiochemicalfactors,whichcausethespreadingofthemalignancy,hasresultedinremarkableprogressconcerningtherelativetreatmentmethods;however,theemergenceofresistanceunfortunatelystillposessignificantsetbacksintherapy.Inadditiontothesurgicalmethodsofcurativetherapy,resection,transplantation,andablation,thevariousmethodsofchemotherapy,radiationorphototherapy(50),anti-angiogenicdrugs(51–53)andthe“naturalkiller”(NK)cell-basedimmunotherapy(54)areavailable.However,allofthesemethodsareintrinsictothefactthatthetherapyoftumorigenesis,dependingonthecontext,leadstoresistancetotheseformsoftreatmentandultimatelytometastasis,andthepatientisdeprivedoflong-termgoodprognosisofbothhistotalanddisease-freesurvivalrates. Whileitistruethatmutagenesisisfirstlycausingcancerviathealterationofthegeneticmaterialbymutagenicsubstancesorradiation,thisalterationissufficienttocausecanceronlyifthemitochondria—thepowerorganellesofthecell—aredamaged.Theknockdownorknockoutofautophagy-relatedgenessuchasAtg5andAtg7ensuringmitochondrialfitnessbyremovingdefectivemitochondriathroughmitophagyimpairsthisspecialformofautophagocytosis(37,55–57). Reactiveoxygenspecies,calledROSforshort,arefreeoxygenradicals,which,bytheirrelease,causedamagetothemoleculesessentialforthefunctionsofthecell,suchasDNA,RNA,andamultiplicityofproteinsandlipids.Theaccumulationoftheoncometabolitessuccinate,fumarateand/or2-hydroxyglutarate[whichinhibitα-ketoglutarate(α-KG)—dependentenzymes,liketheJumonjidomain-containing(JMJ),histonelysinedemethylases(JHLDM),andten-eleventranslocation(TET)methylcytosinedioxygenasesregulatingbothgeneexpressionattheepigeneticlevelandtheexpressionofoncogenictranscriptionalprograms]blocksterminaldifferentiation(8,58–62). Germlineorsomaticmutationscausetheaccumulationoftheseoncometabolites.Correspondingtoit,thesuccinatedehydrogenasecomplexiron-sulfursubunitB(SDHB),thefumaratehydratase(FH),andthecytosolicisocitratedehydrogenase[NADP(+)]1(IDH1),orthemitochondrialisocitratedehydrogenase[NAD(+)]2(IDH2),areinvolved[(16);Figure2Q].Aloss-of-function(LOF)mutationinSDHBandFHorgain-of-function(GOF)mutationinIDH1andIDH2leadtoanincreaseinthecytosolicconcentrationsofsuccinateandfumarateontheonehandand2-hydroxyglutarateontheotherhand,respectively(61).FumarateandsuccinateactivateKelch-likeECH-associatedprotein1(KEAP1)throughanon-enzymaticpost-translationalproteinmodificationcalled“succinylation,”whichinturnactivatestheoncogenictranscriptionfactor—namelytheerythroid-derivednuclearfactor2(NRF2orNFE2)(63).Incontrast,2-hydroxyglutaratemodulatestheα-ketoglutarate-dependentactivityofprolylhydroxylases1and2(PHD1,2)andthefollowinghypoxia-induciblefactorsubunit1α(HIF-1α)stabilization(Figure2R),thuspromotingthetransformationofthedevelopingmalignancy(7,8).Expressionlevelsoftransketolase(TKT)—anantagonistofα-KG—could,forinstance,regulatethemetabolicswitchthroughHIF-1αandPDH2viatheα-KG-dependentdioxygenasesignalingandthetranscriptionofSDHandFHtocontrolbreastcancermetastasis(64).Theconcomitantoncogenesignalingpromotesthemitogen-activatedproteinkinase(MAPK)cascade(65),epidermalgrowthfactorreceptor(EGFR)signaling(66),andenhancedprotectionagainsttheoncogene-drivenmitochondrialoutermembranepermeabilization(MOMP),mitochondrialpermeabilitytransition(MPT),senescence,andtheregulatedcelldeath(RCD)(67–70). Theepithelial-mesenchymaltransition(EMT)isalsodependentondown-regulationofsuccinatedehydrogenaseandthesubsequentaccumulationofsuccinateinbreastcancerprogressionandrepresentsSDHasapotentialkeyregulatorofEMT[(71);Figure2Q].Down-regulationofsuccinatedehydrogenaseB(SDHB)iscommonincentralnervoussystem(CNV)—hemangioblastoma(72).Isocitratedehydrogenase1(IDH1)(Figure2Q)—mutanthumangliomasshowahighdependenceoflactateandglutamatebecauseoftheresultingdeficitinα-ketoglutarate(α-KG).TheaccompanyingneuronalcellsandastrocytesinthemicroenvironmentaresupplyingthemwiththesenutrientstoreplenishtheTCAcycle(73). Asmentionedinthe“MetabolisminCancer”sectionofthisreview,tumorprogressionisassociatedwiththerewiringofcancermetabolism.InadditiontoincreasedglycolysisandtheincreaseduseofPPPunderhypoxicconditions,astheyalsooccurincellswithmitochondrialdefects,thereisarealignmenttoothermetabolicpathways.Thisrealignmentincludesreductiveglutaminemetabolism(Figures1A,B,2I)—themainsourceofcytosoliccitrate[(26,74,75);Figure2L].Serinemetabolism(Figure2D)isalsoimportantforlipidsynthesisandthemaintenanceofredoxhomeostasisthroughtheproductionofreducingequivalents,responsibleforasmuchas50%ofcellularNADPHproduction(29,76).Thisoccursviathemitochondrialserinehydroxymethyltransferase2(SHMT2)andthecytosolicSHMT1,whichsynthesizefromtetrahydrofolate(THF)andglycine5,10-methenyl-THFandfurtherviathe5,10-methylene-THFdehydrogenase1and2(L)(MTHFD1/2/2L),5,10-methylene-THF(alsocalledone-carbonorfolatecycle).Asetofreductive-oxidativeconversionsleadstoavarietyofTHFsubtypesthatarerequiredforpurines,thymidine,andS-adenosylmethionine(SAM)biosynthesis(77).Thelatterisanimportantsubstrateforgene-regulatorymethylationreactions. Viathereversibleoxidativedecarboxylationof(S)-malatetopyruvate[(S)-malate+NAD(P)+↔pyruvate+CO2+NAD(P)H],performedbymeansofthecytosolicmalicenzyme1(ME1)—alsocalledmalatedehydrogenase—whichcombinesglycolysiswiththeTCAcycle,NAD(P)HisalsoobtainedinPDACsandhighlyproliferatingbreastcancer[(27,78);Figure2S].Cancercellstakeupextracellularcitratefromthebloodviatheplasmamembranecitrate-transportingprotein(pmCiC)thatsupportsboththecancercellmetabolismandtheproliferationofcancercellsthroughbothitsdeliverytotheglutamateandTCAmetabolismorforfattyacidsynthesis[(79);Figure2C].Similarly,acetoacetate,whichisderivedfromacetyl-CoA,enhancesoncogenesisthroughelevatingtheactivityofBRAFkinase,whichresultsinincreasedMAPKsignaling(80,81). Furthermore,slightlyincreasedROSlevelsstimulateproliferationbyinactivatingtumorsuppressorproteinssuchasthephosphataseandtensinhomologPTENorstabilizingHIF1α[(82,83);Figure2T].Theymanageandcontrolmitochondrialbiogenesisanditsmetabolism(84,85).TheseslightlyincreasedROSlevelsarise,forexample,asasideeffectthroughtheover-expressionofATPaseinhibitoryfactor1(ATPIF1)andtheresultinglimitationofATPproductionafterthedimerizationoftheETCcomplexVintheinnermitochondrialmembrane(86,87).However,evenwhenROS-derivedsenescenceoccurs,thismayparadoxicallyresultinincreasedproliferationviacell-extrinsicsecretionofmitogenicfactorstoneighboringcells(88,89). Inthedevelopmentoftheresistanceofthecancercellintoregulatedcelldeath(RCD),themitochondrialtransmembranepotential(Δψm)andthus,glycolysisincreaseinsometumors(90).Increasedlevelsofglutathione(GSH)preventtheoxidationandtranslocationofcytochromeCfromthemitochondriaintothecytoplasm,thuspreventingMOMPandapoptosis(91).Anti-oxidative,reducingequivalentsaredeliveredthroughglycolysisandreductiveglutaminecarboxylation[(76,92,93);Figures2D,I]. Furthermore,duetothelowROSlevels,hormesis—alreadyformulatedbyParacelsus—occurs,togetherwiththepromotionofautophagy,whichisreminiscentofischemicpreconditioning(94–96).Inadditiontoglycolysis,adequateATPsupplybythemitochondriaensuresoptimalCa2+homeostasisandlimitedmitochondrialpermeabilitytransition(MPT)(86,97).TheresultingglucosedeprivationcausesevenachangeofglycolysistoOxPhosand,throughmitochondrialelongationandmitophagy,theremovalofdysfunctionalcomponentsthankstoboththeinhibitionofdynamin1-likeprotein(DNM1L)andthecreationofamitochondrialnetwork(98,99). Theheterogeneitybetweentheextentsoftheuseofoxidativephosphorylation(OxPhos)inrelationtoglycolysisdependsontheoriginandlocalizationoftheprimarytumorsandtheirmetastases.Chemo-resistancedevelopsbecauseoftheabilityofcancercellstorewiretheirmetabolismflexibly.IncreasedOxPhoscauses,amongotherthings,increasedexpressionofclassIMHCmoleculesontheoutermembraneofthecancercellsandtherebyareductionintheirnaturalkiller(NK)cell-mediatedlysis.TwistingthepolarizationofM1-toM2-macrophages,whichoccursmainlyunderhypoxicconditionsusingOxPhos,supportstumorigenesis(100–104). Lactate-activatedtumor-associatedmacrophages(TAMs)increasechemokine(CC)ligand5(CCL5)expressionviaNotch1andJagged2signaling.ItsactivatedreceptorCCR5,likeitsligand,isstimulatedbythetransforminggrowthfactorbeta1(TGF-ß1),whichleadstoincreasedaerobicglycolysisviaactivatedAMPKandpromotesEMTinthebreastcancercellsinvestigated(105).Duetothefurtherincreaseinglycolysis,thereisapositivefeedbackloop,whichfurtheractivatestheTAMsviatheincreasedlactatesecretion.LactatedehydrogenaseA(LDH-A)expressionhasinfluenceonthetumormicroenvironmentthroughHIFsignaling,andtheimmuneresponseismodulatedviaexpressionlevelsofhexokinase1and2(HK1and2)andVEGFsecretion(106).TheincreasedlactateisresponsibleforimpairedTcellfunctionviahypoxia-reducedmicroRNA34a(miR-34a)expressioningastriccancer-associatedtumor-infiltratinglymphocytes,too(107). Thenon-metabolicfunctionsoflactate,whichcanbeconvertedintopyruvateasanenergysourceintumorcells,remainunknown.Zhangetal.(108)describeapreviouslyunknownhistonemodificationcalledlactylation,whichisderivedfromlactate.Theauthorsshow,byidentifying28lactylationsitesonhumanandmousehistones,thatlactylationofhistonelysineresiduesdisplaysanepigeneticmodification,thusdirectlystimulatingchromatingenetranscription.Glycolysisandlactateproductionisinducedbyhypoxiaandbacterialstress,thusstimulatinghistonelactylation.StimulationofM1macrophagesbyexposingthemtobacteriainitiateshistonelactylationthatistemporallyperformeddifferentlythanhistoneacetylation.HistonelactylationincreasesinalatephaseofM1macrophagepolarizationinducinghomeostaticwoundhealinggenesbyanendogenous“lactateclock,”whichprovidestheopportunitytounderstandlactate'sfunctionsininfectionsandcancer. Arecentstudy(109)foundthattumor-associatedregulatoryTcells(Tregs,alsonamedsuppressorTcells),incontrasttoconventionalTcells(Tconv),enhancedfattyacidsynthesis(FAS),andfattyacidoxidation(FAO)tocompensateforthelackofnutrientsinthetumor,andtheyaccumulatedinitsmicroenvironment,protectingthelatterfrominfiltrationbyconventionalactivatedTcells. Elevatedlevelsofmitochondrialreactiveoxygenspecies(ROS)promotecancermetastasisthroughinductionofEMTthroughmetabolicremodelingviaincreasedfattyacidβ-oxidationandMAPKcascadesincancerstemcells(110).Immatureneutrophilsoflow-density(iLDNs)exhibitincreasedmetabolicflexibilityandglobalbiogeneticcapacitytoactivatemitochondrialATPproduction.Amongotherthings,thegranulocytecolony-stimulatingfactor(G-CSF),secretedbybreastcancercellsmobilizesthecellsmigratingintotheliverandpromotesbreastcancermetastasisviaNETosis.Cancercellsmainlyuseglutamateandprolineintheglucose-deprivedenvironment(111).ThemicroRNAmiR-143controlsmemoryTcelldifferentiationbyreprogrammingTcellmetabolisminesophagealcarcinomapatientsviaareductionincellapoptosisandpro-inflammatorycytokinesecretion.Glucosetransporter1(GLUT-1)—thedecisivetargetgene—andindolamine-2,3-dioxygenase(IDO)anditscrucialmetabolitekynurenineconstitutetheupstreamregulatorsofmiR-143inmemoryTcellsandthereprogrammingofthetumormicroenvironmentmetabolismbyGLUT-1(112).Ontheotherhand,contrarytotheneedforhexokinase2(HK2)forcancerprogressionorgrowthinvariouscancermodels,Tcellscanwithstandthelossofhexokinase2.HK2isthemosthighlyregulatedenzymeincancerandactivatedT-cells,whichsuggeststhatHK2couldbeapromisingtargetforcancertherapyofT-ALLleukemia(113). TheInfluenceofTumorMicroenvironmentonEarlyMalignancy,Full-BlownTumor,andCancerStemCells Diversificationandfunctionalinteractionbetweenthetumormicroenvironmentandthenon-transformedenvironmentoccurduetothemetabolicneedsoftheincreasingphenotypicandmetabolicplasticityofdevelopingmalignancies(114–119).Cancerstemcells(CSCs)withaself-renewingpotentialshowapredominantlyglycolyticmetabolismandareresponsibleforthelocalprogressionandrecurrenceofthetumor(120–123).Nevertheless,therearealsoexceptions;forexample,theCSC'sofovariantumorsshowametabolismbasedmoreonoxidativephosphorylation(124);andtherearealsometabolicdifferenceswithintheindividualsubgroupsofCSCswithinatumor(125,126). Cancercells,suchasprostatecancercells,reprogramso-calledtumor-associatedfibroblasts(TAFs)inthedirectionofglycolysis.Bylactatesecretionintothetumormicroenvironment,theyreceivethemselvesalactate-inducedoxidativemetabolism;thismodelisreferredtoasthe“reverseWarburgeffect”(127–130). Recently,studieshaveshownthattherecouldbeanewmodeltounderstandtheWarburgeffect,concerningcancermetabolisminbreastcancerandlymphoma.Thishypothesissaysthatepithelialtumorcellsprovokeaerobicglycolysisinadjacentfibroblastsofthestroma.Thesefibroblastssecreteenergymetabolitesfromaerobicglycolysis,likelactateandpyruvatethatareabsorbedviathemonocarboxylatetransporter1(MCT-1)andconsumedintheTCAcyclebythecancercells,resultinginaproperenergymetaboliteflowthroughATPgenerationviaOxPhos,promotingahighercancercellproliferation(127,131).Essentially,thetumor-associatedfibroblastswouldfeedthecancercellsinakindofhost-parasiteconjunction.ThisnewmodelstillgoesconvenientwithWarburg'sstatementthattumors(consistingofthecancerandthestroma)areshiftingtheirmetabolismfromoxidativephosphorylationtoaerobicglycolysis.Thisisalsoinlinewithnewstudiesthatshowthatbreastcancerandendometrialcarcinomacellsstilldependonmitochondrialoxidativemetabolism.Withaparasitism-likebehavior,PDACsdrivetheTAFstowardautophagyandthusgeneratelocalalanineavailability,whichthecancercellsharnessasacarbonsourceviaextracellularuptakeofproteinsbytheso-calledmacropinocytosis[(132,133);Figure2G].However,macropinocytosisalsorecruitsfattyacids(FA)fortheoxidativeFAmetabolism(FAO)oflocaladipocytes(134–137).Thegenome-wideanalysishasshowncriticalregulationforadipocyte-associatedbreastcancerthroughtwomicroRNAs—miR-3184-5pandmiR-181-3p—whichweremostup-anddown-regulated,withtheirdirecttargetsbeingforkhead-boxprotein4(FOXP4)andtheperoxisomeproliferator-activatedreceptoralpha(PPARα).Invitroco-cultureofbreastcancercellswithmatureadipocyteshasresultedinanincreaseinproliferation,migration,andinvasionviatheNotch-inducedEMTpathwayandtheincreasedproductionofcytokinesandchemokines.Diabetesmellitusalsopromotesbreastcancerprogression(138). Themetaboliccompetitionfornutrientswithdeprivedavailabilityhas,asalreadymentioned,alsodirecteffectsontheimmunesurveillancebyimmuneeffectorcells—whichshowsimilarmetabolicbehaviorasthehighlyproliferatingcancercells—andthusontheevasionofimmunesurveillancebytumorigenesis(139–141). Inadditiontothemetabolic“parasitism,”therealsoexistsaseemingly“symbiotic”formofmetabolismhappeningbetweencancercellsofhypoxic,withthoseofnormoxicareasandglycolysis-drivenlactatetransportingintooxygen-well-exposedareas.TheseareasareabletometabolizethelactateviaOxPhosand,inturn,toprovidethehypoxicareaswithenergyandbicarbonate(HCO3-)ionstobalancetheirprotonsurplusinthehypoxiccenterpieceoftumorgrowthviatheso-calledconnexin(gap-junctionprotein)-composited“communicating”transitions(142–144). Ultimately,activeHCO3-transportfromnormoxiccellsregulatesthepHiofhypoxiccancercellsinthetumorcoreandsupportslacticaciddischargeandacid-basetransportthroughchemicaltitrationbetweenthealkalineperipheralcellsandtheacidiccentralcellsviaconnexinchannelsinjunction-coupledtumorstomaintainpHhomeostasis.Thereby,thedischargeoflactateintothenormoxicregionsoftheedgesofthetumorrepresentsastrategyforavoidingthecompetitionforglucoseinanutrient-andoxygen-deprivedmicroenvironment. TheMetabolismofCancerCellMetastasis Crucialforthepatient'ssurvivalprognosisisthequestionofthepresenceofmetastasis,calledmetastaticseedingorevendissemination.Afteracertaintime,thetumorhitsthelimitsofitsgrowth.Hypoxiaandhypoglycemiaareincreasinginsidethetumorcore[(145);Figure1C].Ifthesupportfromthetumormicroenvironmentandre-vascularizationofthetumorthroughthegenesisofnewbluntedbloodvessels,togetherwiththereprogrammingofmetabolism,reachtheirlimits,thechancesforfurthertumorgrowthwouldremaininthere-orientationofitsphenotypetoinvadethebloodstreamorlymphaticvessels.Itssubsequenttrans-endothelialescapefromtheprimarysiteintonew,distalbodysiteswouldguaranteeitscontinuedsurvivalbutultimatelykillthepatient(146).Thesedistalsitesofsecondarytumordevelopmentareessentiallywithnutrientsandoxygenrichlysuppliedareas,assuchthelungs,theliver,thebrain,bones,theomentum,andthelymphnodes,thusprovidingthedevelopingmetastasiswiththeidealconditionsforfurthersurvival. Afirstandimportantstepinthedevelopmentofmetastasisofthetumoristhealterationofitscell-specificphenotypefromadifferentiatedepithelialphenotypewithacleardifferentiationintoanapical(outerregion,facingtheskin,orcelllumen)andbasal(innerregion,connectedviaabasalmembranewiththeunderlyingtissue)sideintoamesenchymalphenotype.Thisphenotypeincreasinglylosesitsepithelialfeaturesanditspolarizationandassumesamigratoryphenotypecapableofalteringitsposition,dissolvingthecell-cellcontactstopenetratethebasalmembraneandtoreducetheexpressionofadhesionmoleculeslikeE-cadherin,theepithelialcelladhesionmoleculeEpCAM,andkeratin-14.Theexpressionlevelsofothermolecules,suchasvimentin,N-cadherin,orfibronectin,areupregulated.Onceagain,switchingongenesfromembryonicdevelopmentherebydeterminesthephenotypeofthemigratingcancercell. Themechanismresponsiblefortheso-called“metastaticcascade”gaveititsname:theepithelial-mesenchymaltransitionorEMTforshort.EMTresultsinincreasedmigratoryandinvasivepotentialofthemalignancy(147,148).Forexample,fumarate,succinate,or2-hydroxyglutarateareabletorepresstranscriptionofmicroRNAsthatinhibitmetastasisbyrepressingTen-eleventranslocationmethylcytosinedioxygenase1(TET1)orJumonjidomain-containinghistonedemethylase(JHDM)(149,150).ThemicroRNA[(miRNA)forshort;itmostlyconsistsof21-to23-nucleotidelong,highlyconserved,andnon-codingRNAs,whichplayanimportantroleatthepost-transcriptionallevelofgeneregulation]regulationofmanygenetargetsmakesthematherapeuticallyinterestingtopic(151,152).Ratherthaninhibitingasingleneoplasticprocess,theconcomitantordelayedstagingofmanyprocessesisre-sensitizingthecancercelltotherapy.However,thisswordofmiRNAregulationisdouble-edged:thenon-specificnatureofmiRNAregulationoftenleadstoundesirableinteractionswithtargetgenesthatarenotinvolvedintheregulationofcancerproliferationandmetastasis.Nonetheless,proteasomeinhibitorsdonotfailtowork.MiRNA-basedtherapeuticshavenowundergonePhase1ofclinicaltrials(152). Additionally,up-regulationofthegenesoftheperoxisomeproliferator-activatedreceptorgammaco-activator-1alpha(PPARγco-activator1α,alsoPGC-1α)inbreastcancer(153),orsilencingofthemitochondrialmembraneproteinFAM210Binovariancancerprovideoptimalutilizationofmitochondrialbiogenesisandoxidativephosphorylationthatisimplementedthroughthedown-regulationofpyruvatedehydrogenasekinaseisozyme4(PDK-4)andtheincreasedutilizationofpyruvatefromglycolysisviaTCAcycle[(154);Figure2U].Thisprocessisimportantformitochondrial-oxidativemetabolismatthe“growthbud”ofthetumor,whichlinkstotheformationofcytoskeletalchangesnecessaryforincreasingmotilityofthemigratingandinvadingmalignancies(155–157).PGC-1αisessentialforTGF-ßandNeu/ErbB2-drivenbreastcarcinomaonsetandresistancetobiguanidessuchasmetformin.TheinteractionofPGC-1αwiththeShcAadapterproteintherebyraisesmetabolismandbreasttumorglucose-dependence.However,impairedShcAsignalingincreasesglutaminedependenceduetoareductioninPGC-1αlevels,mitochondrialefficiency,andmetabolicversatilityofbreastcancer(158–161). MitophagydefectsincreasemetastaticdisseminationviaslightlyelevatedROSlevels(162–165).Thisactivatesseveralsignalingcascades,suchastheproto-oncogenictyrosinekinaseSRCandproteintyrosinekinase2beta(PTK2B)signaling,whichareessentialformetastasis(165,166).However,toomanyROSinhibitmetastasisthroughoxidativestress,leadingtosenescenceorregulatedcelldeath(167–169).Dependingontheanatomicaloriginofthemetastaticlesions,thereissignificantheterogeneityinthedifferentialuseofoxidativephosphorylationconcerningglycolysis(116,170,171).Mitochondriaarethereforethelinchpinofcellsignalingandmetabolism,whichdecideaboutthedeterminationoftumorigenesis(59,172–174). Conversely,mitochondrialdysfunctioncanleadtoreducedNADHturnoverandanincreaseinthecytosolicNADHconcentration.Throughthereductiveglutaminecarboxylationand,subsequently,viathemalatedehydrogenaseofthemalate-aspartateshuttle,theNADredoxstateisrestored,andthecytosolicglyceraldehyde-3-phosphatedehydrogenase(GAPDH)andglycolysisactivityisenhanced,resultinginanincreasedATPproductionassociatedwithincreasedcellmigration.Thus,theNADHshuttlecombinescytosolicreductiveglutaminecarboxylationwithglycolysisinmitochondrial-dysfunctionalcells(175–177). Thereissomeevidencethatbreastcancerpatientswithmetabolicpathologies,suchasdiabetesandobesity,arelessresponsivetotherapiesandhaveahigheroverallmortalityrate,withhyperglycemiaappearingtoberesponsibleforthis.Itisalsopossiblethattheexcessleptinproductionleadstoanup-regulationoftheleptinreceptorandsubsequentstimulationoftheJAK2/STAT3orPI3K/AKTsignalingpathwaysviathegeneregulationofFoxc2,Twist2,Vim,Akt3,andSox2toaCSC/EMTphenotypedeterminedintriple-negativebreastcancercells(178).Additionally,suppressionofthepyruvatedehydrogenase(PDH)complex(Figure2U)viaoncogenicmicroRNA-27bcanderegulatebreastcancergrowthbyshiftingthemetabolismfromoxidativephosphorylationtowardglycolysis,thusnegativelyaffectingpatientsurvival(151).Caseinkinase2(CK2)modulatesthepyruvatekinaseMisoforms1/2ratioinfavorofpyruvatekinaseM2(PKM2)(Figure2P),therebytriggeringEMTincoloncarcinomacelllinesbyincreasingglycolyticactivityandLDHA-drivenproliferation(179). Themechanotransductionofsignalsfromthesurroundingstiffeningtissueofthetumoralsodeterminestheextentoftheglycolyticdrift.ThepublicationdatafromParketal.(180)showthattheextentoftheglycolysisoftransformednon-smallcelllungcancercellsreactstothestiffnessoftheactomyosincytoskeletonandthatthemechano-sensingmachineryofthesurroundingtissuecontrolsthecellmetabolism.Non-malignantcellscanadapttheirenergyproductiontochangingenvironments.Cancercells,ontheotherhand,reacttotheconstantlychangingmechanicalambientpressureduringtumorprogressionwithaconstantlyhighglycolyticrateinthecancercells.Thetransferofhumanbronchialepithelialcellsfromstifftosoftsubstratesleadstoaglycolysisreductionthroughthebreakdownofphosphofructokinase(PFK).ThisdegradationismediatedbythedisassemblyofstressfibersreleasingtheE3-ubiquitinligasetripartitemotif(TRIM)containingprotein21(TRIM21).Thetransformedcellsofnon-smallcelllungcancerthat,despitethechangedenvironmentalconditions,maintainhighglycolysisviatheincreasedPFKexpression,down-regulateTRIM21andsequesterresidualTRIM21onasubsetofstressfibersthatareinsensitivetosubstratestiffness. Whiletheassumption,inthepast,was,thattheepithelialandmesenchymalphenotypesofmetastasizingcancerwouldjustshowarigidswitchbetweenthem,eitherepithelialormesenchymal,nowweknowthatthereareseveralintermediarystagesinbetween.Thisdependsonthemetabolicandsignalingconditionsinthetumormicroenvironment,theinvasionlocationintothevascularnetwork,theconditionsfoundinthesiteoftrans-endothelialmigration(extravasation)outofit,andtheconditionsfoundinthemetastaticdestinationsite.Thecurrentneedsofthecancercellsnotonlydeterminesthetransitiontothemesenchymalphenotype,butalsoisresponsibleforthereverseddirecteddevelopmenttowardtheepithelialphenotype,calledmesenchymal-epithelialtransition(MET).Arecentstudy(181)investigatedtransitionalstatestendingmoretotheepithelialorthemesenchymalcharacteristicsandclassifiedthem,besidesmeasuringthelevelsofexpressionofadhesionmoleculesandmoleculesofthemesenchymalstate,basedonthelevelsofCD51,CD61,andCD106,receptorproteinsthatindicateamesenchymalcellstate.Itturnedoutthatthemajorityofthemetastasizingcellsdidnotwhollyde-differentiatethemselvestothemesenchymalphenotypetometastasizeandtofinalizethetransitioninadistantorgansite. Manycancercellsoftheprimarytumor,calledcirculatingtumorcells(CTCs),leavethecirculatory,orlymphaticsystemattheirextravasationsiteandtheyhavetochangetheirmetabolicphenotypetosurviveinthenewtumormicroenvironmentoftheorganoftheirdestinationsite;thereby,onlyfewofthemshowtherequiredmetaboliccharacteristicstobuildmetastaticlesions.Manyofthemremainina“sleeping”mode,calleddormantCTCs,whichpreventsanoikis—theprogrammeddeathofcells,whichwerelosingtheircontacttothecellmatrix.Thesecellsarereactivatedonlywhenthesurvivalconditionsimproveinthemicroenvironmentoftheirchoice. Metabolismiscriticalforsurvivalandstressadaptation,andonebelievesthatCTCspossessanindividualsignaturetofulfillthesemetabolicrequirements.Theseso-calleddisseminatedtumorcells(DTCs)haveacertain“predilection”forahostorganthathasaspecificmetabolicsignatureforcolonizationataspecificorgansite,butthisalsooffersanewAchilles'heelforcancertherapy.Sometumorsmetastasizetospecificorgansites,likeprostatecancertoboneorpancreaticcarcinomatoliver(182,183);onthecontrary,cancersfrombreastandlungarenotfussy.Recentevidencegivesahintthattheflexiblecharacterofmetabolismisdetermining,whetherthemetastaticprocessissuccessfulandpromotesmetastasisindistantorgandestinations(184). TherapeuticImplicationsoftheMetabolicFlexibilityoftheTumorandItsCancerStemCells Embryonicandearlyfetalgrowthmainlyrequiresglycolysisandconstitutivegrowthfactors(forinstance,IGF,mTOR)amongpredominantanaerobicenvironmentalconditions(lowO2partialpressure)andwithoutevolutionoffunctionalmitochondria(185,186).Whenthechildisbornandwithcontacttotheoxygenintheatmosphere,manychallengesoftheenvironmentanditsadaptationtoit,thedevelopmentalprogramadjustments,andtheterminaldifferentiationofthesedevelopmentalprograms;shapingofthelymphoidsystem,maturationofthecellsoftheimmunesystemandtheirthymusandbonemarrowsettlementarenecessaryformitochondrialefficiencyandstrongimmunity.Therefore,thereisaneedforbioenergetichealthandstronglyworkingcell-mediatedandhumoralimmunitytogiveprotectiontoexternalthreadsafterbirthandthroughoutlife(187,188). Agingandoxidativestressnegativelyaffectanefficientimmunity,mitochondrialhealth,andweakenstheimmunesystem;theyarealsoresponsibleforhypoxia,resemblingthestatesofanabolicfetaldevelopmentandmaybethereasonfortumorigenesis(189). Theactivationofconstitutiveembryonicgrowthfactorsofepithelialcellsandtheirepithelial-mesenchymaltransition(EMT)induceimmunoreactivetissueloss.Adisruptedpyruvatetransport,thebiosynthesisofproteinsenrichedwithbranchedandaromaticaminoacids,enhancedactivityofSerin/ThreoninkinaseIRAK-M(190,191)andothergrowthpaths,likemTOR/PI3Ks,VEGF,enhancedglycolysistoaddresstheincreaseddemandsforaberrantcancercellgrowthunderhypoxia,andthedisruptionoftheinhibitionofcell-cellcontact,accompanytheseevents(192–194). Effectiveimmunityinacuteinflammatoryconditionshasthepowertoexterminatecancerandtoreviseorpreventtheinitialstagesofimmunedysfunction.However,ithasbeenshownthatchronicinflammationandanagedimmunesystemreducedstabilityofthegenome,changedtheexpressionofthefactorsoftheinflammatoryandanti-inflammatorymachinery,alteredthemitochondrialandribosomalfitnessandfunctionality,anddisturbedtheacid-basebalance,increasingtheriskofcarcinogenesisintissues.Anti-cancerdrugs,derivedfromidentifyingmultiplemutantordamagedgenesortheirrelatedgrowthenzymesformthebasisforlate-stagecancertherapyas“targeted,”“precision,”or“cancer”therapyorevencalled“personalizedmedicine.”Nonetheless,thissortoftherapynotinfrequentlyshowsdrug-related,undesirableeffectsthatthreatenthelivesofthepatientsleadinginworstcasetodeadlymulti-organfailure(MOF)(195,196). Activationofconstitutivetrophoblastgrowthfactorsrequiredfororderlyplacentalembryonicandfetalgrowthandreceptorproteins—likepyruvatekinasesandtheiractivators—inducetheproductionofanaboliccomponentsofmetabolismaffectingaberrantcancercellgrowthandmetabolismtofacilitateglycolysisunderhypoxicconditionswithdysfunctionalmitochondria.Thesecharacteristicsaresimilartothoseoftheearlyfetalgrowth.Embryonicgrowthfactorsexpressionsfacilitatetheamelioratedglycolysis,andeffects,namedafterLouisPasteur,orHerbertGraceCrabtree(glucose),inducingimmunetolerance,andgeneratingahigh-energystatethatfacilitatescancerproliferation—conditionsnotbeneficialforthesurvivalofnon-malignantcells(197–202). Thecruxattheheartofthechoiceofcancertherapyisduetotheparticularcellcontext.Attemptshavebeenmadetostudytheproliferation,cellcycle,migration,andinvasionofcancercellsandtheirderivedcancerstemcellstocombatautophagy,mitophagy,thebilateralinteractionwithinthetumormicroenvironment,andtheacquisitionofbloodvesselsandthusofnutrientsandoxygenvianeo-angiogenesis.Thetargetingoffactorsthatcausetumorigenesiswithvariousanti-neoplasticdrugstopreventtheprimaryaswellassecondarytumorfromspreadingfurtherhas,inthebestcase,reduceditssizeorkilledthetumorcompletely.Thus,completehealingofthepatienthasbeenachieveddependingontheoriginofcancercells,thedegreeoftheiraggressiveness,andtheirstageofdevelopment,theirabilitytoformmetastasesorcancerstemcells,andtheirchoiceoftheirmetastasissite. Inadditiontotherapywithanti-neoplasticagentsandclassicalchemotherapy,includingradiationtherapy(50),treatmentwithanti-angiogenicdrugs(51–53)and“naturalkiller”(NK)—basedtherapy(54),severalmetabolicpathwaysofmitochondriainfluencethetherapeuticanswer.Forexample,metabolicenzymessuchasthemutatedmitochondrialformofisocitratedehydrogenase2(IDH2),whichblockterminaldifferentiation,havebeenharnessedforthedevelopmentofdrugs(58,203,204).BRAFV600E–inhibitionbyvemurafenibactsasa“switch”fromglycolysistooxidativephosphorylationandconcomitanttherapyresistance.Theinhibitoroftheelectrontransportchainhonokiolreversesthisresistance(205).OncogenicablationofKRASG12D–drivenPDACselectsaresistantpopulationthatreliesonoxidativephosphorylation(206).Breastcancercells,afterMYC/KRAS-orMYC/ERBB2-ablation(207),aresimilartogliomacellsintheiracquiredresistancetophosphoinositol-3-kinase(PIK3)inhibitors(208). TheactivitiesofmanydifferentATP-bindingcassette(ABC)familytransporterproteinsthatmediatechemo-resistanceagainstvariouscancertherapeuticsthroughtheexportofxenobiotic,dependonOxPhos-drivenATPavailability(209);andinsomecases,ahigherinflammatorystateisdrivenbyOxPhos,withinterleukin6(IL-6)andtumornecrosisfactoralpha(TNF-α)secretedinthemicroenvironmentofthetumor(210).Therefore,cancercells,whichshowhigherglycolysis,developaresistancetotherapythroughcells'intrinsicandextrinsicpathwaysfollowinga“switch”toOxPhos.Furthermore,malignantcellsthatusepre-dominantoxidativephosphorylationforenergyproduction,includingtheCSCsofpancreaticcarcinoma,maydevelopresistancetoETCinhibitionbecausetheyacquireMYC-dependentglycolyticmetabolism(211).Chemo-resistantovariancancershowsadriftfromOxPhostoglycolysis,followedbyanenhancedproductionofthePPP-dependentNADPHantioxidant,whichensuresredoxhomeostasisinthecytosol(212).Thus,chemo-resistancewouldbearesultoftheabilityofcancercellstoshapetheirmitochondrialmetabolismflexiblysothattheycanescapeandsurviveconstraintssuchasregulatedcelldeath(RCD)thattheywouldexperiencethroughtherapy. Chaoetal.(213)usedthetargetingoflacticacidosisintheso-calledTILA-TACE(targetingofintratumorallacticacidosis-transarterialchemo-embolization)therapyofhepatocellularcarcinomas(HCCs)largerthan5–10cmandnotsuitableforcurativetherapy.First,theyalkalizedthetumorwithasodiumbicarbonatesolutionviatumor-feedingvesselsandsubsequently,byembolizationofthesevessels,theycutthetumorofffromasubsequentglucosesupply.Astheyshowintheirstudy,thealkalizationoftheglucose-deprivedtumortransfersthemetabolismfromtheeconomyandefficiencymodebacktothe“Warburg”mode.Aftertheembolizationoftheglucose-supplyingvessels,thetumormetabolismliterallyruns“hot,”whichultimatelyleadstointratumoralapoptoticornecroticcelldeath(214–216). Conclusion Ineverythingthatwehavelearnedsofaraboutthedevelopmentofcancer,thereisanall-encompassingbasicideathatsuccessfultherapymustalwaystakeintoaccountthetherapyevasionbehaviorcausedbythemanifoldmetabolicmechanismsofcancercellswereportedinthisreview.Duetothemetabolicflexibilityofthetumorcells,thetherapeuticapproachusuallyshiftsthemetabolismonlyinadifferentdirectionandoftenprovokesamechanismofresistance,mainlyduetotheabilityofthemitochondriatoaltertheenergyandmetabolitesynthesistosustainanadequateproliferation,invasion,andmigrationcapacitytocontinuetumorigenesissuccessfully.Therefore,itisimportanttoincludethesetumorandstemcellmechanismsinthetherapeuticapproach,andtoconsiderthesimultaneousorstaggereddeliveryofdrugsornaturalproductsthatblockmultiplemetabolicpathwaysofthecancercellandatbest,wouldleadtoapoptoticcelldeath. The“Warburg-like”effectpromotesactiveproliferationinrapidlydividingembryonictissuesaswellasintumorigenesisofcancer.Becauseofthismetabolicfeature,theimportantdiagnostictechniqueof18F-fluorodeoxyglucosepositronemissiontomography(18FDG-PET)(217)wasdevelopedandsincethenusedintheclinicforthediagnosisofmalignantdiseases.Momcilovicetal.(218)havebeenusing4-[18F]fluorobenzyl-triphenylphosphonium(18FBnTP)—apositivelychargedtracer-ionthatisaccumulatedonthenegativelychargedinnermembraneofmitochondria—todistinguishsquamouscellcarcinomafromadenocarcinomainmice,thusprovidingtheopportunitytotargettheirdifferentdependencyonoxidativephosphorylation.18FBnTP-PET,togetherwith18FDG-PET,providesuswithanewtoolforinvivo-imagingenergyandmetabolitesfluxestofurtherwidenupourdiagnostichorizonintreatingdifferentstatesofdevelopingcancers.Wecanthussafelyclaimthat,almost100yearsago,OttoWarburglaidthefoundationfortoday'scancerdiagnosisandtherapy(219). AuthorContributions ConceptionanddesignofthemanuscriptwasdonebyMLandCG.ProofreadingwasdonebyGE.Allauthorsreadandapprovedthefinalmanuscript. ConflictofInterest Theauthorsdeclarethattheresearchwasconductedintheabsenceofanycommercialorfinancialrelationshipsthatcouldbeconstruedasapotentialconflictofinterest. 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