Is Cancer a Metabolic Disease?

  • Hilary A. Coller
    Correspondence
    Address correspondence to Hilary A. Coller, Ph.D., Department of Molecular, Cellular and Developmental Biology, 5145 Terasaki Life Sciences, University of California, Los Angeles, CA, 90095, and the Department of Biological Chemistry, David Geffen School of Medicine, Los Angeles, CA 90095.
    Affiliations
    Department of Molecular Biology, Princeton University, Princeton, New Jersey
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Open AccessPublished:October 21, 2013DOI:https://doi.org/10.1016/j.ajpath.2013.07.035
      Although cancer has historically been viewed as a disorder of proliferation, recent evidence has suggested that it should also be considered a metabolic disease. Growing tumors rewire their metabolic programs to meet and even exceed the bioenergetic and biosynthetic demands of continuous cell growth. The metabolic profile observed in cancer cells often includes increased consumption of glucose and glutamine, increased glycolysis, changes in the use of metabolic enzyme isoforms, and increased secretion of lactate. Oncogenes and tumor suppressors have been discovered to have roles in cancer-associated changes in metabolism as well. The metabolic profile of tumor cells has been suggested to reflect the rapid proliferative rate. Cancer-associated metabolic changes may also reveal the importance of protection against reactive oxygen species or a role for secreted lactate in the tumor microenvironment. This article reviews recent research in the field of cancer metabolism, raising the following questions: Why do cancer cells shift their metabolism in this way? Are the changes in metabolism in cancer cells a consequence of the changes in proliferation or a driver of cancer progression? Can cancer metabolism be targeted to benefit patients?
      CME Accreditation Statement: This activity (“ASIP 2014 AJP CME Program in Pathogenesis”) has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the American Society for Clinical Pathology (ASCP) and the American Society for Investigative Pathology (ASIP). ASCP is accredited by the ACCME to provide continuing medical education for physicians.
      The ASCP designates this journal-based CME activity (“ASIP 2014 AJP CME Program in Pathogenesis”) for a maximum of 48 AMA PRA Category 1 Credit(s)™. Physicians should only claim credit commensurate with the extent of their participation in the activity.
      CME Disclosures: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose.

      Discoveries of Otto Warburg

      Otto Warburg’s pioneering work in the 1920s established that tumor cells exhibit altered metabolism. Warburg discovered an important distinction between the relative use of different modes of energy production in normal cells and tumors. In normal tissues, most of the pyruvate formed from glycolysis enters the tricarboxylic acid (TCA) cycle and is oxidized via oxidative phosphorylation. In tumors, in contrast, the pyruvate is largely converted to lactic acid and energy is produced anaerobically.
      • Warburg O.
      On the origin of cancer cells.
      This finding seemed counterintuitive. Surely, a rapidly proliferating cancer cell would prefer the 36 ATPs that can be claimed by complete oxidation of a glucose molecule to the two ATPs available through glycolysis. Furthermore, this shift in metabolism in which pyruvate is converted to lactate and secreted, rather than being oxidized, occurred in tumors even when there was sufficient oxygen to support mitochondrial function. The conversion of most pyruvate to lactate through fermentation, even when oxygen is present, is called aerobic glycolysis or the Warburg effect.

      Evidence that Aerobic Glycolysis Promotes Tumorigenesis

      Since these early discoveries, rapid consumption of glucose and secretion of lactate have been discovered to be a characteristic of many types of tumors. By using the imaging agent 2-[18F]fluoro-2-deoxy-d-glucose, coupled with positron emission tomography (PET), primary and metastatic lesions can be identified with a specificity and sensitivity near 90%.
      • Czernin J.
      • Phelps M.E.
      Positron emission tomography scanning: current and future applications.
      Furthermore, glucose uptake assessed with PET correlates with poor prognosis in oral squamous cell carcinoma,
      • Kunkel M.
      • Reichert T.E.
      • Benz P.
      • Lehr H.A.
      • Jeong J.H.
      • Wieand S.
      • Bartenstein P.
      • Wagner W.
      • Whiteside T.L.
      Overexpression of Glut-1 and increased glucose metabolism in tumors are associated with a poor prognosis in patients with oral squamous cell carcinoma.
      gastric cancer,
      • Mochiki E.
      • Kuwano H.
      • Katoh H.
      • Asao T.
      • Oriuchi N.
      • Endo K.
      Evaluation of 18F-2-deoxy-2-fluoro-D-glucose positron emission tomography for gastric cancer.
      and neoplasms of other tissues.
      • Podoloff D.A.
      • Advani R.H.
      • Allred C.
      • Benson 3rd, A.B.
      • Brown E.
      • Burstein H.J.
      • Carlson R.W.
      • Coleman R.E.
      • Czuczman M.S.
      • Delbeke D.
      • Edge S.B.
      • Ettinger D.S.
      • Grannis Jr., F.W.
      • Hillner B.E.
      • Hoffman J.M.
      • Kiel K.
      • Komaki R.
      • Larson S.M.
      • Mankoff D.A.
      • Rosenzweig K.E.
      • Skibber J.M.
      • Yahalom J.
      • Yu J.M.
      • Zelenetz A.D.
      NCCN task force report: positron emission tomography (PET)/computed tomography (CT) scanning in cancer.
      Tumor-produced lactate concentrations also correlate with shorter survival and increased metastases in cervical and head and neck cancer.
      • Walenta S.
      • Wetterling M.
      • Lehrke M.
      • Schwickert G.
      • Sundfor K.
      • Rofstad E.K.
      • Mueller-Klieser W.
      High lactate levels predict likelihood of metastases, tumor recurrence, and restricted patient survival in human cervical cancers.
      • Brizel D.M.
      • Schroeder T.
      • Scher R.L.
      • Walenta S.
      • Clough R.W.
      • Dewhirst M.W.
      • Mueller-Klieser W.
      Elevated tumor lactate concentrations predict for an increased risk of metastases in head-and-neck cancer.
      • Schwickert G.
      • Walenta S.
      • Sundfor K.
      • Rofstad E.K.
      • Mueller-Klieser W.
      Correlation of high lactate levels in human cervical cancer with incidence of metastasis.
      Overall, the association between a glycolytic phenotype and poor prognosis, along with the consistency of the phenotype and its usefulness for diagnosis, supports a model in which metabolic changes are a reproducible characteristic of cancer cells and may even promote disease progression.
      In this review, we consider the way in which cancer cells rewire their metabolism with a focus on a few key questions. What is the metabolic phenotype of cancer cells and how is it achieved molecularly? How do oncogenes and tumor suppressors coordinate and enforce the metabolic changes that occur with cancer? Is the metabolic phenotype of cancer cells a reflection of their rapid growth? Why do tumor cells undergo this dramatic shift (ie, what advantage would an inefficient energy production program confer)? Are metabolic changes drivers of cancer progression or do they just come along for the ride? And finally, is the cancer metabolic profile sufficiently distinct from that of normal cells that it can be targeted therapeutically?

      Molecular Basis for the Cancer Cell Metabolic Phenotype

       Cancer Cells Reengineer Glycolysis

      Cancer cells evade the mechanisms that normally regulate glycolytic flux using multiple different strategies. The levels of many different glycolytic enzymes are induced in tumors
      • Altenberg B.
      • Greulich K.O.
      Genes of glycolysis are ubiquitously overexpressed in 24 cancer classes.
      (Figure 1 and Table 1). In addition, cancer cells subvert the feedback mechanisms that normally allosterically inhibit rate-controlling steps in glycolysis. For instance, phosphofructokinase (PFK) is inhibited by ATP; when the cell is energy rich, glycolysis should decrease. However, when glucose is abundant, the metabolite fructose 2,6-bisphosphate is formed from fructose 6-phosphate by 6-phosphofructo-2-kinase/fructose 2,6-bisphosphatases (PFKFBP1-4), and fructose 2,6-bisphosphate can override ATP-mediated PFK inhibition. In tumor cells, high levels of glucose transport
      • Czernin J.
      • Phelps M.E.
      Positron emission tomography scanning: current and future applications.
      • Medina R.A.
      • Owen G.I.
      Glucose transporters: expression, regulation and cancer.
      • Reske S.N.
      • Grillenberger K.G.
      • Glatting G.
      • Port M.
      • Hildebrandt M.
      • Gansauge F.
      • Beger H.G.
      Overexpression of glucose transporter 1 and increased FDG uptake in pancreatic carcinoma.
      and hexokinase activity
      • Medina R.A.
      • Owen G.I.
      Glucose transporters: expression, regulation and cancer.
      • Bustamante E.
      • Pedersen P.L.
      High aerobic glycolysis of rat hepatoma cells in culture: role of mitochondrial hexokinase.
      • Marin-Hernandez A.
      • Rodriguez-Enriquez S.
      • Vital-Gonzalez P.A.
      • Flores-Rodriguez F.L.
      • Macias-Silva M.
      • Sosa-Garrocho M.
      • Moreno-Sanchez R.
      Determining and understanding the control of glycolysis in fast-growth tumor cells: flux control by an over-expressed but strongly product-inhibited hexokinase.
      lead to elevated levels of fructose 2,6-bisphosphate, which allosterically activates PFK. The specific PFK isozymes overexpressed in cancer cells are less sensitive to allosteric inhibition by ATP and more strongly activated by fructose 2,6-bisphosphate.
      • Vora S.
      • Halper J.P.
      • Knowles D.M.
      Alterations in the activity and isozymic profile of human phosphofructokinase during malignant transformation in vivo and in vitro: transformation- and progression-linked discriminants of malignancy.
      Cancer cells also trick themselves and generate cues that there are higher levels of blood glucose than actually exist by overexpressing PFKFBPs, increasing the levels of fructose 2,6-bisphosphate and, thus, driving glycolysis.
      • Atsumi T.
      • Chesney J.
      • Metz C.
      • Leng L.
      • Donnelly S.
      • Makita Z.
      • Mitchell R.
      • Bucala R.
      High expression of inducible 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (iPFK-2; PFKFB3) in human cancers.
      As a result of these different mechanisms of activation, PFK activity is much higher in cancer cells than normal tissue.
      • Vora S.
      • Halper J.P.
      • Knowles D.M.
      Alterations in the activity and isozymic profile of human phosphofructokinase during malignant transformation in vivo and in vitro: transformation- and progression-linked discriminants of malignancy.
      Figure thumbnail gr1
      Figure 1Cancer metabolism. Scheme shows central carbon metabolism. Metabolic reactions that tend to be faster in tumors are identified in red, whereas reactions that tend to be slower in tumors are identified in green. DHAP, dihydroxyacetone phosphate; GAP, glyceraldehyde 3-phosphate; KG, α-ketoglutarate; OAA, oxaloacetate; PEP, phosphoenolpyruvate.
      Table 1Metabolic Changes in Tumors and Activated Lymphocytes
      Metabolic stepCancer cellsPrimary tumorsFunctional importancePotential targetActivated lymphocytesPotential oncogene target
      Glucose uptake/glucose transportersIncreased
      • Medina R.A.
      • Owen G.I.
      Glucose transporters: expression, regulation and cancer.
      Increased
      • Czernin J.
      • Phelps M.E.
      Positron emission tomography scanning: current and future applications.
      • Reske S.N.
      • Grillenberger K.G.
      • Glatting G.
      • Port M.
      • Hildebrandt M.
      • Gansauge F.
      • Beger H.G.
      Overexpression of glucose transporter 1 and increased FDG uptake in pancreatic carcinoma.
      Yes
      • Rastogi S.
      • Banerjee S.
      • Chellappan S.
      • Simon G.R.
      Glut-1 antibodies induce growth arrest and apoptosis in human cancer cell lines.
      • Keunen O.
      • Johansson M.
      • Oudin A.
      • Sanzey M.
      • Rahim S.A.
      • Fack F.
      • Thorsen F.
      • Taxt T.
      • Bartos M.
      • Jirik R.
      • Miletic H.
      • Wang J.
      • Stieber D.
      • Stuhr L.
      • Moen I.
      • Rygh C.B.
      • Bjerkvig R.
      • Niclou S.P.
      Anti-VEGF treatment reduces blood supply and increases tumor cell invasion in glioblastoma.
      Yes
      • Fine E.J.
      • Segal-Isaacson C.J.
      • Feinman R.D.
      • Herszkopf S.
      • Romano M.C.
      • Tomuta N.
      • Bontempo A.F.
      • Negassa A.
      • Sparano J.A.
      Targeting insulin inhibition as a metabolic therapy in advanced cancer: a pilot safety and feasibility dietary trial in 10 patients.
      Increased
      • Frauwirth K.A.
      • Riley J.L.
      • Harris M.H.
      • Parry R.V.
      • Rathmell J.C.
      • Plas D.R.
      • Elstrom R.L.
      • June C.H.
      • Thompson C.B.
      The CD28 signaling pathway regulates glucose metabolism.
      • Jacobs S.R.
      • Herman C.E.
      • Maciver N.J.
      • Wofford J.A.
      • Wieman H.L.
      • Hammen J.J.
      • Rathmell J.C.
      Glucose uptake is limiting in T cell activation and requires CD28-mediated Akt-dependent and independent pathways.
      • Brand K.
      Glutamine and glucose metabolism during thymocyte proliferation: pathways of glutamine and glutamate metabolism.
      • Hume D.A.
      • Radik J.L.
      • Ferber E.
      • Weidemann M.J.
      Aerobic glycolysis and lymphocyte transformation.
      Induced by MYC,
      • Le A.
      • Lane A.N.
      • Hamaker M.
      • Bose S.
      • Gouw A.
      • Barbi J.
      • Tsukamoto T.
      • Rojas C.J.
      • Slusher B.S.
      • Zhang H.
      • Zimmerman L.J.
      • Liebler D.C.
      • Slebos R.J.
      • Lorkiewicz P.K.
      • Higashi R.M.
      • Fan T.W.
      • Dang C.V.
      Glucose-independent glutamine metabolism via TCA cycling for proliferation and survival in B cells.
      • Osthus R.C.
      • Shim H.
      • Kim S.
      • Li Q.
      • Reddy R.
      • Mukherjee M.
      • Xu Y.
      • Wonsey D.
      • Lee L.A.
      • Dang C.V.
      Deregulation of glucose transporter 1 and glycolytic gene expression by c-Myc.
      AKT,
      • Frauwirth K.A.
      • Riley J.L.
      • Harris M.H.
      • Parry R.V.
      • Rathmell J.C.
      • Plas D.R.
      • Elstrom R.L.
      • June C.H.
      • Thompson C.B.
      The CD28 signaling pathway regulates glucose metabolism.
      and HIF
      • Mathupala S.P.
      • Rempel A.
      • Pedersen P.L.
      Glucose catabolism in cancer cells: identification and characterization of a marked activation response of the type II hexokinase gene to hypoxic conditions.
      and repressed by p53
      • Matoba S.
      • Kang J.G.
      • Patino W.D.
      • Wragg A.
      • Boehm M.
      • Gavrilova O.
      • Hurley P.J.
      • Bunz F.
      • Hwang P.M.
      p53 Regulates mitochondrial respiration.
      • Schwartzenberg-Bar-Yoseph F.
      • Armoni M.
      • Karnieli E.
      The tumor suppressor p53 down-regulates glucose transporters GLUT1 and GLUT4 gene expression.
      HexokinaseHexokinase II increased
      • Bustamante E.
      • Pedersen P.L.
      High aerobic glycolysis of rat hepatoma cells in culture: role of mitochondrial hexokinase.
      • Marin-Hernandez A.
      • Rodriguez-Enriquez S.
      • Vital-Gonzalez P.A.
      • Flores-Rodriguez F.L.
      • Macias-Silva M.
      • Sosa-Garrocho M.
      • Moreno-Sanchez R.
      Determining and understanding the control of glycolysis in fast-growth tumor cells: flux control by an over-expressed but strongly product-inhibited hexokinase.
      Hexokinase II increased
      • Marin-Hernandez A.
      • Rodriguez-Enriquez S.
      • Vital-Gonzalez P.A.
      • Flores-Rodriguez F.L.
      • Macias-Silva M.
      • Sosa-Garrocho M.
      • Moreno-Sanchez R.
      Determining and understanding the control of glycolysis in fast-growth tumor cells: flux control by an over-expressed but strongly product-inhibited hexokinase.
      Yes
      • Wolf A.
      • Agnihotri S.
      • Micallef J.
      • Mukherjee J.
      • Sabha N.
      • Cairns R.
      • Hawkins C.
      • Guha A.
      Hexokinase 2 is a key mediator of aerobic glycolysis and promotes tumor growth in human glioblastoma multiforme.
      Yes
      • Kalia V.K.
      • Prabhakara S.
      • Narayanan V.
      Modulation of cellular radiation responses by 2-deoxy-D-glucose and other glycolytic inhibitors: implications for cancer therapy.
      Increased
      • Brand K.
      Glutamine and glucose metabolism during thymocyte proliferation: pathways of glutamine and glutamate metabolism.
      • Wang R.
      • Dillon C.P.
      • Shi L.Z.
      • Milasta S.
      • Carter R.
      • Finkelstein D.
      • McCormick L.L.
      • Fitzgerald P.
      • Chi H.
      • Munger J.
      • Green D.R.
      The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation.
      Induced by MYC
      • Gottlob K.
      • Majewski N.
      • Kennedy S.
      • Kandel E.
      • Robey R.B.
      • Hay N.
      Inhibition of early apoptotic events by Akt/PKB is dependent on the first committed step of glycolysis and mitochondrial hexokinase.
      and AKT
      • Kim J.W.
      • Gao P.
      • Liu Y.C.
      • Semenza G.L.
      • Dang C.V.
      Hypoxia-inducible factor 1 and dysregulated c-Myc cooperatively induce vascular endothelial growth factor and metabolic switches hexokinase 2 and pyruvate dehydrogenase kinase 1.
      PhosphofructokinaseLiver isozyme induced
      • Vora S.
      • Halper J.P.
      • Knowles D.M.
      Alterations in the activity and isozymic profile of human phosphofructokinase during malignant transformation in vivo and in vitro: transformation- and progression-linked discriminants of malignancy.
      Liver isozyme increased
      • Vora S.
      • Halper J.P.
      • Knowles D.M.
      Alterations in the activity and isozymic profile of human phosphofructokinase during malignant transformation in vivo and in vitro: transformation- and progression-linked discriminants of malignancy.
      Yes
      • Yi W.
      • Clark P.M.
      • Mason D.E.
      • Keenan M.C.
      • Hill C.
      • Goddard 3rd, W.A.
      • Peters E.C.
      • Driggers E.M.
      • Hsieh-Wilson L.C.
      Phosphofructokinase 1 glycosylation regulates cell growth and metabolism.
      Yes
      • Yi W.
      • Clark P.M.
      • Mason D.E.
      • Keenan M.C.
      • Hill C.
      • Goddard 3rd, W.A.
      • Peters E.C.
      • Driggers E.M.
      • Hsieh-Wilson L.C.
      Phosphofructokinase 1 glycosylation regulates cell growth and metabolism.
      Increased
      • Brand K.
      Glutamine and glucose metabolism during thymocyte proliferation: pathways of glutamine and glutamate metabolism.
      Induced by MYC
      • Osthus R.C.
      • Shim H.
      • Kim S.
      • Li Q.
      • Reddy R.
      • Mukherjee M.
      • Xu Y.
      • Wonsey D.
      • Lee L.A.
      • Dang C.V.
      Deregulation of glucose transporter 1 and glycolytic gene expression by c-Myc.
      and AKT
      • Deprez J.
      • Vertommen D.
      • Alessi D.R.
      • Hue L.
      • Rider M.H.
      Phosphorylation and activation of heart 6-phosphofructo-2-kinase by protein kinase B and other protein kinases of the insulin signaling cascades.
      6-Phosphofructo-2-kinaseInduced
      • Atsumi T.
      • Chesney J.
      • Metz C.
      • Leng L.
      • Donnelly S.
      • Makita Z.
      • Mitchell R.
      • Bucala R.
      High expression of inducible 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (iPFK-2; PFKFB3) in human cancers.
      Increased
      • Atsumi T.
      • Chesney J.
      • Metz C.
      • Leng L.
      • Donnelly S.
      • Makita Z.
      • Mitchell R.
      • Bucala R.
      High expression of inducible 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (iPFK-2; PFKFB3) in human cancers.
      Yes
      • Telang S.
      • Yalcin A.
      • Clem A.L.
      • Bucala R.
      • Lane A.N.
      • Eaton J.W.
      • Chesney J.
      Ras transformation requires metabolic control by 6-phosphofructo-2-kinase.
      Yes
      • Clem B.
      • Telang S.
      • Clem A.
      • Yalcin A.
      • Meier J.
      • Simmons A.
      • Rasku M.A.
      • Arumugam S.
      • Dean W.L.
      • Eaton J.
      • Lane A.
      • Trent J.O.
      • Chesney J.
      Small-molecule inhibition of 6-phosphofructo-2-kinase activity suppresses glycolytic flux and tumor growth.
      Increased
      • Telang S.
      • Clem B.F.
      • Klarer A.C.
      • Clem A.L.
      • Trent J.O.
      • Bucala R.
      • Chesney J.
      Small molecule inhibition of 6-phosphofructo-2-kinase suppresses T cell activation.
      Induced by p53
      • Bensaad K.
      • Tsuruta A.
      • Selak M.A.
      • Vidal M.N.
      • Nakano K.
      • Bartrons R.
      • Gottlieb E.
      • Vousden K.H.
      TIGAR, a p53-inducible regulator of glycolysis and apoptosis.
      Pyruvate kinaseShift to PKM2
      • Christofk H.R.
      • Vander Heiden M.G.
      • Harris M.H.
      • Ramanathan A.
      • Gerszten R.E.
      • Wei R.
      • Fleming M.D.
      • Schreiber S.L.
      • Cantley L.C.
      The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth.
      Shift to PKM2
      • Christofk H.R.
      • Vander Heiden M.G.
      • Harris M.H.
      • Ramanathan A.
      • Gerszten R.E.
      • Wei R.
      • Fleming M.D.
      • Schreiber S.L.
      • Cantley L.C.
      The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth.
      Yes
      • Christofk H.R.
      • Vander Heiden M.G.
      • Harris M.H.
      • Ramanathan A.
      • Gerszten R.E.
      • Wei R.
      • Fleming M.D.
      • Schreiber S.L.
      • Cantley L.C.
      The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth.
      • Goldberg M.S.
      • Sharp P.A.
      Pyruvate kinase M2-specific siRNA induces apoptosis and tumor regression.
      • Anastasiou D.
      • Yu Y.
      • Israelsen W.J.
      • Jiang J.K.
      • Boxer M.B.
      • Hong B.S.
      • et al.
      Pyruvate kinase M2 activators promote tetramer formation and suppress tumorigenesis.
      Yes
      • Christofk H.R.
      • Vander Heiden M.G.
      • Harris M.H.
      • Ramanathan A.
      • Gerszten R.E.
      • Wei R.
      • Fleming M.D.
      • Schreiber S.L.
      • Cantley L.C.
      The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth.
      • Goldberg M.S.
      • Sharp P.A.
      Pyruvate kinase M2-specific siRNA induces apoptosis and tumor regression.
      • Anastasiou D.
      • Yu Y.
      • Israelsen W.J.
      • Jiang J.K.
      • Boxer M.B.
      • Hong B.S.
      • et al.
      Pyruvate kinase M2 activators promote tetramer formation and suppress tumorigenesis.
      Increased
      • Brand K.
      Glutamine and glucose metabolism during thymocyte proliferation: pathways of glutamine and glutamate metabolism.
      • Wang R.
      • Dillon C.P.
      • Shi L.Z.
      • Milasta S.
      • Carter R.
      • Finkelstein D.
      • McCormick L.L.
      • Fitzgerald P.
      • Chi H.
      • Munger J.
      • Green D.R.
      The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation.
      Pyruvate dehydrogenase kinaseIncreased
      • Wigfield S.M.
      • Winter S.C.
      • Giatromanolaki A.
      • Taylor J.
      • Koukourakis M.L.
      • Harris A.L.
      PDK-1 regulates lactate production in hypoxia and is associated with poor prognosis in head and neck squamous cancer.
      Yes
      • McFate T.
      • Mohyeldin A.
      • Lu H.
      • Thakar J.
      • Henriques J.
      • Halim N.D.
      • Wu H.
      • Schell M.J.
      • Tsang T.M.
      • Teahan O.
      • Zhou S.
      • Califano J.A.
      • Jeoung N.H.
      • Harris R.A.
      • Verma A.
      Pyruvate dehydrogenase complex activity controls metabolic and malignant phenotype in cancer cells.
      • Sun R.C.
      • Fadia M.
      • Dahlstrom J.E.
      • Parish C.R.
      • Board P.G.
      • Blackburn A.C.
      Reversal of the glycolytic phenotype by dichloroacetate inhibits metastatic breast cancer cell growth in vitro and in vivo.
      Yes
      • Sun R.C.
      • Fadia M.
      • Dahlstrom J.E.
      • Parish C.R.
      • Board P.G.
      • Blackburn A.C.
      Reversal of the glycolytic phenotype by dichloroacetate inhibits metastatic breast cancer cell growth in vitro and in vivo.
      • Michelakis E.D.
      • Sutendra G.
      • Dromparis P.
      • Webster L.
      • Haromy A.
      • Niven E.
      • Maguire C.
      • Gammer T.L.
      • Mackey J.R.
      • Fulton D.
      • Abdulkarim B.
      • McMurtry M.S.
      • Petruk K.C.
      Metabolic modulation of glioblastoma with dichloroacetate.
      Increased by HIF
      • Kim J.W.
      • Tchernyshyov I.
      • Semenza G.L.
      • Dang C.V.
      HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia.
      and repressed by p53
      • Contractor T.
      • Harris C.R.
      p53 negatively regulates transcription of the pyruvate dehydrogenase kinase Pdk2.
      Lactate dehydrogenaseIncreased
      • Magrath I.
      • Lee Y.J.
      • Anderson T.
      • Henle W.
      • Ziegler J.
      • Simon R.
      • Schein P.
      Prognostic factors in Burkitt’s lymphoma: importance of total tumor burden.
      Yes
      • Fantin V.R.
      • St-Pierre J.
      • Leder P.
      Attenuation of LDH-A expression uncovers a link between glycolysis, mitochondrial physiology, and tumor maintenance.
      • Shim H.
      • Dolde C.
      • Lewis B.C.
      • Wu C.S.
      • Dang G.
      • Jungmann R.A.
      • Dalla-Favera R.
      • Dang C.V.
      c-Myc transactivation of LDH-A: implications for tumor metabolism and growth.
      Yes
      • Granchi C.
      • Roy S.
      • De Simone A.
      • Salvetti I.
      • Tuccinardi T.
      • Martinelli A.
      • Macchia M.
      • Lanza M.
      • Betti L.
      • Giannaccini G.
      • Lucacchini A.
      • Giovannetti E.
      • Sciarrillo R.
      • Peters G.J.
      • Minutolo F.
      N-hydroxyindole-based inhibitors of lactate dehydrogenase against cancer cell proliferation.
      Increased
      • Wang R.
      • Dillon C.P.
      • Shi L.Z.
      • Milasta S.
      • Carter R.
      • Finkelstein D.
      • McCormick L.L.
      • Fitzgerald P.
      • Chi H.
      • Munger J.
      • Green D.R.
      The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation.
      Increased by MYC
      • Shim H.
      • Dolde C.
      • Lewis B.C.
      • Wu C.S.
      • Dang G.
      • Jungmann R.A.
      • Dalla-Favera R.
      • Dang C.V.
      c-Myc transactivation of LDH-A: implications for tumor metabolism and growth.
      Monocarboxylate transportersIncreased
      • Hao J.
      • Chen H.
      • Madigan M.C.
      • Cozzi P.J.
      • Beretov J.
      • Xiao W.
      • Delprado W.J.
      • Russell P.J.
      • Li Y.
      Co-expression of CD147 (EMMPRIN), CD44v3-10, MDR1 and monocarboxylate transporters is associated with prostate cancer drug resistance and progression.
      Increased
      • Hao J.
      • Chen H.
      • Madigan M.C.
      • Cozzi P.J.
      • Beretov J.
      • Xiao W.
      • Delprado W.J.
      • Russell P.J.
      • Li Y.
      Co-expression of CD147 (EMMPRIN), CD44v3-10, MDR1 and monocarboxylate transporters is associated with prostate cancer drug resistance and progression.
      Yes
      • Sonveaux P.
      • Vegran F.
      • Schroeder T.
      • Wergin M.C.
      • Verrax J.
      • Rabbani Z.N.
      • De Saedeleer C.J.
      • Kennedy K.M.
      • Diepart C.
      • Jordan B.F.
      • Kelley M.J.
      • Gallez B.
      • Wahl M.L.
      • Feron O.
      • Dewhirst M.W.
      Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice.
      Yes
      • Sonveaux P.
      • Vegran F.
      • Schroeder T.
      • Wergin M.C.
      • Verrax J.
      • Rabbani Z.N.
      • De Saedeleer C.J.
      • Kennedy K.M.
      • Diepart C.
      • Jordan B.F.
      • Kelley M.J.
      • Gallez B.
      • Wahl M.L.
      • Feron O.
      • Dewhirst M.W.
      Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice.
      Increased
      • Wang R.
      • Dillon C.P.
      • Shi L.Z.
      • Milasta S.
      • Carter R.
      • Finkelstein D.
      • McCormick L.L.
      • Fitzgerald P.
      • Chi H.
      • Munger J.
      • Green D.R.
      The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation.
      Repressed by p53
      • Boidot R.
      • Vegran F.
      • Meulle A.
      • Le Breton A.
      • Dessy C.
      • Sonveaux P.
      • Lizard-Nacol S.
      • Feron O.
      Regulation of monocarboxylate transporter MCT1 expression by p53 mediates inward and outward lactate fluxes in tumors.
      Lactate secretionIncreased
      • Fantin V.R.
      • St-Pierre J.
      • Leder P.
      Attenuation of LDH-A expression uncovers a link between glycolysis, mitochondrial physiology, and tumor maintenance.
      Yes
      • Fantin V.R.
      • St-Pierre J.
      • Leder P.
      Attenuation of LDH-A expression uncovers a link between glycolysis, mitochondrial physiology, and tumor maintenance.
      • Shim H.
      • Dolde C.
      • Lewis B.C.
      • Wu C.S.
      • Dang G.
      • Jungmann R.A.
      • Dalla-Favera R.
      • Dang C.V.
      c-Myc transactivation of LDH-A: implications for tumor metabolism and growth.
      Increased
      • Frauwirth K.A.
      • Riley J.L.
      • Harris M.H.
      • Parry R.V.
      • Rathmell J.C.
      • Plas D.R.
      • Elstrom R.L.
      • June C.H.
      • Thompson C.B.
      The CD28 signaling pathway regulates glucose metabolism.
      Increased by MYC
      • Le A.
      • Lane A.N.
      • Hamaker M.
      • Bose S.
      • Gouw A.
      • Barbi J.
      • Tsukamoto T.
      • Rojas C.J.
      • Slusher B.S.
      • Zhang H.
      • Zimmerman L.J.
      • Liebler D.C.
      • Slebos R.J.
      • Lorkiewicz P.K.
      • Higashi R.M.
      • Fan T.W.
      • Dang C.V.
      Glucose-independent glutamine metabolism via TCA cycling for proliferation and survival in B cells.
      and repressed by p53
      • Matoba S.
      • Kang J.G.
      • Patino W.D.
      • Wragg A.
      • Boehm M.
      • Gavrilova O.
      • Hurley P.J.
      • Bunz F.
      • Hwang P.M.
      p53 Regulates mitochondrial respiration.
      ATP citrate lyaseIncreased
      • Wang Y.
      • Wang Y.
      • Shen L.
      • Pang Y.
      • Qiao Z.
      • Liu P.
      Prognostic and therapeutic implications of increased ATP citrate lyase expression in human epithelial ovarian cancer.
      Yes
      • Hatzivassiliou G.
      • Zhao F.
      • Bauer D.E.
      • Andreadis C.
      • Shaw A.N.
      • Dhanak D.
      • Hingorani S.R.
      • Tuveson D.A.
      • Thompson C.B.
      ATP citrate lyase inhibition can suppress tumor cell growth.
      Yes
      • Hatzivassiliou G.
      • Zhao F.
      • Bauer D.E.
      • Andreadis C.
      • Shaw A.N.
      • Dhanak D.
      • Hingorani S.R.
      • Tuveson D.A.
      • Thompson C.B.
      ATP citrate lyase inhibition can suppress tumor cell growth.
      Activated by AKT
      • Manning B.D.
      • Cantley L.C.
      AKT/PKB signaling: navigating downstream.
      Glutamine consumption/glutamine transportersIncreased
      • Hassanein M.
      • Hoeksema M.D.
      • Shiota M.
      • Qian J.
      • Harris B.K.
      • Chen H.
      • Clark J.E.
      • Alborn W.E.
      • Eisenberg R.
      • Massion P.P.
      SLC1A5 mediates glutamine transport required for lung cancer cell growth and survival.
      Increased
      • Brand K.
      Glutamine and glucose metabolism during thymocyte proliferation: pathways of glutamine and glutamate metabolism.
      • Wang R.
      • Dillon C.P.
      • Shi L.Z.
      • Milasta S.
      • Carter R.
      • Finkelstein D.
      • McCormick L.L.
      • Fitzgerald P.
      • Chi H.
      • Munger J.
      • Green D.R.
      The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation.
      • Carr E.L.
      • Kelman A.
      • Wu G.S.
      • Gopaul R.
      • Senkevitch E.
      • Aghvanyan A.
      • Turay A.M.
      • Frauwirth K.A.
      Glutamine uptake and metabolism are coordinately regulated by ERK/MAPK during T lymphocyte activation.
      Increased by MYC
      • Wise D.R.
      • DeBerardinis R.J.
      • Mancuso A.
      • Sayed N.
      • Zhang X.Y.
      • Pfeiffer H.K.
      • Nissim I.
      • Daikhin E.
      • Yudkoff M.
      • McMahon S.B.
      • Thompson C.B.
      Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction.
      GlutaminaseIncreased
      • Gao P.
      • Tchernyshyov I.
      • Chang T.C.
      • Lee Y.S.
      • Kita K.
      • Ochi T.
      • Zeller K.I.
      • De Marzo A.M.
      • Van Eyk J.E.
      • Mendell J.T.
      • Dang C.V.
      c-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism.
      Yes
      • Seltzer M.J.
      • Bennett B.D.
      • Joshi A.D.
      • Gao P.
      • Thomas A.G.
      • Ferraris D.V.
      • Tsukamoto T.
      • Rojas C.J.
      • Slusher B.S.
      • Rabinowitz J.D.
      • Dang C.V.
      • Riggins G.J.
      Inhibition of glutaminase preferentially slows growth of glioma cells with mutant IDH1.
      Yes
      • Le A.
      • Lane A.N.
      • Hamaker M.
      • Bose S.
      • Gouw A.
      • Barbi J.
      • Tsukamoto T.
      • Rojas C.J.
      • Slusher B.S.
      • Zhang H.
      • Zimmerman L.J.
      • Liebler D.C.
      • Slebos R.J.
      • Lorkiewicz P.K.
      • Higashi R.M.
      • Fan T.W.
      • Dang C.V.
      Glucose-independent glutamine metabolism via TCA cycling for proliferation and survival in B cells.
      • Seltzer M.J.
      • Bennett B.D.
      • Joshi A.D.
      • Gao P.
      • Thomas A.G.
      • Ferraris D.V.
      • Tsukamoto T.
      • Rojas C.J.
      • Slusher B.S.
      • Rabinowitz J.D.
      • Dang C.V.
      • Riggins G.J.
      Inhibition of glutaminase preferentially slows growth of glioma cells with mutant IDH1.
      Increased
      • Brand K.
      Glutamine and glucose metabolism during thymocyte proliferation: pathways of glutamine and glutamate metabolism.
      • Carr E.L.
      • Kelman A.
      • Wu G.S.
      • Gopaul R.
      • Senkevitch E.
      • Aghvanyan A.
      • Turay A.M.
      • Frauwirth K.A.
      Glutamine uptake and metabolism are coordinately regulated by ERK/MAPK during T lymphocyte activation.
      Increased by MYC
      • Gao P.
      • Tchernyshyov I.
      • Chang T.C.
      • Lee Y.S.
      • Kita K.
      • Ochi T.
      • Zeller K.I.
      • De Marzo A.M.
      • Van Eyk J.E.
      • Mendell J.T.
      • Dang C.V.
      c-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism.
      Glutamate dehydrogenaseYes
      • Qing G.
      • Li B.
      • Vu A.
      • Skuli N.
      • Walton Z.E.
      • Liu X.
      • Mayes P.A.
      • Wise D.R.
      • Thompson C.B.
      • Maris J.M.
      • Hogarty M.D.
      • Simon M.C.
      ATF4 regulates MYC-mediated neuroblastoma cell death upon glutamine deprivation.
      Yes
      • Qing G.
      • Li B.
      • Vu A.
      • Skuli N.
      • Walton Z.E.
      • Liu X.
      • Mayes P.A.
      • Wise D.R.
      • Thompson C.B.
      • Maris J.M.
      • Hogarty M.D.
      • Simon M.C.
      ATF4 regulates MYC-mediated neuroblastoma cell death upon glutamine deprivation.
      Increased
      • Carr E.L.
      • Kelman A.
      • Wu G.S.
      • Gopaul R.
      • Senkevitch E.
      • Aghvanyan A.
      • Turay A.M.
      • Frauwirth K.A.
      Glutamine uptake and metabolism are coordinately regulated by ERK/MAPK during T lymphocyte activation.
      Glutamate oxaloacetate transaminaseYes
      • Qing G.
      • Li B.
      • Vu A.
      • Skuli N.
      • Walton Z.E.
      • Liu X.
      • Mayes P.A.
      • Wise D.R.
      • Thompson C.B.
      • Maris J.M.
      • Hogarty M.D.
      • Simon M.C.
      ATF4 regulates MYC-mediated neuroblastoma cell death upon glutamine deprivation.
      Yes
      • Wise D.R.
      • DeBerardinis R.J.
      • Mancuso A.
      • Sayed N.
      • Zhang X.Y.
      • Pfeiffer H.K.
      • Nissim I.
      • Daikhin E.
      • Yudkoff M.
      • McMahon S.B.
      • Thompson C.B.
      Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction.
      • Qing G.
      • Li B.
      • Vu A.
      • Skuli N.
      • Walton Z.E.
      • Liu X.
      • Mayes P.A.
      • Wise D.R.
      • Thompson C.B.
      • Maris J.M.
      • Hogarty M.D.
      • Simon M.C.
      ATF4 regulates MYC-mediated neuroblastoma cell death upon glutamine deprivation.
      • Thornburg J.M.
      • Nelson K.K.
      • Clem B.F.
      • Lane A.N.
      • Arumugam S.
      • Simmons A.
      • Eaton J.W.
      • Telang S.
      • Chesney J.
      Targeting aspartate aminotransferase in breast cancer.
      Increased
      • Wang R.
      • Dillon C.P.
      • Shi L.Z.
      • Milasta S.
      • Carter R.
      • Finkelstein D.
      • McCormick L.L.
      • Fitzgerald P.
      • Chi H.
      • Munger J.
      • Green D.R.
      The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation.
      • Carr E.L.
      • Kelman A.
      • Wu G.S.
      • Gopaul R.
      • Senkevitch E.
      • Aghvanyan A.
      • Turay A.M.
      • Frauwirth K.A.
      Glutamine uptake and metabolism are coordinately regulated by ERK/MAPK during T lymphocyte activation.
      Oxidative phosphorylationMay increase
      • Rodriguez-Enriquez S.
      • Vital-Gonzalez P.A.
      • Flores-Rodriguez F.L.
      • Marin-Hernandez A.
      • Ruiz-Azuara L.
      • Moreno-Sanchez R.
      Control of cellular proliferation by modulation of oxidative phosphorylation in human and rodent fast-growing tumor cells.
      • Guppy M.
      • Leedman P.
      • Zu X.
      • Russell V.
      Contribution by different fuels and metabolic pathways to the total ATP turnover of proliferating MCF-7 breast cancer cells.
      • Moreno-Sanchez R.
      • Rodriguez-Enriquez S.
      • Saavedra E.
      • Marin-Hernandez A.
      • Gallardo-Perez J.C.
      The bioenergetics of cancer: is glycolysis the main ATP supplier in all tumor cells?.
      Yes
      • Moreno-Sanchez R.
      • Rodriguez-Enriquez S.
      • Saavedra E.
      • Marin-Hernandez A.
      • Gallardo-Perez J.C.
      The bioenergetics of cancer: is glycolysis the main ATP supplier in all tumor cells?.
      Yes
      • Moreno-Sanchez R.
      • Rodriguez-Enriquez S.
      • Saavedra E.
      • Marin-Hernandez A.
      • Gallardo-Perez J.C.
      The bioenergetics of cancer: is glycolysis the main ATP supplier in all tumor cells?.
      Increased
      • Hume D.A.
      • Radik J.L.
      • Ferber E.
      • Weidemann M.J.
      Aerobic glycolysis and lymphocyte transformation.
      Induced by MYC
      • Moreno-Sanchez R.
      • Rodriguez-Enriquez S.
      • Saavedra E.
      • Marin-Hernandez A.
      • Gallardo-Perez J.C.
      The bioenergetics of cancer: is glycolysis the main ATP supplier in all tumor cells?.
      and p53
      • Matoba S.
      • Kang J.G.
      • Patino W.D.
      • Wragg A.
      • Boehm M.
      • Gavrilova O.
      • Hurley P.J.
      • Bunz F.
      • Hwang P.M.
      p53 Regulates mitochondrial respiration.
      Cancer cell lines and tumors also reexpress the embryonic isoform (PKM2) of pyruvate kinase (PK).
      • Christofk H.R.
      • Vander Heiden M.G.
      • Harris M.H.
      • Ramanathan A.
      • Gerszten R.E.
      • Wei R.
      • Fleming M.D.
      • Schreiber S.L.
      • Cantley L.C.
      The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth.
      PKM2 is distinguished from other PK isoforms because it can associate with tyrosine-phosphorylated peptides,
      • Christofk H.R.
      • Vander Heiden M.G.
      • Wu N.
      • Asara J.M.
      • Cantley L.C.
      Pyruvate kinase M2 is a phosphotyrosine-binding protein.
      an association that results in a transition to a dimeric form with low affinity for its substrate, phosphoenolpyruvate.
      • Mazurek S.
      • Boschek C.B.
      • Hugo F.
      • Eigenbrodt E.
      Pyruvate kinase type M2 and its role in tumor growth and spreading.
      The less active PKM2 allows for a diversion of glycolytic metabolites to serine and glycine biosynthetic pathways.
      • Chaneton B.
      • Hillmann P.
      • Zheng L.
      • Martin A.C.
      • Maddocks O.D.
      • Chokkathukalam A.
      • Coyle J.E.
      • Jankevics A.
      • Holding F.P.
      • Vousden K.H.
      • Frezza C.
      • O’Reilly M.
      • Gottlieb E.
      Serine is a natural ligand and allosteric activator of pyruvate kinase M2.
      Phosphorylated PKM2 can also translocate to the nucleus, phosphorylate histone H3, and act as a transcriptional co-activator that induces expression of genes involved in glycolysis.
      • Luo W.
      • Hu H.
      • Chang R.
      • Zhong J.
      • Knabel M.
      • O’Meally R.
      • Cole R.N.
      • Pandey A.
      • Semenza G.L.
      Pyruvate kinase M2 is a PHD3-stimulated coactivator for hypoxia-inducible factor 1.
      The shunting of pyruvate to secreted lactate in tumors is associated with elevated levels of lactate dehydrogenase (LDH)
      • Magrath I.
      • Lee Y.J.
      • Anderson T.
      • Henle W.
      • Ziegler J.
      • Simon R.
      • Schein P.
      Prognostic factors in Burkitt’s lymphoma: importance of total tumor burden.
      and monocarboxylate transporters (MCTs) that cotransport lactate and a proton out of the cell.
      • Hao J.
      • Chen H.
      • Madigan M.C.
      • Cozzi P.J.
      • Beretov J.
      • Xiao W.
      • Delprado W.J.
      • Russell P.J.
      • Li Y.
      Co-expression of CD147 (EMMPRIN), CD44v3-10, MDR1 and monocarboxylate transporters is associated with prostate cancer drug resistance and progression.
      Elevated LDH levels have been discovered in Burkitt’s lymphoma
      • Magrath I.
      • Lee Y.J.
      • Anderson T.
      • Henle W.
      • Ziegler J.
      • Simon R.
      • Schein P.
      Prognostic factors in Burkitt’s lymphoma: importance of total tumor burden.
      and non-small cell lung cancer,
      • Koukourakis M.I.
      • Giatromanolaki A.
      • Sivridis E.
      • Bougioukas G.
      • Didilis V.
      • Gatter K.C.
      • Harris A.L.
      Lactate dehydrogenase-5 (LDH-5) overexpression in non-small-cell lung cancer tissues is linked to tumour hypoxia, angiogenic factor production and poor prognosis.
      whereas increased MCT levels have been detected in ovarian,
      • Chen H.
      • Wang L.
      • Beretov J.
      • Hao J.
      • Xiao W.
      • Li Y.
      Co-expression of CD147/EMMPRIN with monocarboxylate transporters and multiple drug resistance proteins is associated with epithelial ovarian cancer progression.
      prostate,
      • Hao J.
      • Chen H.
      • Madigan M.C.
      • Cozzi P.J.
      • Beretov J.
      • Xiao W.
      • Delprado W.J.
      • Russell P.J.
      • Li Y.
      Co-expression of CD147 (EMMPRIN), CD44v3-10, MDR1 and monocarboxylate transporters is associated with prostate cancer drug resistance and progression.
      gastric,
      • Pinheiro C.
      • Longatto-Filho A.
      • Simoes K.
      • Jacob C.E.
      • Bresciani C.J.
      • Zilberstein B.
      • Cecconello I.
      • Alves V.A.
      • Schmitt F.
      • Baltazar F.
      The prognostic value of CD147/EMMPRIN is associated with monocarboxylate transporter 1 co-expression in gastric cancer.
      and cervical
      • Pinheiro C.
      • Longatto-Filho A.
      • Pereira S.M.
      • Etlinger D.
      • Moreira M.A.
      • Jubé L.F.
      • Queiroz G.S.
      • Schmitt F.
      • Baltazar F.
      Monocarboxylate transporters 1 and 4 are associated with CD147 in cervical carcinoma.
      carcinomas. The shift of pyruvate toward lactate production and away from oxidative phosphorylation also reflects decreased activity of the pyruvate dehydrogenase complex, which can result from induction of the inhibitory pyruvate dehydrogenase kinases (PDKs).
      • Wigfield S.M.
      • Winter S.C.
      • Giatromanolaki A.
      • Taylor J.
      • Koukourakis M.L.
      • Harris A.L.
      PDK-1 regulates lactate production in hypoxia and is associated with poor prognosis in head and neck squamous cancer.
      There is substantial evidence that elevated glucose consumption and increased lactate secretion in tumors contribute to their growth. Patients with type 2 diabetes have high levels of blood glucose and an increased risk of developing cancers of the pancreas, liver, colon, gastrointestinal tract, breast, and endometrium.
      • Giovannucci E.
      • Harlan D.M.
      • Archer M.C.
      • Bergenstal R.M.
      • Gapstur S.M.
      • Habel L.A.
      • Pollak M.
      • Regensteiner J.G.
      • Yee D.
      Diabetes and cancer: a consensus report.
      Inhibiting expression of a glucose transporter GLUT1,
      • Rastogi S.
      • Banerjee S.
      • Chellappan S.
      • Simon G.R.
      Glut-1 antibodies induce growth arrest and apoptosis in human cancer cell lines.
      PKM2,
      • Goldberg M.S.
      • Sharp P.A.
      Pyruvate kinase M2-specific siRNA induces apoptosis and tumor regression.
      LDH,
      • Fantin V.R.
      • St-Pierre J.
      • Leder P.
      Attenuation of LDH-A expression uncovers a link between glycolysis, mitochondrial physiology, and tumor maintenance.
      or PDK
      • McFate T.
      • Mohyeldin A.
      • Lu H.
      • Thakar J.
      • Henriques J.
      • Halim N.D.
      • Wu H.
      • Schell M.J.
      • Tsang T.M.
      • Teahan O.
      • Zhou S.
      • Califano J.A.
      • Jeoung N.H.
      • Harris R.A.
      • Verma A.
      Pyruvate dehydrogenase complex activity controls metabolic and malignant phenotype in cancer cells.
      results in reduced tumorigenicity in xenograft models. Reducing the levels of 6-phosphofructo-2-kinase suppresses glycolytic flux, growth in soft agar, and tumor growth in mice.
      • Telang S.
      • Yalcin A.
      • Clem A.L.
      • Bucala R.
      • Lane A.N.
      • Eaton J.W.
      • Chesney J.
      Ras transformation requires metabolic control by 6-phosphofructo-2-kinase.
      Knocking down the β-catalytic subunit of the mitochondrial H+-ATP synthase results in a higher glycolytic rate and a more aggressive tumor-forming phenotype.
      • Sanchez-Arago M.
      • Chamorro M.
      • Cuezva J.M.
      Selection of cancer cells with repressed mitochondria triggers colon cancer progression.
      Taken together, these studies highlight the importance of the glycolytic phenotype for tumor progression.
      Multiple approaches to reducing glycolytic flux are being considered as potential cancer therapies (Figure 2 and Table 1). In one strategy, patients eat low-carbohydrate diets, thus starving their tumors of glucose, and it was shown to be promising in a recent pilot study.
      • Fine E.J.
      • Segal-Isaacson C.J.
      • Feinman R.D.
      • Herszkopf S.
      • Romano M.C.
      • Tomuta N.
      • Bontempo A.F.
      • Negassa A.
      • Sparano J.A.
      Targeting insulin inhibition as a metabolic therapy in advanced cancer: a pilot safety and feasibility dietary trial in 10 patients.
      Pharmacological approaches are also being attempted. Lonidamine, a derivative of indazole-3-carboxylic acid that inhibits hexokinase, reduces cancer cell proliferation, and sensitizes xenograft tumors to death by radiation and other compounds.
      • Kalia V.K.
      • Prabhakara S.
      • Narayanan V.
      Modulation of cellular radiation responses by 2-deoxy-D-glucose and other glycolytic inhibitors: implications for cancer therapy.
      An inhibitor of PFKFB3, 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one, decreases intracellular concentrations of fructose 2,6-bisphosphate, suppresses glucose uptake, reduces the growth of cells from multiple types of cancer in vitro, and inhibits the growth of established tumors in vivo.
      • Clem B.
      • Telang S.
      • Clem A.
      • Yalcin A.
      • Meier J.
      • Simmons A.
      • Rasku M.A.
      • Arumugam S.
      • Dean W.L.
      • Eaton J.
      • Lane A.
      • Trent J.O.
      • Chesney J.
      Small-molecule inhibition of 6-phosphofructo-2-kinase activity suppresses glycolytic flux and tumor growth.
      Dichloroacetate, a pyruvate mimetic that inhibits pyruvate dehydrogenase kinase, increases pyruvate dehydrogenase activity and the oxidation of glucose, reduces the proliferation of breast cancer cell lines, inhibits proliferation, and slows xenograft tumor growth.
      • Sun R.C.
      • Fadia M.
      • Dahlstrom J.E.
      • Parish C.R.
      • Board P.G.
      • Blackburn A.C.
      Reversal of the glycolytic phenotype by dichloroacetate inhibits metastatic breast cancer cell growth in vitro and in vivo.
      In a pilot study, dichloroacetate resulted in radiological regression in three of five patients with glioblastoma multiforme.
      • Michelakis E.D.
      • Sutendra G.
      • Dromparis P.
      • Webster L.
      • Haromy A.
      • Niven E.
      • Maguire C.
      • Gammer T.L.
      • Mackey J.R.
      • Fulton D.
      • Abdulkarim B.
      • McMurtry M.S.
      • Petruk K.C.
      Metabolic modulation of glioblastoma with dichloroacetate.
      In sum, there are substantial data to suggest that impeding glycolysis, or redirecting pyruvate toward oxidative pathways and away from its conversion to lactate, inhibits tumor growth.
      Figure thumbnail gr2
      Figure 2Metabolic approaches to treating cancer. Scheme shows some of the compounds being explored as anticancer agents and the metabolic reactions that they target. Red lines indicate inhibition; green lines, activation. BPTES, bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide; DHAP, dihydroxyacetone phosphate; GAP, glyceraldehyde 3-phosphate; GLS, glutamine synthetase; GOT, glutamate oxaloacetate transaminase; HK, hexokinase; MCT, monocarboxylate transporters; OAA, oxaloacetate; PD, pyruvate dehydrogenase; PEP, phosphoenolpyruvate; PK, pyruvate kinase.

       Glutamine Is the Major Anaplerotic Source for Cancer Cells

      Some cancer cells also run the TCA cycle in a pattern that distinguishes them from most non-transformed cells. In some cancer cells, pyruvate from glycolysis enters a truncated TCA cycle that ends as citrate is shuttled from the mitochondrial matrix to the cytosol.
      • Kroemer G.
      • Pouyssegur J.
      Tumor cell metabolism: cancer’s Achilles’ heel.
      Citrate is cleaved by ATP citrate lyase (ACL) to provide acetyl-CoA that can be used for fatty acid synthesis. Disruption of ACL impairs tumor growth.
      • Hatzivassiliou G.
      • Zhao F.
      • Bauer D.E.
      • Andreadis C.
      • Shaw A.N.
      • Dhanak D.
      • Hingorani S.R.
      • Tuveson D.A.
      • Thompson C.B.
      ATP citrate lyase inhibition can suppress tumor cell growth.
      This truncated TCA cycle results in a flow of metabolites out of the TCA cycle (cataplerosis) that needs to be balanced by an influx of metabolites (anaplerosis). In many cancer cells, glutamine fulfills this role: it is converted to glutamate and then to the TCA intermediate, α-ketoglutarate.
      • DeBerardinis R.J.
      • Mancuso A.
      • Daikhin E.
      • Nissim I.
      • Yudkoff M.
      • Wehrli S.
      • Thompson C.B.
      Beyond aerobic glycolysis: transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis.
      Although glucose is the precursor for 90% of secreted lactate in cancer cells, oxidative conversion of glutamine accounts for as much as 40% of TCA cycle intermediates
      • DeBerardinis R.J.
      • Mancuso A.
      • Daikhin E.
      • Nissim I.
      • Yudkoff M.
      • Wehrli S.
      • Thompson C.B.
      Beyond aerobic glycolysis: transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis.
      and ≥30% of the ATP generated.
      • Gao P.
      • Tchernyshyov I.
      • Chang T.C.
      • Lee Y.S.
      • Kita K.
      • Ochi T.
      • Zeller K.I.
      • De Marzo A.M.
      • Van Eyk J.E.
      • Mendell J.T.
      • Dang C.V.
      c-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism.
      • DeBerardinis R.J.
      • Mancuso A.
      • Daikhin E.
      • Nissim I.
      • Yudkoff M.
      • Wehrli S.
      • Thompson C.B.
      Beyond aerobic glycolysis: transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis.
      To meet the glutamine requirements, some cancer cells dramatically increase glutamine consumption through induction of glutamine transporters.
      • Hassanein M.
      • Hoeksema M.D.
      • Shiota M.
      • Qian J.
      • Harris B.K.
      • Chen H.
      • Clark J.E.
      • Alborn W.E.
      • Eisenberg R.
      • Massion P.P.
      SLC1A5 mediates glutamine transport required for lung cancer cell growth and survival.
      Cancer cells also induce enzymes that metabolize glutamine, such as glutaminases, that convert glutamine to glutamate (glutaminase1 and glutaminase C)
      • Gao P.
      • Tchernyshyov I.
      • Chang T.C.
      • Lee Y.S.
      • Kita K.
      • Ochi T.
      • Zeller K.I.
      • De Marzo A.M.
      • Van Eyk J.E.
      • Mendell J.T.
      • Dang C.V.
      c-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism.
      and glutamate oxaloacetate transaminases that convert glutamate to α-ketoglutarate.
      • Moreadith R.W.
      • Lehninger A.L.
      The pathways of glutamate and glutamine oxidation by tumor cell mitochondria: role of mitochondrial NAD(P)+-dependent malic enzyme.
      Glutamine withdrawal results in the death of some cancer cells,
      • Wise D.R.
      • DeBerardinis R.J.
      • Mancuso A.
      • Sayed N.
      • Zhang X.Y.
      • Pfeiffer H.K.
      • Nissim I.
      • Daikhin E.
      • Yudkoff M.
      • McMahon S.B.
      • Thompson C.B.
      Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction.
      which is surprising because glutamine is a nonessential amino acid that can be synthesized from glucose. The strict requirement of some tumors for glutamine makes glutaminolysis enzymes attractive anticancer targets. Glutaminase inhibitors, such as bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide, reduce cancer cell growth, transformation, and tumorigenesis.
      • Le A.
      • Lane A.N.
      • Hamaker M.
      • Bose S.
      • Gouw A.
      • Barbi J.
      • Tsukamoto T.
      • Rojas C.J.
      • Slusher B.S.
      • Zhang H.
      • Zimmerman L.J.
      • Liebler D.C.
      • Slebos R.J.
      • Lorkiewicz P.K.
      • Higashi R.M.
      • Fan T.W.
      • Dang C.V.
      Glucose-independent glutamine metabolism via TCA cycling for proliferation and survival in B cells.
      • Seltzer M.J.
      • Bennett B.D.
      • Joshi A.D.
      • Gao P.
      • Thomas A.G.
      • Ferraris D.V.
      • Tsukamoto T.
      • Rojas C.J.
      • Slusher B.S.
      • Rabinowitz J.D.
      • Dang C.V.
      • Riggins G.J.
      Inhibition of glutaminase preferentially slows growth of glioma cells with mutant IDH1.
      Transaminase inhibitors have also been suggested as anticancer agents because glutamine-derived carbons are more likely to enter the TCA cycle through transamination in cancer cells, whereas normal cells tend to rely more heavily on glutamate dehydrogenase.
      • Moreadith R.W.
      • Lehninger A.L.
      The pathways of glutamate and glutamine oxidation by tumor cell mitochondria: role of mitochondrial NAD(P)+-dependent malic enzyme.
      Transaminase inhibitor, aminooxyacetic acid, has a cytotoxic effect specifically on cancer cells,
      • Wise D.R.
      • DeBerardinis R.J.
      • Mancuso A.
      • Sayed N.
      • Zhang X.Y.
      • Pfeiffer H.K.
      • Nissim I.
      • Daikhin E.
      • Yudkoff M.
      • McMahon S.B.
      • Thompson C.B.
      Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction.
      • Qing G.
      • Li B.
      • Vu A.
      • Skuli N.
      • Walton Z.E.
      • Liu X.
      • Mayes P.A.
      • Wise D.R.
      • Thompson C.B.
      • Maris J.M.
      • Hogarty M.D.
      • Simon M.C.
      ATF4 regulates MYC-mediated neuroblastoma cell death upon glutamine deprivation.
      • Thornburg J.M.
      • Nelson K.K.
      • Clem B.F.
      • Lane A.N.
      • Arumugam S.
      • Simmons A.
      • Eaton J.W.
      • Telang S.
      • Chesney J.
      Targeting aspartate aminotransferase in breast cancer.
      with little effect on healthy cells.
      • Thornburg J.M.
      • Nelson K.K.
      • Clem B.F.
      • Lane A.N.
      • Arumugam S.
      • Simmons A.
      • Eaton J.W.
      • Telang S.
      • Chesney J.
      Targeting aspartate aminotransferase in breast cancer.
      Treatment with aminooxyacetic acid reduced the growth of breast cancer cells in a mouse xenograft model without any obvious dose-limiting toxicities.
      • Thornburg J.M.
      • Nelson K.K.
      • Clem B.F.
      • Lane A.N.
      • Arumugam S.
      • Simmons A.
      • Eaton J.W.
      • Telang S.
      • Chesney J.
      Targeting aspartate aminotransferase in breast cancer.

       Reevaluation of the Warburg Effect

      Warburg hypothesized that the shift from respiration to aerobic glycolysis in cancer cells reflects defective mitochondrial respiration.
      • Warburg O.
      On the origin of cancer cells.
      In support of this model, tumors tend to down-regulate the expression of genes involved in oxidative phosphorylation in general,
      • Simonnet H.
      • Alazard N.
      • Pfeiffer K.
      • Gallou C.
      • Beroud C.
      • Demont J.
      • Bouvier R.
      • Schagger H.
      • Godinot C.
      Low mitochondrial respiratory chain content correlates with tumor aggressiveness in renal cell carcinoma.
      and specifically, the β-F1 subunit of the ATP(synth)ase.
      • Lopez-Rios F.
      • Sanchez-Arago M.
      • Garcia-Garcia E.
      • Ortega A.D.
      • Berrendero J.R.
      • Pozo-Rodriguez F.
      • Lopez-Encuentra A.
      • Ballestin C.
      • Cuezva J.M.
      Loss of the mitochondrial bioenergetic capacity underlies the glucose avidity of carcinomas.
      In addition, mutations in mitochondrial DNA have been observed in multiple tumor types.
      • Chatterjee A.
      • Mambo E.
      • Sidransky D.
      Mitochondrial DNA mutations in human cancer.
      Furthermore, experiments in which the levels of mitochondrial components are modulated have largely reinforced the importance of the glycolytic phenotype for tumor growth in vivo.
      • Sanchez-Arago M.
      • Chamorro M.
      • Cuezva J.M.
      Selection of cancer cells with repressed mitochondria triggers colon cancer progression.
      Taken together, the findings of the functional importance of high glycolytic rates and mitochondrial abnormalities in tumors have contributed to the prevailing paradigm that tumors generate most of their ATP through glycolysis.
      However, this model is being reevaluated for several reasons. First, recent studies have indicated that some tumor cell lines do perform oxidative metabolism.
      • Rodriguez-Enriquez S.
      • Vital-Gonzalez P.A.
      • Flores-Rodriguez F.L.
      • Marin-Hernandez A.
      • Ruiz-Azuara L.
      • Moreno-Sanchez R.
      Control of cellular proliferation by modulation of oxidative phosphorylation in human and rodent fast-growing tumor cells.
      • Guppy M.
      • Leedman P.
      • Zu X.
      • Russell V.
      Contribution by different fuels and metabolic pathways to the total ATP turnover of proliferating MCF-7 breast cancer cells.
      • Sotgia F.
      • Martinez-Outschoorn U.E.
      • Pavlides S.
      • Howell A.
      • Pestell R.G.
      • Lisanti M.P.
      Understanding the Warburg effect and the prognostic value of stromal caveolin-1 as a marker of a lethal tumor microenvironment.
      In some studies, respiration actually increases in tumor mitochondria.
      • Rodriguez-Enriquez S.
      • Vital-Gonzalez P.A.
      • Flores-Rodriguez F.L.
      • Marin-Hernandez A.
      • Ruiz-Azuara L.
      • Moreno-Sanchez R.
      Control of cellular proliferation by modulation of oxidative phosphorylation in human and rodent fast-growing tumor cells.
      • Moreno-Sanchez R.
      • Rodriguez-Enriquez S.
      • Saavedra E.
      • Marin-Hernandez A.
      • Gallardo-Perez J.C.
      The bioenergetics of cancer: is glycolysis the main ATP supplier in all tumor cells?.
      In one study, glycolysis contributed 50% to 70% of ATP for some cancer cell lines, consistent with Warburg’s findings, but as little as 10% of cellular ATP in other cell lines.
      • Moreno-Sanchez R.
      • Rodriguez-Enriquez S.
      • Saavedra E.
      • Marin-Hernandez A.
      • Gallardo-Perez J.C.
      The bioenergetics of cancer: is glycolysis the main ATP supplier in all tumor cells?.
      Furthermore, there are studies that indicate that mitochondrial activity and oxidative phosphorylation support tumor growth.
      • Fogal V.
      • Richardson A.D.
      • Karmali P.P.
      • Scheffler I.E.
      • Smith J.W.
      • Ruoslahti E.
      Mitochondrial p32 protein is a critical regulator of tumor metabolism via maintenance of oxidative phosphorylation.
      • Yu M.
      • Shi Y.
      • Wei X.
      • Yang Y.
      • Zhou Y.
      • Hao X.
      • Zhang N.
      • Niu R.
      Depletion of mitochondrial DNA by ethidium bromide treatment inhibits the proliferation and tumorigenesis of T47D human breast cancer cells.
      In particular, overexpression of the mitochondrial citrate transporter has been shown to increase tumor growth in xenograft models, whereas inhibition of the mitochondrial citrate transporter, which enhances glycolysis, actually reduces tumor growth.
      • Catalina-Rodriguez O.
      • Kolukula V.K.
      • Tomita Y.
      • Preet A.
      • Palmieri F.
      • Wellstein A.
      • Byers S.
      • Giaccia A.J.
      • Glasgow E.
      • Albanese C.
      • Avantaggiati M.L.
      The mitochondrial citrate transporter, CIC, is essential for mitochondrial homeostasis.
      Further supporting such a model, some human and rodent tumors are susceptible to death induced by highly specific respiratory inhibitors.
      • Moreno-Sanchez R.
      • Rodriguez-Enriquez S.
      • Saavedra E.
      • Marin-Hernandez A.
      • Gallardo-Perez J.C.
      The bioenergetics of cancer: is glycolysis the main ATP supplier in all tumor cells?.
      The Warburg effect is also being reconsidered by investigators who have argued that some of the cells within a tumor actually consume, rather than secrete, lactate. Lactic acid recycling occurs in normal physiological conditions as contracting skeletal muscle supplies lactate to the liver. The liver uses gluconeogenesis to convert lactate back to glucose that is released into the bloodstream and absorbed by muscle, thus completing the Cori cycle. In the tumor microenvironment, oxidative tumor cells (eg, those near blood vessels) have been proposed to consume lactate secreted by tumor cells that are engaging in aerobic glycolysis.
      • Sonveaux P.
      • Vegran F.
      • Schroeder T.
      • Wergin M.C.
      • Verrax J.
      • Rabbani Z.N.
      • De Saedeleer C.J.
      • Kennedy K.M.
      • Diepart C.
      • Jordan B.F.
      • Kelley M.J.
      • Gallez B.
      • Wahl M.L.
      • Feron O.
      • Dewhirst M.W.
      Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice.
      Absorbed lactate can be converted to pyruvate and used to fuel oxidative phosphorylation in these well-oxygenated cells. The reliance of aerobic cells within a tumor on lactate as a fuel may preserve the available glucose for the hypoxic cells that strictly require it.
      • Sonveaux P.
      • Vegran F.
      • Schroeder T.
      • Wergin M.C.
      • Verrax J.
      • Rabbani Z.N.
      • De Saedeleer C.J.
      • Kennedy K.M.
      • Diepart C.
      • Jordan B.F.
      • Kelley M.J.
      • Gallez B.
      • Wahl M.L.
      • Feron O.
      • Dewhirst M.W.
      Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice.

       Metabolism of the Tumor Stroma

      It has also been proposed that cells within the host tissue, the stroma, and not the tumor cells, perform aerobic glycolysis. Stromal cells, for example, the fibroblasts, in the tumor microenvironment can actively support malignant transformation
      • Orimo A.
      • Gupta P.B.
      • Sgroi D.C.
      • Arenzana-Seisdedos F.
      • Delaunay T.
      • Naeem R.
      • Carey V.J.
      • Richardson A.L.
      • Weinberg R.A.
      Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion.
      and metastasis.
      • Karnoub A.E.
      • Dash A.B.
      • Vo A.P.
      • Sullivan A.
      • Brooks M.W.
      • Bell G.W.
      • Richardson A.L.
      • Polyak K.
      • Tubo R.
      • Weinberg R.A.
      Mesenchymal stem cells within tumour stroma promote breast cancer metastasis.
      A hypothesis has been proposed that the tumor stroma is glycolytic and that stromal cells express MCTs that exude lactate, whereas tumor cells perform oxidative metabolism and express transporters that consume lactate.
      • Whitaker-Menezes D.
      • Martinez-Outschoorn U.E.
      • Flomenberg N.
      • Birbe R.C.
      • Witkiewicz A.K.
      • Howell A.
      • Pavlides S.
      • Tsirigos A.
      • Ertel A.
      • Pestell R.G.
      • Broda P.
      • Minetti C.
      • Lisanti M.P.
      • Sotgia F.
      Hyperactivation of oxidative mitochondrial metabolism in epithelial cancer cells in situ: visualizing the therapeutic effects of metformin in tumor tissue.
      • Martinez-Outschoorn U.E.
      • Pestell R.G.
      • Howell A.
      • Tykocinski M.L.
      • Nagajyothi F.
      • Machado F.S.
      • Tanowitz H.B.
      • Sotgia F.
      • Lisanti M.P.
      Energy transfer in “parasitic” cancer metabolism: mitochondria are the powerhouse and Achilles’ heel of tumor cells.
      The proposed model is that tumor growth is fueled by lactate, ketones, and glutamine provided by stromal cells that are then absorbed by cancer cells and used for oxidative phosphorylation. It has been further suggested that the PET avidity observed by tumors reflects 2-deoxy-glucose uptake by nearby stromal and inflammatory cells rather than the cancer cells themselves.
      • Sotgia F.
      • Martinez-Outschoorn U.E.
      • Pavlides S.
      • Howell A.
      • Pestell R.G.
      • Lisanti M.P.
      Understanding the Warburg effect and the prognostic value of stromal caveolin-1 as a marker of a lethal tumor microenvironment.
      This model has been called the reverse Warburg effect because the increased glycolysis occurs in the surrounding stromal cells, rather than the tumor cells.
      • Martinez-Outschoorn U.E.
      • Pestell R.G.
      • Howell A.
      • Tykocinski M.L.
      • Nagajyothi F.
      • Machado F.S.
      • Tanowitz H.B.
      • Sotgia F.
      • Lisanti M.P.
      Energy transfer in “parasitic” cancer metabolism: mitochondria are the powerhouse and Achilles’ heel of tumor cells.
      From this perspective, cancer is viewed as a parasitic disease that steals energy-rich metabolites from the host organism.
      • Martinez-Outschoorn U.E.
      • Pestell R.G.
      • Howell A.
      • Tykocinski M.L.
      • Nagajyothi F.
      • Machado F.S.
      • Tanowitz H.B.
      • Sotgia F.
      • Lisanti M.P.
      Energy transfer in “parasitic” cancer metabolism: mitochondria are the powerhouse and Achilles’ heel of tumor cells.
      • Martinez-Outschoorn U.E.
      • Pavlides S.
      • Howell A.
      • Pestell R.G.
      • Tanowitz H.B.
      • Sotgia F.
      • Lisanti M.P.
      Stromal-epithelial metabolic coupling in cancer: integrating autophagy and metabolism in the tumor microenvironment.
      • Martinez-Outschoorn U.E.
      • Balliet R.M.
      • Rivadeneira D.B.
      • Chiavarina B.
      • Pavlides S.
      • Wang C.
      • Whitaker-Menezes D.
      • Daumer K.M.
      • Lin Z.
      • Witkiewicz A.K.
      • Flomenberg N.
      • Howell A.
      • Pestell R.G.
      • Knudsen E.S.
      • Sotgia F.
      • Lisanti M.P.
      Oxidative stress in cancer associated fibroblasts drives tumor-stroma co-evolution: a new paradigm for understanding tumor metabolism, the field effect and genomic instability in cancer cells.

       Summary of Molecular Mechanisms of Cancer Metabolism

      In summary, although studies have recently questioned the glucose flux paradigm,
      • Catalina-Rodriguez O.
      • Kolukula V.K.
      • Tomita Y.
      • Preet A.
      • Palmieri F.
      • Wellstein A.
      • Byers S.
      • Giaccia A.J.
      • Glasgow E.
      • Albanese C.
      • Avantaggiati M.L.
      The mitochondrial citrate transporter, CIC, is essential for mitochondrial homeostasis.
      • Martinez-Outschoorn U.E.
      • Pestell R.G.
      • Howell A.
      • Tykocinski M.L.
      • Nagajyothi F.
      • Machado F.S.
      • Tanowitz H.B.
      • Sotgia F.
      • Lisanti M.P.
      Energy transfer in “parasitic” cancer metabolism: mitochondria are the powerhouse and Achilles’ heel of tumor cells.
      the prevailing model is that there is higher flux of glucose through most metabolic pathways in tumor cells compared with normal cells. More glucose is transmitted to metabolic intermediates, lactate, citrate, and fatty acid synthase, and possibly even more to oxidative phosphorylation.
      • Kroemer G.
      • Pouyssegur J.
      Tumor cell metabolism: cancer’s Achilles’ heel.
      Meeting all of these conditions would seem to require a large increase in glucose uptake in tumors. PET imaging has confirmed the increased glucose consumption in many, but not all, tumors, and glucose consumption rates exceed the amounts that can be easily explained by needs for energy or metabolites.
      • Czernin J.
      • Phelps M.E.
      Positron emission tomography scanning: current and future applications.
      Glutamine consumption follows a similar pattern of excess consumption.
      • DeBerardinis R.J.
      • Mancuso A.
      • Daikhin E.
      • Nissim I.
      • Yudkoff M.
      • Wehrli S.
      • Thompson C.B.
      Beyond aerobic glycolysis: transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis.
      We consider now the mechanisms that enforce this metabolic shift and possible explanations for its occurrence.

      Oncogenes and Tumor Suppressors Enforce the Metabolic Shift

      The key to understanding the mechanism(s) affecting changes in metabolism in tumors lies in the discovery that oncogenes and tumor suppressors consistently activated or deleted in tumors are important regulators of metabolism.
      • Kroemer G.
      • Pouyssegur J.
      Tumor cell metabolism: cancer’s Achilles’ heel.
      • Vander Heiden M.G.
      • Cantley L.C.
      • Thompson C.B.
      Understanding the Warburg effect: the metabolic requirements of cell proliferation.
      The oncogenic molecules AKT, MYC, and hypoxia-inducible factor-1 (HIF-1) can all contribute to the metabolic shift that occurs during carcinogenesis (Figure 3 and Table 1), whereas the tumor suppressor p53 acts to minimize the glycolytic phenotype and its loss contributes to aerobic glycolysis and the tumor metabolic phenotype. In tumors, multiple oncogenic mutations likely cooperate with each other to result in a phenotype in which cells absorb nutrients to meet or even exceed the bioenergetic demands of cell growth and proliferation.
      Figure thumbnail gr3
      Figure 3Metabolic effects of oncogenes and tumor suppressors. Scheme shows the metabolic reactions in central carbon metabolism affected by AKT (orange), MYC (blue), HIF (green) and p53 (red). Arrows indicate activation; lines, repression. DHAP, dihydroxyacetone phosphate; GAP, glyceraldehyde 3-phosphate; GDH, glutamate dehydrogenase; GLS, glutamine synthetase; HK, hexokinase; KG, α-ketoglutarate; LDH, lactate dehydrogenase; OAA, oxaloacetate; PEP, phosphoenolpyruvate.

       PI3K/AKT

      In non-transformed cells, the phosphatidyl inositol-3-kinase (PI3K) pathway is activated in response to growth signals.
      • Frauwirth K.A.
      • Riley J.L.
      • Harris M.H.
      • Parry R.V.
      • Rathmell J.C.
      • Plas D.R.
      • Elstrom R.L.
      • June C.H.
      • Thompson C.B.
      The CD28 signaling pathway regulates glucose metabolism.
      In a sizable fraction of all cancers, the PI3K pathway is constitutively activated through mutation or amplification,
      • Shaw R.J.
      • Cantley L.C.
      Ras, PI(3)K and mTOR signalling controls tumour cell growth.
      resulting in constitutive activation of AKT kinase and a growth-promoting metabolic program. AKT activation increases the glycolytic rate, in part by increasing GLUT1 expression
      • Frauwirth K.A.
      • Riley J.L.
      • Harris M.H.
      • Parry R.V.
      • Rathmell J.C.
      • Plas D.R.
      • Elstrom R.L.
      • June C.H.
      • Thompson C.B.
      The CD28 signaling pathway regulates glucose metabolism.
      and translocation of GLUT1 to the plasma membrane.
      • Jacobs S.R.
      • Herman C.E.
      • Maciver N.J.
      • Wofford J.A.
      • Wieman H.L.
      • Hammen J.J.
      • Rathmell J.C.
      Glucose uptake is limiting in T cell activation and requires CD28-mediated Akt-dependent and independent pathways.
      AKT causes the glycolytic enzyme, hexokinase, to associate with the mitochondrial outer membrane.
      • Kim J.W.
      • Gao P.
      • Liu Y.C.
      • Semenza G.L.
      • Dang C.V.
      Hypoxia-inducible factor 1 and dysregulated c-Myc cooperatively induce vascular endothelial growth factor and metabolic switches hexokinase 2 and pyruvate dehydrogenase kinase 1.
      AKT also performs an activating phosphorylation of PFK that releases its inhibition by ATP.
      • Deprez J.
      • Vertommen D.
      • Alessi D.R.
      • Hue L.
      • Rider M.H.
      Phosphorylation and activation of heart 6-phosphofructo-2-kinase by protein kinase B and other protein kinases of the insulin signaling cascades.
      Finally, AKT promotes the conversion of citrate to fatty acids by phosphorylating and activating ACL.
      • Manning B.D.
      • Cantley L.C.
      AKT/PKB signaling: navigating downstream.
      By simultaneously reducing the expression of carnitine palmitoyltransferase 1A,
      • Deberardinis R.J.
      • Lum J.J.
      • Thompson C.B.
      Phosphatidylinositol 3-kinase-dependent modulation of carnitine palmitoyltransferase 1A expression regulates lipid metabolism during hematopoietic cell growth.
      an enzyme that initiates the esterification and breakdown of long-chain fatty acids, AKT may eliminate a potential nutrient source and contribute to the glucose addiction of some cancer cells. Thus, activation of the PI3K/AKT pathway can be a powerful mechanism for altered tumor cell metabolism.

       MYC

      Deregulated expression of c-MYC, an early serum response transcription factor, is one of the most common oncogenic events in cancer.
      • Nesbit C.E.
      • Tersak J.M.
      • Prochownik E.V.
      MYC oncogenes and human neoplastic disease.
      Although MYC has well-established roles in the regulation of cell proliferation, differentiation, and apoptosis, MYC also drives the accumulation of cellular biomass by regulating nucleotide biosynthesis, ribosome and mitochondrial biogenesis, and metabolism.
      • Miller D.M.
      • Thomas S.D.
      • Islam A.
      • Muench D.
      • Sedoris K.
      c-Myc and cancer metabolism.
      In an MYC-inducible human Burkitt’s lymphoma model, glucose consumption, lactate production, glutamine uptake, and glutamine incorporation into the TCA cycle were all induced by MYC.
      • Le A.
      • Lane A.N.
      • Hamaker M.
      • Bose S.
      • Gouw A.
      • Barbi J.
      • Tsukamoto T.
      • Rojas C.J.
      • Slusher B.S.
      • Zhang H.
      • Zimmerman L.J.
      • Liebler D.C.
      • Slebos R.J.
      • Lorkiewicz P.K.
      • Higashi R.M.
      • Fan T.W.
      • Dang C.V.
      Glucose-independent glutamine metabolism via TCA cycling for proliferation and survival in B cells.
      • Osthus R.C.
      • Shim H.
      • Kim S.
      • Li Q.
      • Reddy R.
      • Mukherjee M.
      • Xu Y.
      • Wonsey D.
      • Lee L.A.
      • Dang C.V.
      Deregulation of glucose transporter 1 and glycolytic gene expression by c-Myc.
      • Shim H.
      • Dolde C.
      • Lewis B.C.
      • Wu C.S.
      • Dang G.
      • Jungmann R.A.
      • Dalla-Favera R.
      • Dang C.V.
      c-Myc transactivation of LDH-A: implications for tumor metabolism and growth.
      The induction of LDH by MYC has been specifically demonstrated to be functionally important for tumor growth, because MYC-dependent tumors exhibit reduced proliferative capacity and ability to grow in soft agar when LDH expression is reduced.
      • Shim H.
      • Dolde C.
      • Lewis B.C.
      • Wu C.S.
      • Dang G.
      • Jungmann R.A.
      • Dalla-Favera R.
      • Dang C.V.
      c-Myc transactivation of LDH-A: implications for tumor metabolism and growth.
      MYC also promotes glutamine metabolism by inducing the expression of glutamine transporters
      • Wise D.R.
      • DeBerardinis R.J.
      • Mancuso A.
      • Sayed N.
      • Zhang X.Y.
      • Pfeiffer H.K.
      • Nissim I.
      • Daikhin E.
      • Yudkoff M.
      • McMahon S.B.
      • Thompson C.B.
      Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction.
      and by up-regulating levels of glutaminase indirectly via repression of the miRNA miR-23.
      • Gao P.
      • Tchernyshyov I.
      • Chang T.C.
      • Lee Y.S.
      • Kita K.
      • Ochi T.
      • Zeller K.I.
      • De Marzo A.M.
      • Van Eyk J.E.
      • Mendell J.T.
      • Dang C.V.
      c-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism.
      As a result, some MYC-transformed cells have an absolute requirement for glutamine to maintain continuous replenishment of TCA cycle intermediates.
      • Le A.
      • Lane A.N.
      • Hamaker M.
      • Bose S.
      • Gouw A.
      • Barbi J.
      • Tsukamoto T.
      • Rojas C.J.
      • Slusher B.S.
      • Zhang H.
      • Zimmerman L.J.
      • Liebler D.C.
      • Slebos R.J.
      • Lorkiewicz P.K.
      • Higashi R.M.
      • Fan T.W.
      • Dang C.V.
      Glucose-independent glutamine metabolism via TCA cycling for proliferation and survival in B cells.
      • Wise D.R.
      • DeBerardinis R.J.
      • Mancuso A.
      • Sayed N.
      • Zhang X.Y.
      • Pfeiffer H.K.
      • Nissim I.
      • Daikhin E.
      • Yudkoff M.
      • McMahon S.B.
      • Thompson C.B.
      Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction.
      • Yuneva M.
      • Zamboni N.
      • Oefner P.
      • Sachidanandam R.
      • Lazebnik Y.
      Deficiency in glutamine but not glucose induces MYC-dependent apoptosis in human cells.

       HIF

      The oxygen-sensitive HIF-1 transcription factor is a heterodimer composed of constitutively expressed β subunits and oxygen-sensitive α subunits.
      • Kaelin Jr., W.G.
      • Ratcliffe P.J.
      Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway.
      In well-oxygenated cells, HIF-1α is hydroxylated, which facilitates its ubiquitination and degradation by the proteasome. In hypoxic conditions, HIF-1 is stabilized and activated. During tumorigenesis, localized hypoxic regions in which HIF-1 is stabilized may develop. This results in the expression of HIF-1 target genes, such as angiogenesis factors that increase oxygen delivery to hypoxic tissues.
      • Moreno-Sanchez R.
      • Rodriguez-Enriquez S.
      • Saavedra E.
      • Marin-Hernandez A.
      • Gallardo-Perez J.C.
      The bioenergetics of cancer: is glycolysis the main ATP supplier in all tumor cells?.
      HIF-1 also facilitates the activation of an oxygen-independent mode of energy extraction (ie, glycolysis in oxygen-deprived cancer cells by inducing many enzymes in the glycolytic pathway).
      • Mathupala S.P.
      • Rempel A.
      • Pedersen P.L.
      Glucose catabolism in cancer cells: identification and characterization of a marked activation response of the type II hexokinase gene to hypoxic conditions.
      HIF-1α also promotes aerobic glycolysis by transcriptionally inducing PDK,
      • Kim J.W.
      • Tchernyshyov I.
      • Semenza G.L.
      • Dang C.V.
      HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia.
      thus reducing the oxidative stress expected to occur if the electron transport chain were active. Hypoxic tumors, which induce HIF-1 and glycolysis most strongly, tend to be more invasive and metastatic than those with normal oxygen levels.
      • Keunen O.
      • Johansson M.
      • Oudin A.
      • Sanzey M.
      • Rahim S.A.
      • Fack F.
      • Thorsen F.
      • Taxt T.
      • Bartos M.
      • Jirik R.
      • Miletic H.
      • Wang J.
      • Stieber D.
      • Stuhr L.
      • Moen I.
      • Rygh C.B.
      • Bjerkvig R.
      • Niclou S.P.
      Anti-VEGF treatment reduces blood supply and increases tumor cell invasion in glioblastoma.
      Furthermore, high HIF-1 is associated with higher mortality.
      • Semenza G.L.
      Defining the role of hypoxia-inducible factor 1 in cancer biology and therapeutics.
      Thus, hypoxia experienced by tumors promotes HIF-1 expression, which, in turn, coordinates a transition to an aerobic glycolytic phenotype.

       p53

      The p53 tumor suppressor is also being reconsidered from a metabolic perspective. The role of p53 in orchestrating cell cycle arrest, apoptosis, or senescence in response to DNA damage or cellular stress has been thought to explain its role as a tumor suppressor.
      • Vousden K.H.
      • Prives C.
      Blinded by the light: the growing complexity of p53.
      More recently, p53, like MYC, has been discovered to be an important regulator of cellular metabolism. p53−/− Cells have higher rates of glycolysis, produce more lactate, and exhibit decreased mitochondrial respiration compared with wild-type cells,
      • Matoba S.
      • Kang J.G.
      • Patino W.D.
      • Wragg A.
      • Boehm M.
      • Gavrilova O.
      • Hurley P.J.
      • Bunz F.
      • Hwang P.M.
      p53 Regulates mitochondrial respiration.
      indicating that wild-type p53 suppresses an aerobic glycolysis phenotype. p53 Functions that might enforce these metabolic changes include down-regulation of glucose transporters,
      • Schwartzenberg-Bar-Yoseph F.
      • Armoni M.
      • Karnieli E.
      The tumor suppressor p53 down-regulates glucose transporters GLUT1 and GLUT4 gene expression.
      up-regulation of a fructose-bisphosphate-phosphatase that lowers levels of fructose 2,6-bisphosphate,
      • Bensaad K.
      • Tsuruta A.
      • Selak M.A.
      • Vidal M.N.
      • Nakano K.
      • Bartrons R.
      • Gottlieb E.
      • Vousden K.H.
      TIGAR, a p53-inducible regulator of glycolysis and apoptosis.
      repression of lactate transporters,
      • Boidot R.
      • Vegran F.
      • Meulle A.
      • Le Breton A.
      • Dessy C.
      • Sonveaux P.
      • Lizard-Nacol S.
      • Feron O.
      Regulation of monocarboxylate transporter MCT1 expression by p53 mediates inward and outward lactate fluxes in tumors.
      repression of PDKs,
      • Contractor T.
      • Harris C.R.
      p53 negatively regulates transcription of the pyruvate dehydrogenase kinase Pdk2.
      induction of the mitochondrial oxidation regulator, synthesis of cytochrome c oxidase 2,
      • Matoba S.
      • Kang J.G.
      • Patino W.D.
      • Wragg A.
      • Boehm M.
      • Gavrilova O.
      • Hurley P.J.
      • Bunz F.
      • Hwang P.M.
      p53 Regulates mitochondrial respiration.
      and competition with HIF-1 for limiting amounts of a shared transcriptional co-activator.
      • Schmid T.
      • Zhou J.
      • Kohl R.
      • Brune B.
      p300 relieves p53-evoked transcriptional repression of hypoxia-inducible factor-1 (HIF-1).
      A recent article has critically tested the importance of the role of p53 in metabolism in the prevention of tumorigenesis. Cells with three p53 lysine mutations (p533KR) lack the normal functions of p53 in cell-cycle arrest, senescence, or apoptosis, but retain the ability to suppress glycolytic rates and maintain low reactive oxygen species (ROS) levels.
      • Li T.
      • Kon N.
      • Jiang L.
      • Tan M.
      • Ludwig T.
      • Zhao Y.
      • Baer R.
      • Gu W.
      Tumor suppression in the absence of p53-mediated cell-cycle arrest, apoptosis, and senescence.
      Although p53-null mice rapidly develop thymic lymphomas leading to death, surprisingly, p533KR/3KR mice do not exhibit early-onset tumor formation.
      • Li T.
      • Kon N.
      • Jiang L.
      • Tan M.
      • Ludwig T.
      • Zhao Y.
      • Baer R.
      • Gu W.
      Tumor suppression in the absence of p53-mediated cell-cycle arrest, apoptosis, and senescence.
      These findings suggest that less conventional functions of p53, such as inhibiting the metabolic shift to aerobic glycolysis and reducing ROS levels, are critical for the ability of p53 to suppress early-onset spontaneous tumorigenesis.
      The studies previously described demonstrate that p53 can modulate metabolism. Recent studies have shown that the availability of carbohydrates can, in turn, affect p53 levels. Glucose restriction has been reported to specifically induce deacetylation and degradation of mutant, but not wild-type, p53 both in vitro and in vivo.
      • Rodriguez O.C.
      • Choudhury S.
      • Kolukula V.
      • Vietsch E.E.
      • Catania J.
      • Preet A.
      • Reynoso K.
      • Bargonetti J.
      • Wellstein A.
      • Albanese C.
      • Avantaggiati M.L.
      Dietary downregulation of mutant p53 levels via glucose restriction: mechanisms and implications for tumor therapy.
      • Moon S.H.
      • Prives C.
      Mutant p53 succumbs to starvation.
      Because wild-type p53 inhibits tumor growth and mutant forms of p53 can promote tumorigenesis,
      • Brosh R.
      • Rotter V.
      When mutants gain new powers: news from the mutant p53 field.
      the findings suggest that there may be reciprocal regulation between diet and metabolism on the one hand, and p53 status on the other, that affects tumor growth.

      Cancer Metabolic Phenotype

       Activated Lymphocytes Share Metabolic Properties with Cancer Cells

      The metabolic program of cancer cells, although different from that of most normal, differentiated cells, shares significant similarities with some proliferating cells, including activated lymphocytes. Mature, resting lymphocytes rely on oxidative metabolism of glucose and glutamine for the energetic needs.
      • Wang R.
      • Dillon C.P.
      • Shi L.Z.
      • Milasta S.
      • Carter R.
      • Finkelstein D.
      • McCormick L.L.
      • Fitzgerald P.
      • Chi H.
      • Munger J.
      • Green D.R.
      The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation.
      Recognition of their corresponding antigen results in activation of the lymphocytes and is accompanied by a dramatic shift in metabolism.
      • Altman B.J.
      • Dang C.V.
      Normal and cancer cell metabolism: lymphocytes and lymphoma.
      Activated lymphocytes increase in size, divide rapidly, consume glucose and glutamine in excess of what can be easily explained by their need for biosynthesis or ATP, and secrete the extraneous material as lactate.
      • Frauwirth K.A.
      • Riley J.L.
      • Harris M.H.
      • Parry R.V.
      • Rathmell J.C.
      • Plas D.R.
      • Elstrom R.L.
      • June C.H.
      • Thompson C.B.
      The CD28 signaling pathway regulates glucose metabolism.
      • Brand K.
      Glutamine and glucose metabolism during thymocyte proliferation: pathways of glutamine and glutamate metabolism.
      • Hume D.A.
      • Radik J.L.
      • Ferber E.
      • Weidemann M.J.
      Aerobic glycolysis and lymphocyte transformation.
      Many of the molecular changes that occur when lymphocytes are activated are similar to those that occur in tumors, including increased activity of glucose transporters,
      • Frauwirth K.A.
      • Riley J.L.
      • Harris M.H.
      • Parry R.V.
      • Rathmell J.C.
      • Plas D.R.
      • Elstrom R.L.
      • June C.H.
      • Thompson C.B.
      The CD28 signaling pathway regulates glucose metabolism.
      • Jacobs S.R.
      • Herman C.E.
      • Maciver N.J.
      • Wofford J.A.
      • Wieman H.L.
      • Hammen J.J.
      • Rathmell J.C.
      Glucose uptake is limiting in T cell activation and requires CD28-mediated Akt-dependent and independent pathways.
      glycolytic enzymes,
      • Brand K.
      Glutamine and glucose metabolism during thymocyte proliferation: pathways of glutamine and glutamate metabolism.
      • Wang R.
      • Dillon C.P.
      • Shi L.Z.
      • Milasta S.
      • Carter R.
      • Finkelstein D.
      • McCormick L.L.
      • Fitzgerald P.
      • Chi H.
      • Munger J.
      • Green D.R.
      The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation.
      PFKFBP3,
      • Telang S.
      • Clem B.F.
      • Klarer A.C.
      • Clem A.L.
      • Trent J.O.
      • Bucala R.
      • Chesney J.
      Small molecule inhibition of 6-phosphofructo-2-kinase suppresses T cell activation.
      lactate dehydrogenase,
      • Wang R.
      • Dillon C.P.
      • Shi L.Z.
      • Milasta S.
      • Carter R.
      • Finkelstein D.
      • McCormick L.L.
      • Fitzgerald P.
      • Chi H.
      • Munger J.
      • Green D.R.
      The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation.
      and MCTs.
      • Wang R.
      • Dillon C.P.
      • Shi L.Z.
      • Milasta S.
      • Carter R.
      • Finkelstein D.
      • McCormick L.L.
      • Fitzgerald P.
      • Chi H.
      • Munger J.
      • Green D.R.
      The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation.
      To compensate for the loss of citrate from the TCA cycle, glutamine consumption increases when lymphocytes are activated,
      • Brand K.
      Glutamine and glucose metabolism during thymocyte proliferation: pathways of glutamine and glutamate metabolism.
      • Carr E.L.
      • Kelman A.
      • Wu G.S.
      • Gopaul R.
      • Senkevitch E.
      • Aghvanyan A.
      • Turay A.M.
      • Frauwirth K.A.
      Glutamine uptake and metabolism are coordinately regulated by ERK/MAPK during T lymphocyte activation.
      and this is associated with higher levels of glutamine transporters
      • Brand K.
      Glutamine and glucose metabolism during thymocyte proliferation: pathways of glutamine and glutamate metabolism.
      • Wang R.
      • Dillon C.P.
      • Shi L.Z.
      • Milasta S.
      • Carter R.
      • Finkelstein D.
      • McCormick L.L.
      • Fitzgerald P.
      • Chi H.
      • Munger J.
      • Green D.R.
      The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation.
      • Carr E.L.
      • Kelman A.
      • Wu G.S.
      • Gopaul R.
      • Senkevitch E.
      • Aghvanyan A.
      • Turay A.M.
      • Frauwirth K.A.
      Glutamine uptake and metabolism are coordinately regulated by ERK/MAPK during T lymphocyte activation.
      and enzymes involved in glutaminolysis (Table 1).
      • Brand K.
      Glutamine and glucose metabolism during thymocyte proliferation: pathways of glutamine and glutamate metabolism.
      • Wang R.
      • Dillon C.P.
      • Shi L.Z.
      • Milasta S.
      • Carter R.
      • Finkelstein D.
      • McCormick L.L.
      • Fitzgerald P.
      • Chi H.
      • Munger J.
      • Green D.R.
      The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation.
      • Carr E.L.
      • Kelman A.
      • Wu G.S.
      • Gopaul R.
      • Senkevitch E.
      • Aghvanyan A.
      • Turay A.M.
      • Frauwirth K.A.
      Glutamine uptake and metabolism are coordinately regulated by ERK/MAPK during T lymphocyte activation.
      The increased glucose flux in activated lymphocytes also results in higher levels of oxidative phosphorylation.
      • Hume D.A.
      • Radik J.L.
      • Ferber E.
      • Weidemann M.J.
      Aerobic glycolysis and lymphocyte transformation.
      The similarity between the metabolic profile of tumor cells and activated lymphocytes suggests that this metabolic pattern and may be associated more generally with rapid cell division.

       Not All Proliferating Cells Use Aerobic Glycolysis

      In addition to lymphocytes, many fast-growing unicellular organisms, including the baker’s yeast Saccharomyces cerevisiae, rely on glucose fermentation during proliferation, even when oxygen is available.
      • Lunt S.Y.
      • Vander Heiden M.G.
      Aerobic glycolysis: meeting the metabolic requirements of cell proliferation.
      However, despite the similarities between tumors, activated lymphocytes, and fermenting yeast, respiration can sustain fast cell growth. Some tumor cells rely on oxidation to generate ATP,
      • Rodriguez-Enriquez S.
      • Vital-Gonzalez P.A.
      • Flores-Rodriguez F.L.
      • Marin-Hernandez A.
      • Ruiz-Azuara L.
      • Moreno-Sanchez R.
      Control of cellular proliferation by modulation of oxidative phosphorylation in human and rodent fast-growing tumor cells.
      • Guppy M.
      • Leedman P.
      • Zu X.
      • Russell V.
      Contribution by different fuels and metabolic pathways to the total ATP turnover of proliferating MCF-7 breast cancer cells.
      and some aerobic yeasts, such as Yarrowia lipolytica, rely on respiration for growth.
      • Christen S.
      • Sauer U.
      Intracellular characterization of aerobic glucose metabolism in seven yeast species by 13C flux analysis and metabolomics.
      Conversely, nondividing cells can preferentially rely on glycolysis. Hematopoietic stem cells, which are largely quiescent, have higher glycolytic activity, lower mitochondrial activity,
      • Simsek T.
      • Kocabas F.
      • Zheng J.
      • Deberardinis R.J.
      • Mahmoud A.I.
      • Olson E.N.
      • Schneider J.W.
      • Zhang C.C.
      • Sadek H.A.
      The distinct metabolic profile of hematopoietic stem cells reflects their location in a hypoxic niche.
      and higher PDK activity,
      • Takubo K.
      • Nagamatsu G.
      • Kobayashi C.I.
      • Nakamura-Ishizu A.
      • Kobayashi H.
      • Ikeda E.
      • Goda N.
      • Rahimi Y.
      • Johnson R.S.
      • Soga T.
      • Hirao A.
      • Suematsu M.
      • Suda T.
      Regulation of glycolysis by Pdk functions as a metabolic checkpoint for cell cycle quiescence in hematopoietic stem cells.
      compared with their more proliferative descendants. In a primary human fibroblast model system, a shift between proliferation and quiescence was not found to be associated with a dramatic difference in glycolytic rate.
      • Lemons J.M.
      • Feng X.J.
      • Bennett B.D.
      • Legesse-Miller A.
      • Johnson E.L.
      • Raitman I.
      • Pollina E.A.
      • Rabitz H.A.
      • Rabinowitz J.D.
      • Coller H.A.
      Quiescent fibroblasts exhibit high metabolic activity.
      Finally, recent studies report that the shift to glycolysis in lymphocytes is not necessary for proliferation or survival, but rather supports cytokine secretion.
      • Chang C.H.
      • Curtis J.D.
      • Maggi Jr., L.B.
      • Faubert B.
      • Villarino A.V.
      • O’Sullivan D.
      • Huang S.C.
      • van der Windt G.J.
      • Blagih J.
      • Qiu J.
      • Weber J.D.
      • Pearce E.J.
      • Jones R.G.
      • Pearce E.L.
      Posttranscriptional control of T cell effector function by aerobic glycolysis.
      Thus, in some model systems, the metabolic changes observed in tumors occur with a shift to a high proliferative rate, but this transition is not always observed when proliferative rate changes; even if it does occur, it may not facilitate faster proliferation.

      The Advantages of the Tumor Cell Metabolic Profile to the Tumor

       Rapid ATP

      Why is a less efficient catabolic pathway so strongly induced in tumor cells? One suggestion is that aerobic glycolysis is advantageous because it provides ATP more rapidly than oxidative phosphorylation.
      • Guppy M.
      • Leedman P.
      • Zu X.
      • Russell V.
      Contribution by different fuels and metabolic pathways to the total ATP turnover of proliferating MCF-7 breast cancer cells.
      However, some cancer cells actually recover a significant fraction of their ATP from oxidative phosphorylation.
      • Guppy M.
      • Leedman P.
      • Zu X.
      • Russell V.
      Contribution by different fuels and metabolic pathways to the total ATP turnover of proliferating MCF-7 breast cancer cells.
      Furthermore, it is not clear that ATP levels, or the speed which ATP can be extracted, is actually limiting for cellular growth.
      • Vander Heiden M.G.
      • Cantley L.C.
      • Thompson C.B.
      Understanding the Warburg effect: the metabolic requirements of cell proliferation.
      Even rapidly dividing mammalian cells have been found to maintain high ratios of ATP/ADP.
      • Christofk H.R.
      • Vander Heiden M.G.
      • Harris M.H.
      • Ramanathan A.
      • Gerszten R.E.
      • Wei R.
      • Fleming M.D.
      • Schreiber S.L.
      • Cantley L.C.
      The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth.
      And, signaling pathways exist that allow cells to increase low ATP levels by activating catabolic pathways that generate ATP.
      • Vander Heiden M.G.
      • Cantley L.C.
      • Thompson C.B.
      Understanding the Warburg effect: the metabolic requirements of cell proliferation.
      For these reasons, the rationale that cells shift to aerobic glycolysis to recover rapid ATP is being reconsidered, and other interpretations for the Warburg effect have been offered.

       Carbon Skeletons for Growth

      Although there may not be selective pressure for generating ATP, per se, one can imagine selective pressure for the rate of cellular proliferative expansion.
      • Vander Heiden M.G.
      • Cantley L.C.
      • Thompson C.B.
      Understanding the Warburg effect: the metabolic requirements of cell proliferation.
      Organisms in which immune cells can respond to the presence of invaders by rapidly mounting an immune response ought to be less likely to succumb to infection and, therefore, be more fit. Increased glycolysis in tumor cells provides a constant supply of metabolic intermediates that can be diverted to support cell growth.
      • Vander Heiden M.G.
      • Cantley L.C.
      • Thompson C.B.
      Understanding the Warburg effect: the metabolic requirements of cell proliferation.
      Furthermore, because glucose is one of the two main nutrients that the cell consumes, it is needed to provide all of the molecules necessary for cell growth.
      To make a fatty acyl chain, a single glucose molecule can provide five times the ATP required, whereas seven glucose molecules are needed to generate the necessary NADPH through the pentose phosphate pathway.
      • Vander Heiden M.G.
      • Cantley L.C.
      • Thompson C.B.
      Understanding the Warburg effect: the metabolic requirements of cell proliferation.
      If all of the available glucose were converted efficiently and completely to ATP in mitochondria, there would not be any glucose to provide acetyl-CoA to make fatty acids. There would also be no glucose available to divert from glycolysis for the synthesis of NADPH, nonessential amino acids, or ribose needed for generating nucleotides. Furthermore, complete oxidation of each glucose molecule would result in high ATP levels that would feedback and shut down glycolysis.
      • Vander Heiden M.G.
      • Cantley L.C.
      • Thompson C.B.
      Understanding the Warburg effect: the metabolic requirements of cell proliferation.
      The fact that rapidly proliferating lymphocytes and yeast also rely heavily on glycolysis over oxidative phosphorylation could support the argument that the cancer metabolism phenotype is the metabolic profile that channels glucose among the available pathways in a way that facilitates rapid proliferation and growth.
      • Lunt S.Y.
      • Vander Heiden M.G.
      Aerobic glycolysis: meeting the metabolic requirements of cell proliferation.
      But, one might reasonably wonder, if the goal of cancer cells is to increase their biomass, then why do they secrete and waste 90% of the glucose carbons they consume?
      • Hume D.A.
      • Radik J.L.
      • Ferber E.
      • Weidemann M.J.
      Aerobic glycolysis and lymphocyte transformation.
      • DeBerardinis R.J.
      • Mancuso A.
      • Daikhin E.
      • Nissim I.
      • Yudkoff M.
      • Wehrli S.
      • Thompson C.B.
      Beyond aerobic glycolysis: transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis.
      • Lunt S.Y.
      • Vander Heiden M.G.
      Aerobic glycolysis: meeting the metabolic requirements of cell proliferation.
      There are several possible explanations. One possibility is that the cell needs a high rate of flux through glycolysis to ensure that metabolic intermediates can be siphoned off to anabolic pathways without dramatically affecting the sizes of the metabolite pools.
      • Lunt S.Y.
      • Vander Heiden M.G.
      Aerobic glycolysis: meeting the metabolic requirements of cell proliferation.
      • Newsholme E.A.
      • Crabtree B.
      • Ardawi M.S.
      The role of high rates of glycolysis and glutamine utilization in rapidly dividing cells.
      Another important consideration is that achieving a high level of glycolytic flux actually requires NAD+ to be regenerated, which is achieved by converting pyruvate into lactate.
      • Lunt S.Y.
      • Vander Heiden M.G.
      Aerobic glycolysis: meeting the metabolic requirements of cell proliferation.
      Furthermore, the secreted lactate is not, in fact, lost. As previously described, aerobic tumor cells might absorb the extracellular lactate released by glycolytic cells, convert it to pyruvate, and use it as a fuel for mitochondrial oxidative phosphorylation.
      • Sonveaux P.
      • Vegran F.
      • Schroeder T.
      • Wergin M.C.
      • Verrax J.
      • Rabbani Z.N.
      • De Saedeleer C.J.
      • Kennedy K.M.
      • Diepart C.
      • Jordan B.F.
      • Kelley M.J.
      • Gallez B.
      • Wahl M.L.
      • Feron O.
      • Dewhirst M.W.
      Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice.

       Optimization of Fitness

      A somewhat different perspective is to view the Warburg effect as an extension of a pattern of metabolic pathway use that exists in simpler model organisms. As growth rate, cell size, and ribosomal content increase, there is often an associated shift toward metabolic pathways with less efficient energy recovery.
      • Molenaar D.
      • van Berlo R.
      • de Ridder D.
      • Teusink B.
      Shifts in growth strategies reflect tradeoffs in cellular economics.
      This has been interpreted as a tradeoff between two different catabolic pathways, one of which is more expensive to generate, but generates more ATP, and the other uses less enzyme, but produces less energy. At low extracellular substrate concentrations, intracellular substrate is expensive, so an efficient catabolic method is necessary. At higher substrate concentrations, however, the catabolic pathway that requires less energy to produce its components becomes more valuable. Thus, a pathway that seems wasteful in that all possible ATP is not recovered from each nutrient, may be cheap in terms of the resources needed to construct the pathway, and may actually be the more desirable pathway when cells are in a nutrient-rich environment. A logical extension of the argument to cancer cells might be to recognize that performing oxidative phosphorylation requires the generation and maintenance of entire organelles, the mitochondria, complete with their own genomes and ribosomes, and an expensive-to-maintain membrane potential. Respiration, from this perspective, is a costly catabolic path that requires a substantial investment, but is useful for efficiently extracting ATP when nutrients are scarce. When nutrients are abundant, the less resource-intensive process of glycolysis might be more desirable. Thus, if resources are not limiting, cells may benefit from engaging a cheap, but seemingly wasteful, metabolic program.
      Despite these cogent arguments, there are still unanswered questions about the metabolic phenotype of cancer cells. For instance, if the cancer cell phenotype is designed to facilitate cell growth, then why do cancer cell lines have higher glucose, lactate, and glutamine fluxes per unit area of cell membrane, higher hexokinase activity, and higher pentose phosphate pathway activity than nonmalignant cells growing at the same rate?
      • Meadows A.L.
      • Kong B.
      • Berdichevsky M.
      • Roy S.
      • Rosiva R.
      • Blanch H.W.
      • Clark D.S.
      Metabolic and morphological differences between rapidly proliferating cancerous and normal breast epithelial cells.
      Are other benefits conferred on the tumor by this metabolic strategy in addition to simply a faster growth rate?

       Minimizing ROS

      The use of aerobic glycolysis allows cells to expend less energy in the generation and maintenance of mitochondria and protects tumor cells from ROS that would be generated by performing oxidative phosphorylation in conditions of limited oxygen. In addition, both the glucose and the glutamine consumed by cancer cells can be metabolized to generate NADPH,
      • DeBerardinis R.J.
      • Mancuso A.
      • Daikhin E.
      • Nissim I.
      • Yudkoff M.
      • Wehrli S.
      • Thompson C.B.
      Beyond aerobic glycolysis: transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis.
      a necessary cofactor for the replenishment of the cell’s most important antioxidant, reduced glutathione. The importance of the pentose phosphate pathway and ROS detoxification in tumor cell growth was highlighted in a recent study in which hypoxia was found to induce glycosylation and inhibition of PFK, leading to redirection of glycolytic intermediates into the pentose phosphate pathway.
      • Yi W.
      • Clark P.M.
      • Mason D.E.
      • Keenan M.C.
      • Hill C.
      • Goddard 3rd, W.A.
      • Peters E.C.
      • Driggers E.M.
      • Hsieh-Wilson L.C.
      Phosphofructokinase 1 glycosylation regulates cell growth and metabolism.
      Blocking PFK glycosylation reduced cancer cell proliferation in vitro and impaired tumor formation in vivo. Thus, reducing ROS levels and protecting against ROS-mediated cell death may represent an advantage conferred by a Warburg effect metabolic phenotype.

       Protection against Apoptosis

      In addition to controlling ROS levels, the aerobic glycolysis phenotype of cancer cells may also protect them from apoptosis by inhibiting the release of pro-apoptotic factors from the mitochondria through the mitochondrial permeability transition pore. The ease with which this pore opens depends on the mitochondrial membrane potential generated as hydrogen ions are transferred out of the inner mitochondrial membrane during oxidative phosphorylation. The low flux through the electron transport chain in cancer cells results in mitochondria with higher membrane potential
      • Michelakis E.D.
      • Sutendra G.
      • Dromparis P.
      • Webster L.
      • Haromy A.
      • Niven E.
      • Maguire C.
      • Gammer T.L.
      • Mackey J.R.
      • Fulton D.
      • Abdulkarim B.
      • McMurtry M.S.
      • Petruk K.C.
      Metabolic modulation of glioblastoma with dichloroacetate.
      and a higher threshold for transition pore opening, thus suppressing apoptosis. If the hyperpolarization in cancer mitochondria is reversed by forcing pyruvate into the mitochondria, glucose oxidation increases, mitochondrial membrane potential decreases, and cancer cells undergo more cell death.
      • Michelakis E.D.
      • Sutendra G.
      • Dromparis P.
      • Webster L.
      • Haromy A.
      • Niven E.
      • Maguire C.
      • Gammer T.L.
      • Mackey J.R.
      • Fulton D.
      • Abdulkarim B.
      • McMurtry M.S.
      • Petruk K.C.
      Metabolic modulation of glioblastoma with dichloroacetate.
      Thus, active electron transport flux may facilitate mitochondria-mediated cell death, and cancer cells may maintain viability, in part, by minimizing respiration.
      High levels of glycolysis also protect against apoptosis via hexokinase. Hexokinases can be found physically associated with the outer surface of mitochondria.
      • Bustamante E.
      • Pedersen P.L.
      High aerobic glycolysis of rat hepatoma cells in culture: role of mitochondrial hexokinase.
      Some tumor cells have higher levels of hexokinase
      • Bustamante E.
      • Pedersen P.L.
      High aerobic glycolysis of rat hepatoma cells in culture: role of mitochondrial hexokinase.
      • Marin-Hernandez A.
      • Rodriguez-Enriquez S.
      • Vital-Gonzalez P.A.
      • Flores-Rodriguez F.L.
      • Macias-Silva M.
      • Sosa-Garrocho M.
      • Moreno-Sanchez R.
      Determining and understanding the control of glycolysis in fast-growth tumor cells: flux control by an over-expressed but strongly product-inhibited hexokinase.
      and a tighter association between hexokinase and the mitochondrial membrane.
      • Pedersen P.L.
      Warburg, me and hexokinase 2: multiple discoveries of key molecular events underlying one of cancers’ most common phenotypes, the “Warburg Effect”, i.e., elevated glycolysis in the presence of oxygen.
      The localization of hexokinase to the mitochondria, which is facilitated by active AKT,
      • Gottlob K.
      • Majewski N.
      • Kennedy S.
      • Kandel E.
      • Robey R.B.
      • Hay N.
      Inhibition of early apoptotic events by Akt/PKB is dependent on the first committed step of glycolysis and mitochondrial hexokinase.
      inhibits the release of apoptosis-inducing factors, and suppresses apoptosis.
      • Pastorino J.G.
      • Hoek J.B.
      Hexokinase II: the integration of energy metabolism and control of apoptosis.
      Thus, aerobic glycolysis may provide a survival advantage for tumor cells that helps to explain its prevalence in human cancers.

       Adaptation to the Tumor Microenvironment

      Another possibility is that aerobic glycolysis is selected for in tumors because they are found in a hypoxic environment. According to this model, as a tumor grows, cells will be found further and further from the blood supply and po2 levels decline even more rapidly with distance from blood vessels than glucose levels. Lack of oxygen will reduce mitochondrial respiration and lead to a decline in mitochondrial ATP. Lower ATP levels are expected to relieve allosteric inhibition of PFK and PK and promote glycolysis. Hypoxia also induces HIF-1α stabilization and activity, which will promote glycolysis and the growth of new blood vessels. Even if new blood vessels are formed, the solid tumor microenvironment will still be characterized by disorganized microvasculature and cycles of normoxia-hypoxia.
      • Kimura H.
      • Braun R.D.
      • Ong E.T.
      • Hsu R.
      • Secomb T.W.
      • Papahadjopoulos D.
      • Hong K.
      • Dewhirst M.W.
      Fluctuations in red cell flux in tumor microvessels can lead to transient hypoxia and reoxygenation in tumor parenchyma.
      Aerobic glycolysis would continue to benefit cells in this environment. Thus, the tumor microenvironment, in this model, induces an aerobic glycolysis metabolic profile and then provides a selective advantage for tumor cells with high glycolytic metabolism. Aerobic glycolysis would provide a strong selective advantage during metastasis as well and, indeed, cells pretreated with hypoxia are more likely to survive during metastasis than their normoxic counterparts.
      • Rofstad E.K.
      • Danielsen T.
      Hypoxia-induced metastasis of human melanoma cells: involvement of vascular endothelial growth factor-mediated angiogenesis.
      There are a few questions surrounding this model. Some studies have questioned whether oxygen levels in the tumor microenvironment are, in fact, lower than the Km for the rate-limiting enzymes in oxidative phosphorylation.
      • Moreno-Sanchez R.
      • Rodriguez-Enriquez S.
      • Saavedra E.
      • Marin-Hernandez A.
      • Gallardo-Perez J.C.
      The bioenergetics of cancer: is glycolysis the main ATP supplier in all tumor cells?.
      Others have questioned the implied timing of the model, and argued that cancer cells activate a glycolytic metabolism even before they are exposed to hypoxic conditions.
      • Vander Heiden M.G.
      • Cantley L.C.
      • Thompson C.B.
      Understanding the Warburg effect: the metabolic requirements of cell proliferation.
      In addition, the aerobic glycolysis metabolic profile is not limited to hypoxic tumors.
      • Vander Heiden M.G.
      • Cantley L.C.
      • Thompson C.B.
      Understanding the Warburg effect: the metabolic requirements of cell proliferation.
      Leukemic cells and lung tumors found in airways are highly glycolytic, even though they are exposed to oxygen.
      • Vander Heiden M.G.
      • Cantley L.C.
      • Thompson C.B.
      Understanding the Warburg effect: the metabolic requirements of cell proliferation.
      Furthermore, although the tumor microenvironment might select for cells with an aerobic glycolysis phenotype, tumor cells maintain the metabolic phenotypes in culture under normoxic conditions. This may reflect the stabilization of HIF-1α and the persistent effects on gene expression of the combination of HIF-1α, oncogenes, and tumor suppressors. Thus, a more inclusive model might be that, in response to a combination of microenvironmental conditions, including hypoxia, and the activity of oncogenes and tumor suppressors, cancer cells acquire a metabolic phenotype that is stable and heritable, persists even when oxygen is available, and provides a selective advantage in the tumor environment and during metastasis.

       Functional Role of Secreted Lactate

      A final proposed explanation for the Warburg effect is that lactate secreted from tumor cells has an important functional role in promoting tumorigenesis. In support of this explanation, much of the glucose consumed by cancer cells is converted to lactate,
      • Hume D.A.
      • Radik J.L.
      • Ferber E.
      • Weidemann M.J.
      Aerobic glycolysis and lymphocyte transformation.
      • DeBerardinis R.J.
      • Mancuso A.
      • Daikhin E.
      • Nissim I.
      • Yudkoff M.
      • Wehrli S.
      • Thompson C.B.
      Beyond aerobic glycolysis: transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis.
      • Lunt S.Y.
      • Vander Heiden M.G.
      Aerobic glycolysis: meeting the metabolic requirements of cell proliferation.
      and high levels of lactate are associated with a poor tumor prognosis.
      • Brizel D.M.
      • Schroeder T.
      • Scher R.L.
      • Walenta S.
      • Clough R.W.
      • Dewhirst M.W.
      • Mueller-Klieser W.
      Elevated tumor lactate concentrations predict for an increased risk of metastases in head-and-neck cancer.
      MCTs cotransport lactate and a hydrogen ion out of the cell, resulting in an acidification of the local environment. The ensuing decrease in pH might promote cancer cell invasion and metastasis by killing normal host cells, thus generating space for the tumor and possibly releasing nutrients that the tumor can consume. A low pH might also stimulate invasion
      • Martínez-Zaguilán R.
      • Seftor E.A.
      • Seftor R.E.
      • Chu Y.W.
      • Gillies R.J.
      • Hendrix M.J.
      Acidic pH enhances the invasive behavior of human melanoma cells.
      and metastasis
      • Schlappack O.K.
      • Zimmermann A.
      • Hill R.P.
      Glucose starvation and acidosis: effect on experimental metastatic potential: DNA content and MTX resistance of murine tumour cells.
      by activating pH-sensitive metalloproteinases and/or cathepsins that degrade proteins in the extracellular matrix and basement membranes.
      • Rozhin J.
      • Sameni M.
      • Ziegler G.
      • Sloane B.F.
      Pericellular pH affects distribution and secretion of cathepsin B in malignant cells.
      Furthermore, as previously described, secreted lactate has been proposed to provide nutrients to surrounding cells.
      • Sonveaux P.
      • Vegran F.
      • Schroeder T.
      • Wergin M.C.
      • Verrax J.
      • Rabbani Z.N.
      • De Saedeleer C.J.
      • Kennedy K.M.
      • Diepart C.
      • Jordan B.F.
      • Kelley M.J.
      • Gallez B.
      • Wahl M.L.
      • Feron O.
      • Dewhirst M.W.
      Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice.
      Lactate secreted by cancer cells has also been proposed to feed nontumor, stromal cells.
      • Rattigan Y.I.
      • Patel B.B.
      • Ackerstaff E.
      • Sukenick G.
      • Koutcher J.A.
      • Glod J.W.
      • Banerjee D.
      Lactate is a mediator of metabolic cooperation between stromal carcinoma associated fibroblasts and glycolytic tumor cells in the tumor microenvironment.
      Thus, from the perspective of lactate recycling, the cancer can be considered a microecosystem in which the different tumor components engage in complementary metabolic pathways that allow for the recycling of the waste product metabolites of aerobic glycolysis to support tumor growth.
      • Sonveaux P.
      • Vegran F.
      • Schroeder T.
      • Wergin M.C.
      • Verrax J.
      • Rabbani Z.N.
      • De Saedeleer C.J.
      • Kennedy K.M.
      • Diepart C.
      • Jordan B.F.
      • Kelley M.J.
      • Gallez B.
      • Wahl M.L.
      • Feron O.
      • Dewhirst M.W.
      Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice.
      • Sotgia F.
      • Martinez-Outschoorn U.E.
      • Pavlides S.
      • Howell A.
      • Pestell R.G.
      • Lisanti M.P.
      Understanding the Warburg effect and the prognostic value of stromal caveolin-1 as a marker of a lethal tumor microenvironment.
      • Rattigan Y.I.
      • Patel B.B.
      • Ackerstaff E.
      • Sukenick G.
      • Koutcher J.A.
      • Glod J.W.
      • Banerjee D.
      Lactate is a mediator of metabolic cooperation between stromal carcinoma associated fibroblasts and glycolytic tumor cells in the tumor microenvironment.
      Finally, the secretion of lactic acid has also been proposed to play a role in suppressing the host anticancer immune response.
      • Fischer K.
      • Hoffmann P.
      • Voelkl S.
      • Meidenbauer N.
      • Ammer J.
      • Edinger M.
      • Gottfried E.
      • Schwarz S.
      • Rothe G.
      • Hoves S.
      • Renner K.
      • Timischl B.
      • Mackensen A.
      • Kunz-Schughart L.
      • Andreesen R.
      • Krause S.W.
      • Kreutz M.
      Inhibitory effect of tumor cell-derived lactic acid on human T cells.
      The metabolism of cytotoxic T lymphocytes, like that of the tumor cells, requires lactate secretion to drive high rates of glycolysis. In an advanced tumor, the high levels of lactate in the microenvironment may impede the ability of immune cells to export the intracellular lactate because secretion depends on a concentration gradient between intracellular and extracellular lactate. The resulting lactate overload reduces the ability of the T cells to secrete cytokines,
      • Fischer K.
      • Hoffmann P.
      • Voelkl S.
      • Meidenbauer N.
      • Ammer J.
      • Edinger M.
      • Gottfried E.
      • Schwarz S.
      • Rothe G.
      • Hoves S.
      • Renner K.
      • Timischl B.
      • Mackensen A.
      • Kunz-Schughart L.
      • Andreesen R.
      • Krause S.W.
      • Kreutz M.
      Inhibitory effect of tumor cell-derived lactic acid on human T cells.
      thus reducing the defense normally provided by the host immune response.

      Conclusions

       The Role of Metabolic Changes in Cancer

      For many years, cancer was considered fundamentally a disease of uncontrolled cell proliferation. Although metabolic changes were acknowledged to occur in cancer cells, it was considered a secondary phenomenon. More recently, the metabolic changes that occur during cancer are being reconsidered as more central to the disease itself. So, is cancer a disease of metabolism? Are the proliferation changes primary and the metabolic changes come along for the ride, or vice versa? One possible model is that oncogenes and tumor suppressors make cancer cells hyperproliferative, and the coordinated shift in metabolism is a consequence. For instance, MYC would be expected to promote proliferation, whereas the loss of p53 may protect cells from senescence. Because these molecules also affect metabolism, metabolic changes would ensue.
      A variation on this model would stress that the effects of oncogenes and tumor suppressors on proliferation are closely associated with metabolic changes that are also necessary to promote cell growth. The similarity in the changes between cancer cells and rapidly proliferating immune cells,
      • Frauwirth K.A.
      • Riley J.L.
      • Harris M.H.
      • Parry R.V.
      • Rathmell J.C.
      • Plas D.R.
      • Elstrom R.L.
      • June C.H.
      • Thompson C.B.
      The CD28 signaling pathway regulates glucose metabolism.
      • Brand K.
      Glutamine and glucose metabolism during thymocyte proliferation: pathways of glutamine and glutamate metabolism.
      • Hume D.A.
      • Radik J.L.
      • Ferber E.
      • Weidemann M.J.
      Aerobic glycolysis and lymphocyte transformation.
      and even yeast,
      • Lunt S.Y.
      • Vander Heiden M.G.
      Aerobic glycolysis: meeting the metabolic requirements of cell proliferation.
      supports a model in which altered metabolism provides the building blocks needed to form new cells. From this perspective, inappropriate cell proliferation would still be considered the primary driver of the tumorigenesis phenotype, and the metabolic changes are considered a coordinated and complementary program that supports the higher proliferative rate. Treating cell proliferation will, as a consequence, reverse the metabolic phenotype. A dramatic demonstration in support of this view is the ability of the tyrosine kinase inhibitor, imatinib, to normalize glucose metabolism in leukemic cells.
      • Gottschalk S.
      • Anderson N.
      • Hainz C.
      • Eckhardt S.G.
      • Serkova N.J.
      Imatinib (STI571)-mediated changes in glucose metabolism in human leukemia BCR-ABL-positive cells.
      An alternative model would propose that changes in metabolism are necessary to support biomass accumulation and drive the cancer phenotype. This argument is based on the premise that the aerobic glycolysis phenotype per se, and not just increased growth rate, contributes to tumorigenesis, a statement supported by the findings that glycolytic tumors are more invasive and more likely to cause the patient’s death.
      • Walenta S.
      • Wetterling M.
      • Lehrke M.
      • Schwickert G.
      • Sundfor K.
      • Rofstad E.K.
      • Mueller-Klieser W.
      High lactate levels predict likelihood of metastases, tumor recurrence, and restricted patient survival in human cervical cancers.
      This argument might stress that the excessive lactate secreted by tumor cells indicates that glucose carbons are not required just for biomass accumulation, but rather that secreted lactate likely actively promotes tumorigenesis, possibly by suppressing the host immune response or promoting invasion or metastasis. This argument would also stress that the changes in metabolism in tumor cells are more extreme than,
      • Meadows A.L.
      • Kong B.
      • Berdichevsky M.
      • Roy S.
      • Rosiva R.
      • Blanch H.W.
      • Clark D.S.
      Metabolic and morphological differences between rapidly proliferating cancerous and normal breast epithelial cells.
      and somewhat distinct from,
      • Bustamante E.
      • Pedersen P.L.
      High aerobic glycolysis of rat hepatoma cells in culture: role of mitochondrial hexokinase.
      those observed in most proliferating cells, some of which do not demonstrate the aerobic glycolytic phenotype of activated lymphocytes.
      • Lemons J.M.
      • Feng X.J.
      • Bennett B.D.
      • Legesse-Miller A.
      • Johnson E.L.
      • Raitman I.
      • Pollina E.A.
      • Rabitz H.A.
      • Rabinowitz J.D.
      • Coller H.A.
      Quiescent fibroblasts exhibit high metabolic activity.
      For example, the association of hexokinase with mitochondria is observed in hepatoma cells, but not in normal liver, even when it is regenerating.
      • Bustamante E.
      • Pedersen P.L.
      High aerobic glycolysis of rat hepatoma cells in culture: role of mitochondrial hexokinase.
      Glucose transporters are induced in pancreatic cancer, but not mass-forming pancreatitis.
      • Reske S.N.
      • Grillenberger K.G.
      • Glatting G.
      • Port M.
      • Hildebrandt M.
      • Gansauge F.
      • Beger H.G.
      Overexpression of glucose transporter 1 and increased FDG uptake in pancreatic carcinoma.
      Finally, one might argue, well-established oncogenes and tumor suppressors repeatedly observed as amplified, mutated, or deleted in tumors, such as those previously reported, RAS
      • Ying H.
      • Kimmelman A.C.
      • Lyssiotis C.A.
      • Hua S.
      • Chu G.C.
      • Fletcher-Sananikone E.
      • Locasale J.W.
      • Son J.
      • Zhang H.
      • Coloff J.L.
      • Yan H.
      • Wang W.
      • Chen S.
      • Viale A.
      • Zheng H.
      • Paik J.H.
      • Lim C.
      • Guimaraes A.R.
      • Martin E.S.
      • Chang J.
      • Hezel A.F.
      • Perry S.R.
      • Hu J.
      • Gan B.
      • Xiao Y.
      • Asara J.M.
      • Weissleder R.
      • Wang Y.A.
      • Chin L.
      • Cantley L.C.
      • DePinho R.A.
      Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism.
      and JAK2V617F,
      • Reddy M.M.
      • Fernandes M.S.
      • Deshpande A.
      • Weisberg E.
      • Inguilizian H.V.
      • Abdel-Wahab O.
      • Kung A.L.
      • Levine R.L.
      • Griffin J.D.
      • Sattler M.
      The JAK2V617F oncogene requires expression of inducible phosphofructokinase/fructose-bisphosphatase 3 for cell growth and increased metabolic activity.
      are being discovered to have direct effects on metabolism.
      An extreme version of this model would argue that all of the more classically accepted attributes of tumors actually derive from the metabolic phenotype of tumor cells.
      • Seyfried T.N.
      • Shelton L.M.
      Cancer as a metabolic disease.
      Then, is an aerobic glycolytic phenotype sufficient to transform a cell in the absence of other nonmetabolic cancer attributes? It seems unlikely—many immune cells temporarily adopt an aerobic glycolysis phenotype in response to antigen exposure. When they no longer receive inflammatory signals, they revert to the resting state and rarely form tumors.
      • Altman B.J.
      • Dang C.V.
      Normal and cancer cell metabolism: lymphocytes and lymphoma.
      On the other hand, a p53 mutant that can counter aerobic glycolysis and ROS production, but cannot induce apoptosis, senescence, or cell cycle arrest, retains the ability to suppress tumorigenesis.
      • Li T.
      • Kon N.
      • Jiang L.
      • Tan M.
      • Ludwig T.
      • Zhao Y.
      • Baer R.
      • Gu W.
      Tumor suppression in the absence of p53-mediated cell-cycle arrest, apoptosis, and senescence.
      These recent findings with p53 support a model in which metabolic changes are critical drivers of tumorigenesis, and highlight the need for more studies to clarify this issue.

       The Prospects for Targeting Cancer through Metabolism

      The first anticancer agents targeted metabolic pathways required for proliferation (eg, by depleting pools of nucleotide precursors).
      • Farber S.
      • Diamond L.K.
      Temporary remissions in acute leukemia in children produced by folic acid antagonist, 4-aminopteroyl-glutamine acid.
      Successful anticancer agents designed more recently have largely focused on a specific activated oncogene. These targeted therapies have been extremely successful in achieving a rapid remission of some tumors, but unfortunately, for many patients, the disease recurs. Metabolism-based therapeutics might have advantages over gene-based therapies. Although most genes are important drivers of only a subset of tumor types, some of the shifts in metabolism observed in tumors are common to tumors derived from many different tissues. In addition, it may be more challenging, although certainly not impossible, for a tumor to acquire mutations that confer resistance to an anti-metabolism therapy than a gene-based therapy.
      • Altman B.J.
      • Dang C.V.
      Normal and cancer cell metabolism: lymphocytes and lymphoma.
      If the metabolic characteristics of tumors are essential for the tumor’s growth and survival, targeting the tumor’s metabolism could have a dramatic effect on tumor viability.
      However, there are drawbacks to a metabolism-based approach to therapy as well. Metabolism-based therapies face a major hurdle of non-specific toxicity: the same metabolic pathways are required for the survival of all cells. Activated immune cells might be expected to be especially vulnerable to anticancer therapies, which is especially concerning because these are the cells that would normally target the tumor.
      • Altman B.J.
      • Dang C.V.
      Normal and cancer cell metabolism: lymphocytes and lymphoma.
      Neurons consume large amounts of glucose, and peripheral neuropathy has been detected as the dose-limiting toxicity for some anti-glycolytic therapies.
      • Michelakis E.D.
      • Sutendra G.
      • Dromparis P.
      • Webster L.
      • Haromy A.
      • Niven E.
      • Maguire C.
      • Gammer T.L.
      • Mackey J.R.
      • Fulton D.
      • Abdulkarim B.
      • McMurtry M.S.
      • Petruk K.C.
      Metabolic modulation of glioblastoma with dichloroacetate.
      Nevertheless, there is some reason to be hopeful about the prospects of metabolic targeting. A combination of energy metabolism inhibitors with other antitumor drugs could represent a powerful new approach to treatment.
      • Kroemer G.
      • Pouyssegur J.
      Tumor cell metabolism: cancer’s Achilles’ heel.
      Energetic collapse due to blocked glycolysis could make other physical and chemical anticancer agents more effective (eg, by reducing the effectiveness of efflux transporters and allowing drugs to accumulate to higher effective doses). Alternatively, forcing cancer cells to reactivate the mitochondria might strengthen the therapeutic activity of antineoplastic treatments that depend on the induction of free radicals.
      There is also hope that tumor-specific metabolic programs can be exploited for therapy. Some tumors organize the TCA cycles so that they are addicted to glucose for anaplerosis and survival,
      • Yuneva M.
      • Zamboni N.
      • Oefner P.
      • Sachidanandam R.
      • Lazebnik Y.
      Deficiency in glutamine but not glucose induces MYC-dependent apoptosis in human cells.
      whereas other tumors are glutamine dependent.
      • Wise D.R.
      • DeBerardinis R.J.
      • Mancuso A.
      • Sayed N.
      • Zhang X.Y.
      • Pfeiffer H.K.
      • Nissim I.
      • Daikhin E.
      • Yudkoff M.
      • McMahon S.B.
      • Thompson C.B.
      Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction.
      • Yuneva M.
      • Zamboni N.
      • Oefner P.
      • Sachidanandam R.
      • Lazebnik Y.
      Deficiency in glutamine but not glucose induces MYC-dependent apoptosis in human cells.
      Tumors characterized by a strict reliance on either glucose or glutamine may be targetable through this metabolic vulnerability. There may be opportunities to target cancer-specific isozymes
      • Bustamante E.
      • Pedersen P.L.
      High aerobic glycolysis of rat hepatoma cells in culture: role of mitochondrial hexokinase.
      • Pastorino J.G.
      • Hoek J.B.
      Hexokinase II: the integration of energy metabolism and control of apoptosis.
      or pathways that are relied on more heavily by cancer cells than normal cells (eg, the conversion of glutamine to glutamate through transamination).
      • Thornburg J.M.
      • Nelson K.K.
      • Clem B.F.
      • Lane A.N.
      • Arumugam S.
      • Simmons A.
      • Eaton J.W.
      • Telang S.
      • Chesney J.
      Targeting aspartate aminotransferase in breast cancer.
      PKM2 is another attractive target; both allosteric activators and inhibitors of PKM2 reduce tumor growth.
      • Goldberg M.S.
      • Sharp P.A.
      Pyruvate kinase M2-specific siRNA induces apoptosis and tumor regression.
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      Pyruvate kinase M2 activators promote tetramer formation and suppress tumorigenesis.
      Further studies that elucidate the molecular basis for distinguishing cancer cell metabolism from a proliferative phenotype, and the range of metabolic profiles in different types of cancer cells, will allow for prioritization among the targets that have been identified and will likely suggest even more targets for exploration.

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