Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Metabolic reprogramming of the tumor

Abstract

Cancer is classically considered as a genetic and, more recently, epigenetic multistep disease. Despite seminal studies in the 1920s by Warburg showing a characteristic metabolic pattern for tumors, cancer bioenergetics has often been relegated to the backwaters of cancer biology. This review aims to provide a historical account on cancer metabolism research, and to try to integrate and systematize the metabolic strategies in which cancer cells engage to overcome selective pressures during their inception and evolution. Implications of this renovated view on some common concepts and in therapeutics are also discussed.

Your institute does not have access to this article

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1
Figure 2
Figure 3

References

  • Ahmad IM, Aykin-Burns N, Sim JE, Walsh SA, Higashikubo R, Buettner GR et al. (2005). Mitochondrial O2•− and H2O2 mediate glucose deprivation-induced cytotoxicity and oxidative stress in human cancer cells. J Biol Chem 280: 4254–4263.

    CAS  PubMed  Google Scholar 

  • Akakura N, Kobayashi M, Horiuchi I, Suzuki A, Wang JX, Chen J et al. (2001). Constitutive expression of hypoxia-inducible factor-1 alpha renders pancreatic cancer cells resistant to apoptosis induced by hypoxia and nutrient deprivation. Cancer Res 61: 6548–6554.

    CAS  PubMed  Google Scholar 

  • Alexander S, Koehl GE, Hirschberg M, Geissler EK, Friedl P . (2008). Dynamic imaging of cancer growth and invasion: a modified skin-fold chamber model. Histochem Cell Biol 130: 1147–1154.

    CAS  PubMed  Google Scholar 

  • An WG, Kanekal M, Simon MC, Maltepe E, Blagosklonny MV, Neckers LM . (1998). Stabilization of wild-type p53 by hypoxia-inducible factor 1alpha. Nature 392: 405–408.

    CAS  PubMed  Google Scholar 

  • Atkinson DE . (1968). The energy charge of the adenylate pool as a regulatory parameter. Interaction with feedback modifiers. Biochemistry 7: 4030–4034.

    CAS  PubMed  Google Scholar 

  • Bauer DE, Hatzivassiliou G, Zhao F, Andreadis C, Thompson CB . (2005). ATP citrate lyase is an important component of cell growth and transformation. Oncogene 24: 6314–6322.

    CAS  PubMed  Google Scholar 

  • Bensaad K, Tsuruta A, Selak MA, Vidal MNC, Nakano K, Bartrons R et al. (2006). TIGAR, a p53-inducible regulator of glycolysis and apoptosis. Cell 126: 107–120.

    CAS  PubMed  Google Scholar 

  • Berardi MJ, Fantin VR . (2011). Survival of the fittest: metabolic adaptations in cancer. Curr Opin Genet Dev 21: 59–66.

    CAS  PubMed  Google Scholar 

  • Bertout JA, Patel SA, Simon MC . (2008). The impact of O−2 availability on human cancer. Nat Rev Cancer 8: 967–975.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Berx G, van Roy F . (2009). Involvement of members of the cadherin superfamily in cancer. Cold Spring Harb Perspect Biol 1: a003129.

    PubMed  PubMed Central  Google Scholar 

  • Bonora E, Porcelli AM, Gasparre G, Biondi A, Ghelli A, Carelli V et al. (2006). Defective oxidative phosphorylation in thyroid oncocytic carcinoma is associated with pathogenic mitochondrial DNA mutations affecting complexes I and III. Cancer Res 66: 6087–6096.

    CAS  PubMed  Google Scholar 

  • Boveri T . (1914). Zur Frage der Entstehung maligner Tumoren. Gustav Fischer: Jena.

    Google Scholar 

  • Boyland E, Boyland ME . (1935). XXXV. Studies in tissue metabolism: VIII. The effect of fumarate and succinate on tumour respiration. Biochem J 30: 224–226.

    Google Scholar 

  • Brahimi-Horn MC, Bellot G, Pouyssegur J . (2011). Hypoxia and energetic tumour metabolism. Curr Opin Genet Dev 21: 67–72.

    CAS  PubMed  Google Scholar 

  • Bruick RK, McKnight SL . (2001). A conserved family of prolyl-4-hydroxylases that modify HIF. Science 294: 1337–1340.

    CAS  PubMed  Google Scholar 

  • Burk D, Schade AL . (1956). On respiratory impairment in cancer cells. Science 124: 270–272.

    CAS  PubMed  Google Scholar 

  • Cai Z, Semenza GL . (2005). PTEN activity is modulated during ischemia and reperfusion: involvement in the induction and decay of preconditioning. Circ Res 97: 1351–1359.

    CAS  PubMed  Google Scholar 

  • Cairns RA, Harris IS, Mak TW . (2011). Regulation of cancer cell metabolism. Nat Rev Cancer 11: 85–95.

    CAS  PubMed  Google Scholar 

  • Campbell PJ, Yachida S, Mudie LJ, Stephens PJ, Pleasance ED, Stebbings LA et al. (2010). The patterns and dynamics of genomic instability in metastatic pancreatic cancer. Nature 467: 1109–1113.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Cannito S, Novo E, di Bonzo LV, Busletta C, Colombatto S, Parola M . (2010). Epithelial–mesenchymal transition: from molecular mechanisms, redox regulation to implications in human health and disease. Antioxid Redox Signal 12: 1383–1430.

    CAS  PubMed  Google Scholar 

  • Carnero A, Hudson JD, Price CM, Beach DH . (2000). p16INK4A and p19ARF act in overlapping pathways in cellular immortalization. Nat Cell Biol 2: 148–155.

    CAS  PubMed  Google Scholar 

  • Carrel A, Ebeling AH . (1921). Age and multiplication of fibroblasts. J Exp Med 34: 599–623.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Christofk HR, Vander Heiden MG, Wu N, Asara JM, Cantley LC . (2008). Pyruvate kinase M2 is a phosphotyrosine-binding protein. Nature 452: 181–186.

    CAS  PubMed  Google Scholar 

  • Cooke MS, Evans MD, Dizdaroglu M, Lunec J . (2003). Oxidative DNA damage: mechanisms, mutation, and disease. FASEB J 17: 1195–1214.

    CAS  PubMed  Google Scholar 

  • Cori CF, Cori GT . (1925a). The carbohydrate metabolism of tumors. II. Changes in the sugar, lactic acid, and co-combing power of blood passing through a tumor. J Biol Chem 65: 397–405.

    CAS  Google Scholar 

  • Cori CF, Cori GT . (1925b). The carbohydrate metabolism of tumors. I. The free sugar, lactic acid, and glycogen content of malignant tumors. J Biol Chem 64: 11–22.

    CAS  Google Scholar 

  • Cramer W . (1926). A British Medical Association Lecture on the New Outlook on Cancer. Br Med J 1: 175–180.

    CAS  PubMed  PubMed Central  Google Scholar 

  • D'Errico I, Salvatore L, Murzilli S, Lo Sasso G, Latorre D, Martelli N et al. (2011). Peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC1alpha) is a metabolic regulator of intestinal epithelial cell fate. Proc Natl Acad Sci USA 108: 6603–6608.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Dang CV, Kim JW, Gao P, Yustein J . (2008). The interplay between MYC and HIF in cancer. Nat Rev Cancer 8: 51–56.

    CAS  PubMed  Google Scholar 

  • David CJ, Chen M, Assanah M, Canoll P, Manley JL . (2010). HnRNP proteins controlled by c-Myc deregulate pyruvate kinase mRNA splicing in cancer. Nature 463: 364–368.

    CAS  PubMed  Google Scholar 

  • De Bari L, Chieppa G, Marra E, Passarella S . (2010). L-lactate metabolism can occur in normal and cancer prostate cells via the novel mitochondrial L-lactate dehydrogenase. Int J Oncol 37: 1607–1620.

    CAS  PubMed  Google Scholar 

  • DeBerardinis RJ, Mancuso A, Daikhin E, Nissim I, Yudkoff M, Wehrli S et al. (2007). Beyond aerobic glycolysis: transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis. Proc Natl Acad Sci USA 104: 19345–19350.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Droge W, Eck HP, Mihm S . (1992). HIV-induced cysteine deficiency and T-cell dysfunction—a rationale for treatment with N-acetylcysteine. Immunol Today 13: 211–214.

    CAS  PubMed  Google Scholar 

  • Eck HP, Drings P, Droge W . (1989). Plasma glutamate levels, lymphocyte reactivity and death rate in patients with bronchial carcinoma. J Cancer Res Clin Oncol 115: 571–574.

    CAS  PubMed  Google Scholar 

  • Elstrom RL, Bauer DE, Buzzai M, Karnauskas R, Harris MH, Plas DR et al. (2004). Akt stimulates aerobic glycolysis in cancer cells. Cancer Res 64: 3892–3899.

    CAS  PubMed  Google Scholar 

  • Eng CH, Yu K, Lucas J, White E, Abraham RT . (2010). Ammonia derived from glutaminolysis is a diffusable regulator of autophagy. Sci Signal 3: ra31.

    PubMed  Google Scholar 

  • Erecinska M, Deas J, Silver IA . (1995). The effect of pH on glycolysis and phosphofructokinase activity in cultured cells and synaptosomes. J Neurochem 65: 2765–2772.

    CAS  PubMed  Google Scholar 

  • Evans T, Rosenthal ET, Youngblom J, Distel D, Hunt T . (1983). Cyclin: a protein specified by maternal mRNA in sea urchin eggs that is destroyed at each cleavage division. Cell 33: 389–396.

    CAS  PubMed  Google Scholar 

  • Fearon ER, Vogelstein B . (1990). A genetic model for colorectal tumorigenesis. Cell 61: 759–767.

    CAS  PubMed  Google Scholar 

  • Feinberg AP, Ohlsson R, Henikoff S . (2006). The epigenetic progenitor origin of human cancer. Nat Rev Genet 7: 21–33.

    CAS  PubMed  Google Scholar 

  • Feng Z, Levine AJ . (2010). The regulation of energy metabolism and the IGF-1/mTOR pathways by the p53 protein. Trends Cell Biol 20: 427–434.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ferreira LMR . (2010). Cancer metabolism: the Warburg effect today. Exp Mol Pathol 89: 372–380.

    CAS  PubMed  Google Scholar 

  • Fischer K, Hoffmann P, Voelkl S, Meidenbauer N, Ammer J, Edinger M et al. (2007). Inhibitory effect of tumor cell-derived lactic acid on human T cells. Blood 109: 3812–3819.

    CAS  PubMed  Google Scholar 

  • Flier JS, Mueckler MM, Usher P, Lodish HF . (1987). Elevated levels of glucose transport and transporter messenger RNA are induced by ras or src oncogenes. Science 235: 1492–1495.

    CAS  PubMed  Google Scholar 

  • Floor S, van Staveren WC, Larsimont D, Dumont JE, Maenhaut C . (2011). Cancer cells in epithelial-to-mesenchymal transition and tumor-propagating-cancer stem cells: distinct, overlapping or same populations. Oncogene 30: 4609–4621.

    CAS  PubMed  Google Scholar 

  • Fogal V, Richardson AD, Karmali PP, Scheffler IE, Smith JW, Ruoslahti E . (2010). Mitochondrial p32 protein is a critical regulator of tumor metabolism via maintenance of oxidative phosphorylation. Mol Cell Biol 30: 1303–1318.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Folkman J . (2003). Fundamental concepts of the angiogenic process. Curr Mol Med 3: 643–651.

    CAS  PubMed  Google Scholar 

  • Friedl P, Gilmour D . (2009). Collective cell migration in morphogenesis, regeneration and cancer. Nat Rev Mol Cell Biol 10: 445–457.

    CAS  PubMed  Google Scholar 

  • Funes JM, Quintero M, Henderson S, Martinez D, Qureshi U, Westwood C et al. (2007). Transformation of human mesenchymal stem cells increases their dependency on oxidative phosphorylation for energy production. Proc Natl Acad Sci USA 104: 6223–6228.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Gallagher SM, Castorino JJ, Wang D, Philp NJ . (2007). Monocarboxylate transporter 4 regulates maturation and trafficking of CD147 to the plasma membrane in the metastatic breast cancer cell line MDA-MB-231. Cancer Res 67: 4182–4189.

    CAS  PubMed  Google Scholar 

  • Gao P, Tchernyshyov I, Chang TC, Lee YS, Kita K, Ochi T et al. (2009). c-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism. Nature 458: 762–765.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Gao P, Zhang H, Dinavahi R, Li F, Xiang Y, Raman V et al. (2007). HIF-dependent antitumorigenic effect of antioxidants in vivo. Cancer Cell 12: 230–238.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Gatenby RA, Gillies RJ . (2004). Why do cancers have high aerobic glycolysis? Nat Rev Cancer 4: 891–899.

    CAS  PubMed  Google Scholar 

  • Geschwind JF, Ko YH, Torbenson MS, Magee C, Pedersen PL . (2002). Novel therapy for liver cancer: direct intraarterial injection of a potent inhibitor of ATP production. Cancer Res 62: 3909–3913.

    CAS  PubMed  Google Scholar 

  • Giampieri S, Manning C, Hooper S, Jones L, Hill CS, Sahai E . (2009). Localized and reversible TGFbeta signalling switches breast cancer cells from cohesive to single cell motility. Nat Cell Biol 11: 1287–1296.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Gil J, Kerai P, Lleonart M, Bernard D, Cigudosa JC, Peters G et al. (2005). Immortalization of primary human prostate epithelial cells by c-Myc. Cancer Res 65: 2179–2185.

    CAS  PubMed  Google Scholar 

  • Gladden LB . (2004). Lactate metabolism: a new paradigm for the third millennium. J Physiol 558: 5–30.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Goldblatt H, Cameron G . (1953). Induced malignancy in cells from rat myocardium subjected to intermittent anaerobiosis during long propagation in vitro. J Exp Med 97: 525–552.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Guppy M . (2002). The hypoxic core: a possible answer to the cancer paradox. Biochem Biophys Res Commun 299: 676–680.

    CAS  PubMed  Google Scholar 

  • Guppy M, Greiner E, Brand K . (1993). The role of the Crabtree effect and an endogenous fuel in the energy metabolism of resting and proliferating thymocytes. Eur J Biochem 212: 95–99.

    CAS  PubMed  Google Scholar 

  • Hahn WC, Weinberg RA . (2002). Modelling the molecular circuitry of cancer. Nat Rev Cancer 2: 331–341.

    CAS  PubMed  Google Scholar 

  • Halabe Bucay A . (2009). Hypothesis proved…citric acid (citrate) does improve cancer: a case of a patient suffering from medullary thyroid cancer. Med Hypotheses 73: 271.

    PubMed  Google Scholar 

  • Hammond EM, Giaccia AJ . (2005). The role of p53 in hypoxia-induced apoptosis. Biochem Biophys Res Commun 331: 718–725.

    CAS  PubMed  Google Scholar 

  • Hanahan D, Weinberg RA . (2011). Hallmarks of cancer: the next generation. Cell 144: 646–674.

    CAS  PubMed  Google Scholar 

  • Hansemann D . (1890). Über asymmetrische Zelltheilung in Epithelhresbsen und deren biologische bedeutung. Virchows Arch A Pathol Anat Histopathol 119: 299–326.

    Google Scholar 

  • Hatzivassiliou G, Zhao F, Bauer DE, Andreadis C, Shaw AN, Dhanak D et al. (2005). ATP citrate lyase inhibition can suppress tumor cell growth. Cancer Cell 8: 311–321.

    CAS  PubMed  Google Scholar 

  • Holley RW, Kiernan JA . (1974). Control of the initiation of DNA synthesis in 3T3 cells: low-molecular-weight nutrients. Proc Natl Acad Sci USA 71: 2942–2945.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Hollstein M, Sidransky B, Vogelstein B, Harris CC . (1991). p53 mutations in human cancers. Science 253: 49–53.

    CAS  PubMed  Google Scholar 

  • Hu S, Balakrishnan A, Bok RA, Anderton B, Larson PE, Nelson SJ et al. (2011). 13C-pyruvate imaging reveals alterations in glycolysis that precede c-Myc-induced tumor formation and regression. Cell Metab 14: 131–142.

    CAS  PubMed  Google Scholar 

  • Huebner RJ, Todaro GJ . (1969). Oncogenes of RNA tumor viruses as determinants of cancer. Proc Natl Acad Sci USA 64: 1087–1094.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ikeda E, Achen MG, Breier G, Risau W . (1995). Hypoxia-induced transcriptional activation and increased mRNA stability of vascular endothelial growth factor in C6 glioma cells. J Biol Chem 270: 19761–19766.

    CAS  PubMed  Google Scholar 

  • Imai T, Horiuchi A, Wang C, Oka K, Ohira S, Nikaido T et al. (2003). Hypoxia attenuates the expression of E-cadherin via upregulation of SNAIL in ovarian carcinoma cells. Am J Pathol 163: 1437–1447.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Isidoro A, Martinez M, Fernandez PL, Ortega AD, Santamaria G, Chamorro M et al. (2004). Alteration of the bioenergetic phenotype of mitochondria is a hallmark of breast, gastric, lung and oesophageal cancer. Biochem J 378: 17–20.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Johnston LA . (2009). Competitive interactions between cells: death, growth, and geography. Science 324: 1679–1682.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Jones RG . (2009). Tumor suppressors and cell metabolism: a recipe for cancer growth. Genes Dev 23: 537–548.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Jones RG, Plas DR, Kubek S, Buzzai M, Mu J, Xu Y et al. (2005). AMP-activated protein kinase induces a p53-dependent metabolic checkpoint. Mol Cell 18: 283–293.

    CAS  PubMed  Google Scholar 

  • Kahn BB, Alquier T, Carling D, Hardie DG . (2005). AMP-activated protein kinase: ancient energy gauge provides clues to modern understanding of metabolism. Cell Metab 1: 15–25.

    CAS  PubMed  Google Scholar 

  • Kiebish MA, Han XL, Cheng H, Chuang JH, Seyfried TN . (2008). Cardiolipin and electron transport chain abnormalities in mouse brain tumor mitochondria: lipidomic evidence supporting the Warburg theory of cancer. J Lipid Res 49: 2545–2556.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kim J, Yu W, Kovalski K, Ossowski L . (1998). Requirement for specific proteases in cancer cell intravasation as revealed by a novel semiquantitative PCR-based assay. Cell 94: 353–362.

    CAS  PubMed  Google Scholar 

  • Kim JW, Gao P, Liu YC, Semenza GL, Dang CV . (2007). Hypoxia-inducible factor 1 and dysregulated c-Myc cooperatively induce vascular endothelial growth factor and metabolic switches hexokinase 2 and pyruvate dehydrogenase kinase 1. Mol Cell Biol 27: 7381–7393.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kim JW, Zeller KI, Wang Y, Jegga AG, Aronow BJ, O'Donnell KA et al. (2004). Evaluation of myc E-box phylogenetic footprints in glycolytic genes by chromatin immunoprecipitation assays. Mol Cell Biol 24: 5923–5936.

    CAS  PubMed  PubMed Central  Google Scholar 

  • King A, Selak MA, Gottlieb E . (2006). Succinate dehydrogenase and fumarate hydratase: linking mitochondrial dysfunction and cancer. Oncogene 25: 4675–4682.

    CAS  PubMed  Google Scholar 

  • Klimova T, Chandel NS . (2008). Mitochondrial complex III regulates hypoxic activation of HIF. Cell Death Diff 15: 660–666.

    CAS  Google Scholar 

  • Knox WE, Horowitz ML, Friedell GH . (1969). The proportionality of glutaminase content to growth rate and morphology of rat neoplasms. Cancer Res 29: 669–680.

    CAS  PubMed  Google Scholar 

  • Knox WE, Tremblay GC, Spanier BB, Friedell GH . (1967). Glutaminase activities in normal and neoplastic tissues of the rat. Cancer Res 27: 1456–1458.

    CAS  PubMed  Google Scholar 

  • Knudson Jr AG . (1971). Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci USA 68: 820–823.

    PubMed  PubMed Central  Google Scholar 

  • Kondoh H, Lleonart ME, Gil J, Wang J, Degan P, Peters G et al. (2005). Glycolytic enzymes can modulate cellular life span. Cancer Res 65: 177–185.

    CAS  PubMed  Google Scholar 

  • Koshiji M, Kageyama Y, Pete EA, Horikawa I, Barrett JC, Huang LE . (2004). HIF-1alpha induces cell cycle arrest by functionally counteracting Myc. EMBO J 23: 1949–1956.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Koukourakis MI, Giatromanolaki A, Harris AL, Sivridis E . (2006). Comparison of metabolic pathways between cancer cells and stromal cells in colorectal carcinomas: a metabolic survival role for tumor-associated stroma. Cancer Res 66: 632–637.

    CAS  PubMed  Google Scholar 

  • Krebs HA, Johnson WA . (1937). The role of citric acid in intermediate metabolism in animal tissues. Enzymologia 4: 148–156.

    CAS  Google Scholar 

  • Kroemer G, Pouyssegur J . (2008). Tumor cell metabolism: cancer's Achilles’ heel. Cancer Cell 13: 472–482.

    CAS  PubMed  Google Scholar 

  • Lardner A . (2001). The effects of extracellular pH on immune function. J Leukoc Biol 69: 522–530.

    CAS  PubMed  Google Scholar 

  • Lebedeva MA, Eaton JS, Shadel GS . (2009). Loss of p53 causes mitochondrial DNA depletion and altered mitochondrial reactive oxygen species homeostasis. Biochim Biophys Acta 1787: 328–334.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lee WH, Bookstein R, Hong F, Young LJ, Shew JY, Lee EY . (1987). Human retinoblastoma susceptibility gene: cloning, identification, and sequence. Science 235: 1394–1399.

    CAS  PubMed  Google Scholar 

  • Levine AJ . (1997). p53, the cellular gatekeeper for growth and division. Cell 88: 323–331.

    CAS  PubMed  Google Scholar 

  • Li F, Wang Y, Zeller KI, Potter JJ, Wonsey DR, O'Donnell KA et al. (2005). Myc stimulates nuclearly encoded mitochondrial genes and mitochondrial biogenesis. Mol Cell Biol 25: 6225–6234.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Li X, Lewis MT, Huang J, Gutierrez C, Osborne CK, Wu MF et al. (2008). Intrinsic resistance of tumorigenic breast cancer cells to chemotherapy. J Natl Cancer Inst 100: 672–679.

    CAS  PubMed  Google Scholar 

  • Lin CM, Abcouwer SF, Souba WW . (1999). Effect of dietary glutamate on chemotherapy-induced immunosuppression. Nutrition 15: 687–696.

    CAS  PubMed  Google Scholar 

  • Loeffler DA, Juneau PL, Masserant S . (1992). Influence of tumour physico-chemical conditions on interleukin-2-stimulated lymphocyte proliferation. Br J Cancer 66: 619–622.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lowe SW, Cepero E, Evan G . (2004). Intrinsic tumour suppression. Nature 432: 307–315.

    CAS  PubMed  Google Scholar 

  • Luo J, Kuo MH . (2009). Linking nutrient metabolism to epigenetics. Cell Sci Rev 6: 49–54.

    Google Scholar 

  • Luo W, Hu H, Chang R, Zhong J, Knabel M, O'Meally R et al. (2011). Pyruvate kinase M2 is a PHD3-stimulated coactivator for hypoxia-inducible factor 1. Cell 145: 732–744.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lynen F . (1942). Die Rolle der Phosphorsäure bei Dehydrierungsvorgängen und ihre biologische Bedeutung. Naturwissenschaften 30: 398–406.

    CAS  Google Scholar 

  • Madsen CD, Sahai E . (2010). Cancer dissemination—lessons from leukocytes. Dev Cell 19: 13–26.

    CAS  PubMed  Google Scholar 

  • Mandriota SJ, Pepper MS . (1998). Regulation of angiopoietin-2 mRNA levels in bovine microvascular endothelial cells by cytokines and hypoxia. Circ Res 83: 852–859.

    CAS  PubMed  Google Scholar 

  • Mani SA, Guo W, Liao MJ, Eaton EN, Ayyanan A, Zhou AY et al. (2008). The epithelial–mesenchymal transition generates cells with properties of stem cells. Cell 133: 704–715.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Martinez-Zaguilan R, Seftor EA, Seftor RE, Chu YW, Gillies RJ, Hendrix MJ . (1996). Acidic pH enhances the invasive behavior of human melanoma cells. Clin Exp Metastasis 14: 176–186.

    CAS  PubMed  Google Scholar 

  • Matoba S, Kang JG, Patino WD, Wragg A, Boehm M, Gavrilova O et al. (2006). p53 regulates mitochondrial respiration. Science 312: 1650–1653.

    CAS  PubMed  Google Scholar 

  • Michelakis ED, Sutendra G, Dromparis P, Webster L, Haromy A, Niven E et al. (2010). Metabolic modulation of glioblastoma with dichloroacetate. Sci Transl Med 2: 31ra34.

    CAS  PubMed  Google Scholar 

  • Miles FL, Pruitt FL, van Golen KL, Cooper CR . (2008). Stepping out of the flow: capillary extravasation in cancer metastasis. Clin Exp Metastasis 25: 305–324.

    CAS  PubMed  Google Scholar 

  • Milovanova TN, Bhopale VM, Sorokina EM, Moore JS, Hunt TK, Hauer-Jensen M et al. (2008). Lactate stimulates vasculogenic stem cells via the thioredoxin system and engages an autocrine activation loop involving hypoxia-inducible factor 1. Mol Cell Biol 28: 6248–6261.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Mitchell P . (1961). Coupling of phosphorylation to electron and hydrogen transfer by a chemi-osmotic type of mechanism. Nature 191: 144–148.

    CAS  PubMed  Google Scholar 

  • Miyamoto S, Murphy AN, Brown JH . (2008). Akt mediates mitochondrial protection in cardiomyocytes through phosphorylation of mitochondrial hexokinase-II. Cell Death Differ 15: 521–529.

    CAS  PubMed  Google Scholar 

  • Mizushima N, Levine B, Cuervo AM, Klionsky DJ . (2008). Autophagy fights disease through cellular self-digestion. Nature 451: 1069–1075.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Newberne PM . (2002). Choline deficiency associated with diethanolamine carcinogenicity. Toxicol Sci 67: 1–3.

    CAS  PubMed  Google Scholar 

  • Oakhill JS, Steel R, Chen ZP, Scott JW, Ling N, Tam S et al. (2011). AMPK is a direct adenylate charge-regulated protein kinase. Science 332: 1433–1435.

    CAS  PubMed  Google Scholar 

  • Okoshi R, Ozaki T, Yamamoto H, Ando K, Koida N, Ono S et al. (2008). Activation of AMP-activated protein kinase induces p53-dependent apoptotic cell death in response to energetic stress. J Biol Chem 283: 3979–3987.

    CAS  PubMed  Google Scholar 

  • Oliva CR, Nozell SE, Diers A, McClugage 3rd SG, Sarkaria JN, Markert JM et al. (2010). Acquisition of temozolomide chemoresistance in gliomas leads to remodeling of mitochondrial electron transport chain. J Biol Chem 285: 39759–39767.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Osthus RC, Shim H, Kim S, Li Q, Reddy R, Mukherjee M et al. (2000). Deregulation of glucose transporter 1 and glycolytic gene expression by c-Myc. J Biol Chem 275: 21797–21800.

    CAS  PubMed  Google Scholar 

  • Pasteur L . (1876). Expériences et vues nouvelles sur la nature des fermentations. Compt Rend Acad Sci 52: 1260–1264.

    Google Scholar 

  • Pauwels EKJ, Sturm EJC, Bombardieri E, Cleton FJ, Stokkel MPM . (2000). Positron-emission tomography with [F-18]fluorodeoxyglucose Part I. Biochemical uptake mechanism and its implication for clinical studies. J Cancer Res Clin Oncol 126: 549–559.

    CAS  PubMed  Google Scholar 

  • Pinner S, Jordan P, Sharrock K, Bazley L, Collinson L, Marais R et al. (2009). Intravital imaging reveals transient changes in pigment production and Brn2 expression during metastatic melanoma dissemination. Cancer Res 69: 7969–7977.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Pouyssegur J, Dayan F, Mazure NM . (2006). Hypoxia signalling in cancer and approaches to enforce tumour regression. Nature 441: 437–443.

    CAS  PubMed  Google Scholar 

  • Racker E, Spector M . (1981). Warburg effect revisited—merger of biochemistry and molecular biology. Science 213: 303–307.

    CAS  PubMed  Google Scholar 

  • Ralph SJ, Rodriguez-Enriquez S, Neuzil J, Moreno-Sanchez R . (2010). Bioenergetic pathways in tumor mitochondria as targets for cancer therapy and the importance of the ROS-induced apoptotic trigger. Mol Aspects Med 31: 29–59.

    CAS  PubMed  Google Scholar 

  • Ramos-Montoya A, Lee W-NP, Bassilian S, Lim S, Trebukhina RV, Kazhyna MV et al. (2006). Pentose phosphate cycle oxidative and nonoxidative balance: a new vulnerable target for overcoming drug resistance in cancer. Int J Cancer 119: 2733–2741.

    CAS  PubMed  Google Scholar 

  • Ravi R, Mookerjee B, Bhujwalla ZM, Sutter CH, Artemov D, Zeng Q et al. (2000). Regulation of tumor angiogenesis by p53-induced degradation of hypoxia-inducible factor 1alpha. Genes Dev 14: 34–44.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Rempel A, Bannasch P, Mayer D . (1994). Differences in expression and intracellular-distribution of hexokinase isoenzymes in rat-liver cells of different transformation stages. Biochim Biophys Acta 1219: 660–668.

    PubMed  Google Scholar 

  • Reshkin SJ, Bellizzi A, Caldeira S, Albarani V, Malanchi I, Poignee M et al. (2000). Na+/H+ exchanger-dependent intracellular alkalinization is an early event in malignant transformation and plays an essential role in the development of subsequent transformation-associated phenotypes. FASEB J 14: 2185–2197.

    CAS  PubMed  Google Scholar 

  • Rischin D, Peters L, Fisher R, Macann A, Denham J, Poulsen M et al. (2005). Tirapazamine, cisplatin, and radiation versus fluorouracil, cisplatin, and radiation in patients with locally advanced head and neck cancer: a randomized phase II trial of the Trans-Tasman Radiation Oncology Group (TROG 98.02). J Clin Oncol 23: 79–87.

    CAS  PubMed  Google Scholar 

  • Rischin D, Peters LJ, O'Sullivan B, Giralt J, Fisher R, Yuen K et al. (2010). Tirapazamine, cisplatin, and radiation versus cisplatin and radiation for advanced squamous cell carcinoma of the head and neck (TROG 02.02, HeadSTART): a phase III trial of the Trans-Tasman Radiation Oncology Group. J Clin Oncol 28: 2989–2995.

    CAS  PubMed  Google Scholar 

  • Rodgers JT, Lerin C, Haas W, Gygi SP, Spiegelman BM, Puigserver P . (2005). Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1. Nature 434: 113–118.

    CAS  PubMed  Google Scholar 

  • Ronzoni E, Ehrenfest E . (1936). The effect of dinitrophenol on the metabolism of frog muscle. J Biol Chem 15: 749–768.

    Google Scholar 

  • Samudio I, Fiegl M, Andreeff M . (2009). Mitochondrial uncoupling and the Warburg effect: molecular basis for the reprogramming of cancer cell metabolism. Cancer Res 69: 2163–2166.

    CAS  PubMed  Google Scholar 

  • Santamaria G, Martinez-Diez M, Fabregat I, Cuezva JM . (2006). Efficient execution of cell death in non-glycolytic cells requires the generation of ROS controlled by the activity of mitochondrial H+-ATP synthase. Carcinogenesis 27: 925–935.

    CAS  PubMed  Google Scholar 

  • Schulz TJ, Thierbach R, Voigt A, Drewes G, Mietzner B, Steinberg P et al. (2006). Induction of oxidative metabolism by mitochondrial frataxin inhibits cancer growth: Otto Warburg revisited. J Biol Chem 281: 977–981.

    CAS  PubMed  Google Scholar 

  • Schuman VL, Levitt SH, Song CW . (1982). The radioprotective effect of 5-thio-D-glucose on normal tissues in vivo. Int J Radiat Oncol Biol Phys 8: 589–591.

    CAS  PubMed  Google Scholar 

  • Schwartzenberg-Bar-Yoseph F, Armoni M, Karnieli E . (2004). The tumor suppressor p53 downregulates glucose transporters GLUT1 and GLUT4 gene expression. Cancer Res 64: 2627–2633.

    CAS  PubMed  Google Scholar 

  • Semenza GL . (2003). Targeting HIF-1 for cancer therapy. Nat Rev Cancer 3: 721–732.

    CAS  PubMed  Google Scholar 

  • Semenza GL . (2009). Regulation of cancer cell metabolism by hypoxia-inducible factor 1. Semin Cancer Biol 19: 12–16.

    CAS  PubMed  Google Scholar 

  • Semenza GL . (2010). HIF-1: upstream and downstream of cancer metabolism. Curr Opin Genet Dev 20: 51–56.

    CAS  PubMed  Google Scholar 

  • Shim H, Dolde C, Lewis BC, Wu CS, Dang G, Jungmann RA et al. (1997). c-Myc transactivation of LDH-A: implications for tumor metabolism and growth. Proc Natl Acad Sci USA 94: 6658–6663.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Shin YK, Yoo BC, Chang HJ, Jeon E, Hong SH, Jung MS et al. (2005). Downregulation of mitochondrial F1F0-ATP synthase in human colon cancer cells with induced 5-fluorouracil resistance. Cancer Res 65: 3162–3170.

    CAS  PubMed  Google Scholar 

  • Song CW, Sung JH, Clement JJ, Levitt SH . (1978). Cytotoxic effect of 5-thio-D-glucose on chronically hypoxic cells in multicell spheroids. Br J Cancer Suppl 3: 136–140.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Sonveaux P, Vegran F, Schroeder T, Wergin MC, Verrax J, Rabbani ZN et al. (2008). Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice. J Clin Invest 118: 3930–3942.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Staal SP . (1987). Molecular cloning of the akt oncogene and its human homologues AKT1 and AKT2: amplification of AKT1 in a primary human gastric adenocarcinoma. Proc Natl Acad Sci USA 84: 5034–5037.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Stehelin D, Guntaka RV, Varmus HE, Bishop JM . (1976). Purification of DNA complementary to nucleotide sequences required for neoplastic transformation of fibroblasts by avian sarcoma viruses. J Mol Biol 101: 349–365.

    CAS  PubMed  Google Scholar 

  • Stern R, Shuster S, Neudecker BA, Fromby B . (2002). Lactate stimulates fibroblast expression of hyaluronan and CD44: the Warburg effect revisited. Exp Cell Res 276: 24–31.

    CAS  PubMed  Google Scholar 

  • Stewart TJ, Abrams SI . (2008). How tumours escape mass destruction. Oncogene 27: 5894–5903.

    CAS  PubMed  Google Scholar 

  • Tennant DA, Durán RV, Gottlieb E . (2010). Targeting metabolic transformation for cancer therapy. Nat Rev Cancer 10: 267–277.

    CAS  PubMed  Google Scholar 

  • Thangaraju M, Gopal E, Martin PM, Ananth S, Smith SB, Prasad PD et al. (2006). SLC5A8 triggers tumor cell apoptosis through pyruvate-dependent inhibition of histone deacetylases. Cancer Res 66: 11560–11564.

    CAS  PubMed  Google Scholar 

  • Thierbach R, Schulz TJ, Isken F, Voigt A, Mietzner B, Drewes G et al. (2005). Targeted disruption of hepatic frataxin expression causes impaired mitochondrial function, decreased life span and tumor growth in mice. Hum Mol Genet 14: 3857–3864.

    CAS  PubMed  Google Scholar 

  • Thiery JP . (2002). Epithelial–mesenchymal transitions in tumour progression. Nat Rev Cancer 2: 442–454.

    CAS  PubMed  Google Scholar 

  • Thiery JP, Acloque H, Huang RY, Nieto MA . (2009). Epithelial–mesenchymal transitions in development and disease. Cell 139: 871–890.

    CAS  PubMed  Google Scholar 

  • Thiery JP, Sleeman JP . (2006). Complex networks orchestrate epithelial–mesenchymal transitions. Nat Rev Mol Cell Biol 7: 131–142.

    CAS  PubMed  Google Scholar 

  • Thomlinson RH, Gray LH . (1955). The histological structure of some human lung cancers and the possible implications for radiotherapy. Br J Cancer 9: 539.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Tijo KH, Levan A . (1956). The chromosome number of man. Hereditas 42: 1–6.

    Google Scholar 

  • Toffoli S, Michiels C . (2008). Intermittent hypoxia is a key regulator of cancer cell and endothelial cell interplay in tumours. FEBS J 275: 2991–3002.

    CAS  PubMed  Google Scholar 

  • Tubiana M, Koscielny S . (2008). On clonogenic tumour cells and metastasis-forming cells. Nat Rev Cancer 8: 990.

    CAS  PubMed  Google Scholar 

  • Vander Heiden MG, Locasale JW, Swanson KD, Sharfi H, Heffron GJ, Amador-Noguez D et al. (2010). Evidence for an alternative glycolytic pathway in rapidly proliferating cells. Science 329: 1492–1499.

    CAS  PubMed  Google Scholar 

  • Varum S, Momcilovic O, Castro C, Ben-Yehudah A, Ramalho-Santos J, Navara CS . (2009). Enhancement of human embryonic stem cell pluripotency through inhibition of the mitochondrial respiratory chain. Stem Cell Res 3: 142–156.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Warburg O . (1923). Tests on surviving carcinoma cultures. Biochemische Zeitschrift 142: 317–333.

    CAS  Google Scholar 

  • Warburg O . (1929). Is aerobic glycolysis specific to tumours? Biochemische Zeitschrift 204: 482–483.

    CAS  Google Scholar 

  • Warburg O . (1930). Note on the metabolism of tumours. Biochemische Zeitschrift 228: 257–258.

    CAS  Google Scholar 

  • Warburg O . (1956a). On the origin of cancer cells. Science 123: 309–314.

    CAS  PubMed  Google Scholar 

  • Warburg O . (1956b). On respiratory impairment in cancer cells. Science 124: 269–270.

    CAS  PubMed  Google Scholar 

  • Warburg O, Hiepler E . (1952). Versuche mit Ascites-Tumorzellen. Z Naturforsch 7b: 193–194.

    CAS  Google Scholar 

  • Warburg O, Minami S . (1923). Tests on surviving carcinoma cultures. Klinische Wochenschrift 2: 776–777.

    Google Scholar 

  • Warburg O, Posener K, Negelein E . (1924). On the metabolism of carcinoma cells. Biochemische Zeitschrift 152: 309–344.

    CAS  Google Scholar 

  • Warburg O, Wind F, Negelein E . (1927). The metabolism of tumors in the body. J Gen Physiol 8: 519–530.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ward PS, Patel J, Wise DR, Abdel-Wahab O, Bennett BD, Coller HA et al. (2010). The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate. Cancer Cell 17: 225–234.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Weinhouse S . (1956). On respiratory impairment in cancer cells. Science 124: 267–269.

    CAS  PubMed  Google Scholar 

  • Weinhouse S . (1972). Glycolysis, respiration, and anomalous gene expression in experimental hepatomas: GHA Clowes memorial lecture. Cancer Res 32: 2007–2016.

    CAS  PubMed  Google Scholar 

  • Wenner CE, Weinhouse S . (1953). Metabolism of neoplastic tissue. III. Diphosphopyridine nucleotide requirements for oxidations by mitochondria of neoplastic and non-neoplastic tissues. Cancer Res 13: 21–26.

    CAS  PubMed  Google Scholar 

  • Williams AC, Collard TJ, Paraskeva C . (1999). An acidic environment leads to p53 dependent induction of apoptosis in human adenoma and carcinoma cell lines: implications for clonal selection during colorectal carcinogenesis. Oncogene 18: 3199–3204.

    CAS  PubMed  Google Scholar 

  • Wong DJ, Liu H, Ridky TW, Cassarino D, Segal E, Chang HY . (2008). Module map of stem cell genes guides creation of epithelial cancer stem cells. Cell Stem Cell 2: 333–344.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wu KJ, Zeng J, Zhu GD, Zhang LL, Zhang D, Li L et al. (2009). Silibinin inhibits prostate cancer invasion, motility and migration by suppressing vimentin and MMP-2 expression. Acta Pharmacol Sin 30: 1162–1168.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Yalcin A, Telang S, Clem B, Chesney J . (2009). Regulation of glucose metabolism by 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatases in cancer. Exp Mol Pathol 86: 174–179.

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to L M R Ferreira or J E Dumont.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Ferreira, L., Hebrant, A. & Dumont, J. Metabolic reprogramming of the tumor. Oncogene 31, 3999–4011 (2012). https://doi.org/10.1038/onc.2011.576

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2011.576

Keywords

  • cancer
  • metabolism
  • microenvironment
  • evolution

Further reading

Search

Quick links