Review Article | Published:

Why do cancers have high aerobic glycolysis?

Nature Reviews Cancer volume 4, pages 891899 (2004) | Download Citation



If carcinogenesis occurs by somatic evolution, then common components of the cancer phenotype result from active selection and must, therefore, confer a significant growth advantage. A near-universal property of primary and metastatic cancers is upregulation of glycolysis, resulting in increased glucose consumption, which can be observed with clinical tumour imaging. We propose that persistent metabolism of glucose to lactate even in aerobic conditions is an adaptation to intermittent hypoxia in pre-malignant lesions. However, upregulation of glycolysis leads to microenvironmental acidosis requiring evolution to phenotypes resistant to acid-induced cell toxicity. Subsequent cell populations with upregulated glycolysis and acid resistance have a powerful growth advantage, which promotes unconstrained proliferation and invasion.

Key points

  • Widespread clinical use of 18fluorodeoxyglucose positron-emission tomography has demonstrated that the glycolytic phenotype is observed in most human cancers.

  • The concept of carcinogenesis as a process that occurs by somatic evolution clearly implies that common traits of the malignant phenotype, such as upregulation of glycolysis, are the result of active selection processes and must confer a significant, identifiable growth advantage.

  • Constitutive upregulation of glycolysis is likely to be an adaptation to hypoxia that develops as pre-malignant lesions grow progressively further from their blood supply. At this stage, the blood supply remains physically separated from the growing cells by an intact basement membrane.

  • Increased acid production from upregulation of glycolysis results in microenvironmental acidosis and requires further adaptation through somatic evolution to phenotypes resistant to acid-induced toxicity.

  • Cell populations that emerge from this evolutionary sequence have a powerful growth advantage, as they alter their environment through increased glycolysis in a way that is toxic to other phenotypes, but harmless to themselves. The environmental acidosis also facilitates invasion through destruction of adjacent normal populations, degradation of the extracellular matrix and promotion of angiogenesis.

  • We propose that the glycolytic phenotype, by conferring a powerful growth advantage, is necessary for evolution of invasive human cancers.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


  1. 1.

    & A progression puzzle. Nature 418, 823 (2002). A compelling opinion piece, in which the authors convincingly argue that the molecular phenotypes of metastatic cancers arose early during carcinogenesis. Although somatic evolution is implied in this work, the environmental nature of the selection pressures are not discussed.

  2. 2.

    History of the Pasteur effect and its pathobiology. Mol. Cell. Biochem. 5, 17–23 (1974).

  3. 3.

    Ueber den stoffwechsel der tumoren. (Constable, London, 1930).

  4. 4.

    et al. 'The metabolism of tumours': 70 years later. Novartis Found. Symp. 240, 251–260 (2001). In this timely review, Semenza describes the relation between HIF1α and the regulation of glycolysis.

  5. 5.

    The Warburg hypothesis fifty years later. Z. Krebsforsch. Klin. Onkol. Cancer Res. Clin. Oncol. 87, 115–126 (1976).

  6. 6.

    & PET in clinical oncology. Cancer Metastasis Rev. 7, 119–142 (1988).

  7. 7.

    , & Relevance of positron emission tomography (PET) in oncology. Strahlenther. Onkol. 175, 356–373 (1999).

  8. 8.

    Molecular imaging of cancer with positron emission tomography. Nature Rev. Cancer 2, 683–693 (2002). A well written review on FdG PET imaging.

  9. 9.

    & Positron emission tomography scanning: current and future applications. Annu. Rev. Med. 53, 89–112 (2002). A comprehensive review of extant literature. The authors convincingly document the very high sensitivity and specificity of FdG PET in diagnosing and staging diverse types of metastatic cancers.

  10. 10.

    et al. Biologic correlates of 18fluorodeoxyglucose uptake in human breast cancer measured by positron emission tomography. J.Clin.Oncol. 20, 379–387 (2002). This well-conducted study quantitatively analysed the molecular phenotypes of tumours that had either high or low rates of FdG trapping.

  11. 11.

    et al. Using positron emission tomography with [18F]FDG to predict tumor behavior in experimental colorectal cancer. Neoplasia (New York) 3, 189–195 (2001).

  12. 12.

    , , & Metabolic pathway analysis: basic concepts and scientific applications in the post-genomic era. Biotechnol. Prog. 15, 296–303 (1999).

  13. 13.

    , , , & Oncogenes in tumor metabolism, tumorigenesis, and apoptosis. J. Bioenerg. Biomembr. 29, 345–354 (1997). One of many papers in this issue of the Journal of Bioenergetics and Biomembranes that dealt with the molecular controls of glucose metabolism. In this review, primary data were presented to support the importance and molecular controls of the glucose transporter and its regulation by MYC.

  14. 14.

    , , , & Glycolysis and glucose transporter 1 as markers of response to hormonal therapy in breast cancer. Int. J. Cancer 107, 177–182 (2003). One of many papers that demonstrates the important role of the glucose transporter in regulating glycolytic flux.

  15. 15.

    , , & Two-compartment model for determination of glycolytic rates of solid tumors by in vivo 13C NMR spectroscopy. NMR Biomed. 11, 395–404 (1998).

  16. 16.

    , & Aberrant glycolytic metabolism of cancer cells: a remarkable coordination of genetic, transcriptional, post-translational, and mutational events that lead to a critical role for type II hexokinase. J. Bioenerg. Biomembr. 29, 339–343 (1997). Provides a cogent argument for the role of hexokinase in regulating glycolytic flux and its regulation by oncogenes and subcellular localization.

  17. 17.

    et al. Overexpression of Glut-1 and increased glucose metabolism in tumors are associated with a poor prognosis in patients with oral squamous cell carcinoma. Cancer 97, 1015–1024 (2003). This careful study is one of many that document the diagnostic importance of GLUT1 and glycolysis in carcinomas.

  18. 18.

    et al. Evaluation of 18F-2-deoxy-2-fluoro-D-glucose positron emission tomography for gastric cancer. World J. Surg. 28, 247–253 (2004).

  19. 19.

    , , , & Oxygen-mediated regulation of tumor cell invasiveness. Involvement of a nitric oxide signaling pathway. J. Biol. Chem. 277, 35730–35737 (2002).

  20. 20.

    et al. Hypoxia increases heparanase-dependent tumor cell invasion, which can be inhibited by antiheparanase antibodies. Cancer Res. 64, 3928–3933 (2004).

  21. 21.

    et al. Hypoxia-inducible factor 1 regulates vascular endothelial growth factor expression in human pancreatic cancer. Pancreas 26, 56–64 (2003).

  22. 22.

    , , , & Nitric oxide-mediated regulation of hypoxia-induced B16F10 melanoma metastasis. Int. J. Cancer 108, 47–53 (2004).

  23. 23.

    & Hypoxia arrests ovarian carcinoma cell cycle progression, but invasion is unaffected. Cancer Res. 56, 1168–1173 (1996).

  24. 24.

    & Contributions of cell metabolism and H+ diffusion to the acidic pH of tumors. Neoplasia (New York) 5, 135–145 (2003). Determined proton production rates in breast cancer lines with low and high metastatic capability, and related these to glycolytic rate. These rates were used in a reaction–diffusion model to predict steady-state tumour pH values.

  25. 25.

    , , & Why are cancers acidic? A carrier-mediated diffusion model for H+ transport in the interstitial fluid. Novartis Found. Symp. 240, 46–62 (2001).

  26. 26.

    et al. Combined vascular and extracellular pH imaging of solid tumors. NMR Biomed. 15, 114–119 (2002). Used spectroscopic imaging to measure the spatial variations in tumour pH, and these were related to vascular perfusion measures in the same tumours.

  27. 27.

    The number and distribution of capillaries in muscles with calculations of the oxygen pressure head necessary for supplying the tissue. J. Physiol. 52, 409–415 (1919). Demonstrates the annulus of tissues that can be oxygenated by a single capillary.

  28. 28.

    & The histological structure of some human lung cancers and the possible implications for radiotherapy. Br. J. Cancer 9, 539–549 (1955). Documents that necrosis in tumours occurs at distances from blood vessels and that this was consistent with the oxygen diffusion distances.

  29. 29.

    , , , & Determination of local oxygen consumption rates in tumors. Cancer Res. 54, 3333–3336 (1994).

  30. 30.

    , , & Interstitial pH and pO2 gradients in solid tumors in vivo: high-resolution measurements reveal a lack of correlation. Nature Med. 3, 177–182 (1997). Despite its title, this very well conducted study documents the correlation between pH and oxygenation as they decrease with distances from feeding capillaries.

  31. 31.

    et al. Hypoxia-mediated selection of cells with diminished apoptotic potential in solid tumours. Nature 379, 88–91 (1996). Documents the somatic evolutionary pressure mediated by hypoxia.

  32. 32.

    & A reaction-diffusion model of cancer invasion. Cancer Res. 56, 5745–5753 (1996). Mathematical methods and empirical evidence were used to demonstrate the acid-induced tumour-invasion model for the first time.

  33. 33.

    & An evolutionary model of carcinogenesis. Cancer Res. 63, 6212–6220 (2003). The formal mathematical development of evolutionary game theory in carcinogenesis.

  34. 34.

    & A genetic model for colorectal tumorigenesis. Cell 61, 759–767 (1990). Introduced the molecular genetic changes that occur during gastrointestinal carcinogenesis and discussed the concept of clonal outgrowth in this context. There was no discussion of environmental selection pressures.

  35. 35.

    , & Optimum fiber spacing in a hollow fiber bioreactor. Biotechnol. Bioeng. 32, 983–992 (1988).

  36. 36.

    et al. Theoretical simulation of oxygen transport to tumors by three-dimensional networks of microvessels. Adv. Exp. Med. Biol. 454, 629–634 (1998).

  37. 37.

    et al. Expression of the hypoxia-inducible and tumor-associated carbonic anhydrases in ductal carcinoma in situ of the breast. Am. J. Pathol. 158, 1011–1019 (2001). This work shows, with histopathology, the expression of CA IX and CA XII in carcinoma in situ lesions. These two carbonic anhydrases are sensitive to hypoxia and these data are consistent with significant hypoxia in in situ lesions.

  38. 38.

    et al. Fluctuations in red cell flux in tumor microvessels can lead to transient hypoxia and reoxygenation in tumor parenchyma. Cancer Res. 56, 5522–5528 (1996).

  39. 39.

    , , & pH, hypoxia and metastasis. Novartis Found. Symp. 240, 154–165 (2001).

  40. 40.

    & Dynamic remodeling of the vascular bed precedes tumor growth: MLS ovarian carcinoma spheroids implanted in nude mice. Neoplasia (New York) 1, 226–230 (1999).

  41. 41.

    et al. Physiological noise in murine solid tumors using T2*-weighted gradient echo imaging: a marker for tumor acute hypoxia? Phys. Med. Biol. 49, 3389–3411 (2004).

  42. 42.

    , & Fourier analysis of fluctuations of oxygen tension and blood flow in R3230Ac tumors and muscle in rats. Am. J. Physiol. 277, H551–H568 (1999).

  43. 43.

    et al. Microvascular studies on the origins of perfusion-limited hypoxia. Br. J. Cancer Suppl. 27, S247–S251 (1996).

  44. 44.

    et al. Endothelin-1 is a critical mediator of myogenic tone in tumor arterioles: implications for cancer treatment. Cancer Res. 64, 3209–3214 (2004).

  45. 45.

    et al. Vascular morphogenesis and remodeling in a human tumor xenograft: blood vessel formation and growth after ovariectomy and tumor implantation. Circ. Res. 89, 732–739 (2001).

  46. 46.

    , , , & Fluctuations in microvascular blood flow parameters caused by hemodynamic mechanisms. Am. J. Physiol. 266, H1822–H1828 (1994). References 38–46 document the periodic nature of tumour oxygenation.

  47. 47.

    , , & Acidic environment causes apoptosis by increasing caspase activity. Br. J. Cancer 80, 1892–1897 (1999).

  48. 48.

    , & 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 (1999).

  49. 49.

    , & Role of intracellular pH in proliferation, transformation, and apoptosis. J. Bioenerg. Biomembr. 29, 393–399 (1997). References 47–49 deal with pH-induced apoptosis. Grinstein's review concludes that cytoplasmic acidification is unlikely to be part of the apoptosis paradigm, but that externally lowered pH might promote apoptotic cell death.

  50. 50.

    & Heterogeneity of intracellular pH and of mechanisms that regulate intracellular pH in populations of cultured cells. Cancer Res. 58, 1901–1908 (1998).

  51. 51.

    & Intracellular pH is increased after transformation of Chinese hamster embryo fibroblasts. Proc. Natl Acad. Sci. USA 84, 2766–2770 (1987).

  52. 52.

    , , , & Malignant gliomas display altered pH regulation by NHE1 compared with nontransformed astrocytes. Am. J. Physiol. 278, C676–C688 (2000).

  53. 53.

    , , & Vacuolar type proton ATPases are functionally expressed in the plasma membranes of human tumor cells. Am. J. Physiol. 265, c1015–c1029 (1993). References 50–53 describe mechanisms of pH regulation that are documented to be upregulated in cancers.

  54. 54.

    , , , & Cell acidification in apoptosis: granulocyte colony-stimulating factor delays programmed cell death in neutrophils by up-regulating the vacuolar H+-ATPase. Proc. Natl Acad. Sci. USA 92, 5965–5968 (1995). Demonstrates that vacuolar H+-ATPase activity is anti-apoptotic.

  55. 55.

    , , , & Human erythrocyte glucose transporter (Glut1) is immunohistochemically detected as a late event during malignant progression in Barrett's metaplasia. Cancer Epidemiol. Biomarkers Prev. 6, 303–305 (1997).

  56. 56.

    et al. Glut1 expression in T1 and T2 stage colorectal carcinomas: its relationship to clinicopathological features. Eur. J. Cancer 37, 204–209 (2001).

  57. 57.

    , , , & Role for glucose transporter 1 protein in human breast cancer. Pathol. Oncol. Res. 4, 115–120 (1998).

  58. 58.

    Hypoxia-inducible factor 1: master regulator of O2 homeostasis. Curr. Opin. Genet. Dev. 8, 588–594 (1998).

  59. 59.

    et al. Hexokinase II and VEGF expression in liver tumors: correlation with hypoxia-inducible factor 1α and its significance. J. Hepatol. 40, 117–123 (2004).

  60. 60.

    et al. Role of HIF-1α in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis. Nature 394, 485–490 (1998).

  61. 61.

    , , , & HIF-1α and the glycolytic phenotype in tumors. Neoplasia (in the press).

  62. 62.

    , & Hypoxia-inducible factor 1 activation by aerobic glycolysis implicates the Warburg effect in carcinogenesis. J. Biol. Chem. 277, 23111–23115 (2002).

  63. 63.

    Targeting HIF-1 for cancer therapy. Nature Rev. Cancer 3, 1–13 (2003). References 58–63 describe the role of HIF1α in regulating aerobic and anaerobic glycolysis.

  64. 64.

    Signal transduction to hypoxia-inducible factor 1. Biochem. Pharmacol. 64, 993–998 (2002).

  65. 65.

    , , & The redox protein thioredoxin-1 (Trx-1) increases hypoxia-inducible factor 1α protein expression: Trx-1 overexpression results in increased vascular endothelial growth factor production and enhanced tumor angiogenesis. Cancer Res. 62, 5089–5095 (2002).

  66. 66.

    , , & Radiation activates HIF-1 to regulate vascular radiosensitivity in tumors: role of reoxygenation, free radicals, and stress granules. Cancer Cell 5, 429–441 (2004).

  67. 67.

    et al. Transcription Factor HIF-1 is a necessary mediator of the Pasteur effect in mammalian cells. Mol. Cell. Biol. 21, 3436–3444 (2001).

  68. 68.

    Aerobic glycolysis by proliferating cells: protection against oxidative stress at the expense of energy yield. J. Bioenerg. Biomembr. 29, 355–364 (1997).

  69. 69.

    et al. Deregulation of glucose transporter 1 and glycolytic gene expression by c-Myc. J. Biol. Chem. 275, 21797–21800 (2000).

  70. 70.

    et al. Expression of facilitative glucose transporter 1 mRNA in colon cancer was not regulated by k-ras. Cancer Letters 154, 137–142 (2000).

  71. 71.

    , , , & Regulation of glut1 mRNA by hypoxia-inducible factor-1. Interaction between H-ras and hypoxia. J. Biol. Chem. 276, 9519–9525 (2001).

  72. 72.

    , & Glucose catabolism in cancer cells. The type II hexokinase promoter contains functionally active response elements for the tumor suppressor p53. J. Biol. Chem. 272, 22776–22780 (1997).

  73. 73.

    , & Glucose metabolism in cancer. Evidence that demethylation events play a role in activating type II hexokinase gene expression. J. Biol. Chem. 278, 15333–15340 (2003).

  74. 74.

    , , , & Tumorigenic 3T3 cells maintain an alkaline intracellular pH under physiological conditions. Proc. Natl Acad. Sci. USA 87, 7414–7418 (1990).

  75. 75.

    et al. Na/H exchanger-dependent intracellular alkalinization is an early event in malignant transformation and play an essential role in the development of subsequent transformation-associated phenotypes. FASEB J. 14, 2185–2197 (2000).

  76. 76.

    et al. Relationship of MR-derived lactate, mobile lipids and relative blood volume for in vivo gliomas. Am. J. Neuroradiol. (in the press). Describes the observation of increased lactate in non-enhancing grade III gliomas, indicating that metabolic upregulation might precede angiogenesis.

  77. 77.

    Multivoxel magnetic resonance spectroscopy of brain tumors. Mol. Cancer Ther. 2, 497–507 (2003).

  78. 78.

    , , , & MRI and fluorescence microscopy of the acute vascular response to VEGF165: vasodilation, hyper-permeability and lymphatic uptake, followed by rapid inactivation of the growth factor. NMR Biomed. 15, 120–131 (2002).

  79. 79.

    & Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 86, 353–364 (1996).

  80. 80.

    , & Microenvironmental and cellular consequences of altered blood flow in tumors. Br. J. Radiol. 77, S11–S22 (2004).

  81. 81.

    , , & MR Imaging of the tumor microenvironment. J. Magn. Reson. Imaging 16, 430–450 (2002). A comprehensive review describing MRI of clinical and experimental tumours.

  82. 82.

    , , & Clastogenicity of low pH to various cultured mammalian cells. Mutat. Res. 268, 297–305 (1992).

  83. 83.

    , , & Modification of gap junctional intercellular communication by changes in extracellular pH in syrian hamster embryo cells. Carcinogenesis 11, 909–913 (1990).

  84. 84.

    et al. Acidic pH enhances the invasive behavior of human melanoma cells. Clin. Exp. Metastasis 14, 176–186 (1996).

  85. 85.

    , & Glucose starvation and acidosis: effect on experimental metastasic potential, DNA content and MTX resistance of murine tumour cells. Br. J. Cancer 64, 663–670 (1991).

  86. 86.

    , , & Pericellular pH affects distribution and secretion of cathepsin B in malignant cells. Cancer Res. 54, 6517–6525 (1994).

  87. 87.

    , , , & Breast cancer cells have a high capacity to acidify extracellular milieu by a dual mechanism. Clin. Exp. Metastasis 15, 382–392 (1997).

  88. 88.

    et al. Elevated tumor lactate concentrations predict for an increased risk of metastases in head-and-neck cancer. Int. J. Radiat. Oncol. Biol. Phys. 51, 349–353 (2001).

  89. 89.

    et al. High lactate levels predict likelihood of metastases, tumor recurrence, and restricted patient survival in human cervical cancers. Cancer Res. 60, 916–921 (2000).

  90. 90.

    et al. Coexpression of glucose transporter 1 and matrix metalloproteinase-2 in human cancers. J. Natl Cancer Instit. 94, 1080–1091 (2002).

  91. 91.

    et al. Intravascular origin of metastasis from the proliferation of endothelium-attached tumor cells: a new model for metastasis. Nature Med. 6, 100–102 (2000). A watershed paper describing the microenvironmental behaviour of lung metastases using a novel microscopy method. This paper challenges the paradigm that extravasation is a necessary component of the metastasis programme.

  92. 92.

    et al. Intravascular location of breast cancer cells after spontaneous metastasis to the lung. Am. J. Pathol. 161, 749–753 (2002).

  93. 93.

    & Hypoxia-induced metastasis of human melanoma cells: involvement of vascular endothelial growth factor-mediated angiogenesis. Br. J. Cancer 80, 1697–1707 (1999). Provides clear evidence that pretreatment with acute hypoxia can increase the efficiency of metastasis.

  94. 94.

    , & Overexpression of the human erythrocyte glucose transporter occurs as a late event in human colorectal carcinogenesis and is associated with an increased incidence of lymph node metastases. Clin. Cancer Res. 2, 1151–1154 (1996).

  95. 95.

    et al. 18F-FDG PET detection of colonic adenomas. J. Nucl. Med. 42, 989–992 (2001).

  96. 96.

    , , , & The possible role of postoperative azotemia in enhanced survival of patients with metastatic renal cancer after cytoreductive nephrectomy. Cancer Res. 62, 5218–5222 (2002).

Download references


We wish to acknowledge the invaluable contributions of E. Gawlinski and T. Vincent for their efforts in the mathematical modelling that led to the insights presented here. We also thank E. Racker for stimulating this research by posing to us the question in the title.

Author information


  1. Departments of Radiology and Applied Mathematics, University of Arizona, Tucson, Arizona 85721, USA.

    • Robert A. Gatenby
  2. Departments of Radiology and Biochemistry and Molecular Biophysics, University of Arizona, Tucson, Arizona 85721, USA.

    • Robert J. Gillies


  1. Search for Robert A. Gatenby in:

  2. Search for Robert J. Gillies in:

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Robert A. Gatenby.



Enzymes that catalyse the transfer of phosphate from ATP to glucose to form glucose-6-phosphate. This is the first reaction in the metabolism of glucose and prevents efflux of glucose from the cell.


Refers to a low oxygen level. This means different levels to different investigators, but for radiation biologists hypoxia occurs at levels less than 0.1% oxygen in the gas phase. Normoxia refers to normal levels of oxygen (>10%) and anoxia refers to no oxygen.


A metal chamber with a glass window that is placed on the dorsal skin of an animal. This allows in vivo tumour growth to be continuously observed microscopically.


A measure of the concentration of red cells in the blood. A reduced haematocrit decreases the oxygen-carrying capacity of the blood.


Rhythmic oscillations in vascular tone caused by local changes in smooth muscle.


The active process of altering structure and arrangement in blood vessels through cell growth, cell death, cell migration and production or degradation of the extracellular matrix.


Terms from the Michaelis–Menten model. Applied to transport, Vmax is the maximum possible rate of uptake of a specific substrate. Km is the substrate concentration at which the substrate uptake is half of Vmax. Cell populations with low Km are better adapted to maintaining substrate uptake in conditions in which substrate concentrations are low.


Describing any substance or processes that increases alterations in the structure of chromosomes.


Linked channels through contiguous cell membranes that interconnect the cytoplasm of adjacent cells and allow direct exchange of ions and small molecules.

About this article

Publication history



Further reading