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.

  • Review Article
  • Published:

Hypoxia signalling in cancer and approaches to enforce tumour regression

Abstract

Tumour cells emerge as a result of genetic alteration of signal circuitries promoting cell growth and survival, whereas their expansion relies on nutrient supply. Oxygen limitation is central in controlling neovascularization, glucose metabolism, survival and tumour spread. This pleiotropic action is orchestrated by hypoxia-inducible factor (HIF), which is a master transcriptional factor in nutrient stress signalling. Understanding the role of HIF in intracellular pH (pHi) regulation, metabolism, cell invasion, autophagy and cell death is crucial for developing novel anticancer therapies. There are new approaches to enforce necrotic cell death and tumour regression by targeting tumour metabolism and pHi-control systems.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: VEGF-A and angiopoietin-2 are key angiogenic factors induced by hypoxia.
Figure 2: Oxygen sensors contribute to the destruction and inactivation of HIF-1α.
Figure 3: Working model of two sets of HIF-1-regulated genes.
Figure 4: Hypoxia meets the mTOR pathway.
Figure 5: Hypoxia-induced loss of E-cadherin through the lysyl oxidase–Snail activation pathway.
Figure 6: Intracellular-pH-regulating systems as potential anti-cancer targets.

Similar content being viewed by others

References

  1. Pages, G. et al. Mitogen-activated protein kinases p42mapk and p44mapk are required for fibroblast proliferation. Proc. Natl Acad. Sci. USA 90, 8319–8323 (1993).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  2. Pouyssegur, J. & Lenormand, P. Fidelity and spatio–temporal control in MAP kinase (ERKs) signalling. Eur. J. Biochem. 270, 3291–3299 (2003).

    Article  CAS  PubMed  Google Scholar 

  3. Marshall, C. How do small GTPase signal transduction pathways regulate cell cycle entry? Curr. Opin. Cell Biol. 11, 732–736 (1999).

    Article  CAS  PubMed  Google Scholar 

  4. Downward, J. Mechanisms and consequences of activation of protein kinase B/Akt. Curr. Opin. Cell Biol. 10, 262–267 (1998).

    Article  CAS  PubMed  Google Scholar 

  5. Kinbara, K., Goldfinger, L. E., Hansen, M., Chou, F. L. & Ginsberg, M. H. Ras GTPases: integrins' friends or foes? Nature Rev. Mol. Cell Biol. 4, 767–776 (2003).

    Article  CAS  Google Scholar 

  6. Rak, J. et al. Oncogenes and tumor angiogenesis: differential modes of vascular endothelial growth factor up-regulation in ras-transformed epithelial cells and fibroblasts. Cancer Res. 60, 490–498 (2000).

    CAS  PubMed  Google Scholar 

  7. Berra, E., Pages, G. & Pouyssegur, J. MAP kinases and hypoxia in the control of VEGF expression. Cancer Metastasis Rev. 19, 139–145 (2000).

    Article  CAS  PubMed  Google Scholar 

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

    Article  ADS  CAS  PubMed  Google Scholar 

  9. Pugh, C. W. & Ratcliffe, P. J. Regulation of angiogenesis by hypoxia: role of the HIF system. Nature Med. 9, 677–684 (2003).

    Article  CAS  PubMed  Google Scholar 

  10. Wang, G. L. & Semenza, G. L. Purification and characterization of hypoxia-inducible factor 1. J. Biol. Chem. 270, 1230–1237 (1995).

    Article  CAS  PubMed  Google Scholar 

  11. Semenza, G. L. Regulation of mammalian O2 homeostasis by hypoxia-inducible factor 1. Annu. Rev. Cell Dev. Biol. 15, 551–578 (1999).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  13. Mandriota, S. J. & Pepper, M. S. Regulation of angiopoietin-2 mRNA levels in bovine microvascular endothelial cells by cytokines and hypoxia. Circ. Res. 83, 852–859 (1998).

    Article  CAS  PubMed  Google Scholar 

  14. Semenza, G. L. Targeting HIF-1 for cancer therapy. Nature Rev. Cancer 3, 721–732 (2003).

    Article  CAS  Google Scholar 

  15. Ferrara, N. et al. Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature 380, 439–442 (1996).

    Article  ADS  CAS  PubMed  Google Scholar 

  16. Ferrara, N., Gerber, H. P. & LeCouter, J. The biology of VEGF and its receptors. Nature Med. 9, 669–676 (2003).

    Article  CAS  PubMed  Google Scholar 

  17. Maisonpierre, P. C. et al. Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis. Science 277, 55–60 (1997).

    Article  CAS  PubMed  Google Scholar 

  18. Carmeliet, P. Blood vessels and nerves: common signals, pathways and diseases. Nature Rev. Genet. 4, 710–720 (2003).

    Article  CAS  PubMed  Google Scholar 

  19. Gerhardt, H. et al. VEGF guides angiogenic sprouting utilizing endothelial tip cell filopodia. J. Cell Biol. 161, 1163–1177 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Pages, G. & Pouyssegur, J. Transcriptional regulation of the vascular endothelial growth factor gene: a concert of activating factors. Cardiovasc. Res. 65, 564–573 (2005).

    Article  CAS  PubMed  Google Scholar 

  21. Milanini-Mongiat, J., Pouyssegur, J. & Pages, G. Identification of two Sp1 phosphorylation sites for p42/p44 mitogen-activated protein kinases: their implication in vascular endothelial growth factor gene transcription. J. Biol. Chem. 277, 20631–20639 (2002).

    Article  CAS  PubMed  Google Scholar 

  22. Richard, D. E., Berra, E., Gothie, E., Roux, D. & Pouyssegur, J. p42/p44 mitogen-activated protein kinases phosphorylate hypoxia-inducible factor 1α (HIF-1α) and enhance the transcriptional activity of HIF-1. J. Biol. Chem. 274, 32631–32637 (1999).

    Article  CAS  PubMed  Google Scholar 

  23. Pages, G., Berra, E., Milanini, J., Levy, A. P. & Pouyssegur, J. Stress-activated protein kinases (JNK and p38/HOG) are essential for vascular endothelial growth factor mRNA stability. J. Biol. Chem. 275, 26484–26491 (2000).

    Article  CAS  PubMed  Google Scholar 

  24. Huez, I. et al. Two independent internal ribosome entry sites are involved in translation initiation of vascular endothelial growth factor mRNA. Mol. Cell Biol. 18, 6178–6190 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Lang, K. J., Kappel, A. & Goodall, G. J. Hypoxia-inducible factor-1α mRNA contains an internal ribosome entry site that allows efficient translation during normoxia and hypoxia. Mol. Biol. Cell 13, 1792–1801 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Hegen, A. et al. Expression of angiopoietin-2 in endothelial cells is controlled by positive and negative regulatory promoter elements. Arterioscler. Thromb. Vasc. Biol. 24, 1803–1809 (2004).

    Article  CAS  PubMed  Google Scholar 

  27. Lindblom, P. et al. Endothelial PDGF-B retention is required for proper investment of pericytes in the microvessel wall. Genes Dev. 17, 1835–1840 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Noseda, M. et al. Notch activation induces endothelial cell cycle arrest and participates in contact inhibition: role of p21Cip1 repression. Mol. Cell Biol. 24, 8813–8822 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Fiedler, U. et al. The Tie-2 ligand angiopoietin-2 is stored in and rapidly released upon stimulation from endothelial cell Weibel–Palade bodies. Blood 103, 4150–4156 (2004).

    Article  CAS  PubMed  Google Scholar 

  30. Manalo, D. J. et al. Transcriptional regulation of vascular endothelial cell responses to hypoxia by HIF-1. Blood 105, 659–669 (2005).

    Article  CAS  PubMed  Google Scholar 

  31. Brahimi-Horn, C., Mazure, N. & Pouyssegur, J. Signalling via the hypoxia-inducible factor-1α requires multiple posttranslational modifications. Cell Signal. 17, 1–9 (2005).

    Article  CAS  PubMed  Google Scholar 

  32. Semenza, G. L. Hydroxylation of HIF-1: oxygen sensing at the molecular level. Physiology (Bethesda) 19, 176–182 (2004).

    CAS  Google Scholar 

  33. Berra, E., Ginouves, A. & Pouyssegur, J. The hypoxia-inducible-factor hydroxylases bring fresh air into hypoxia signalling. EMBO Rep. 7, 41–45 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Bruick, R. K. & McKnight, S. L. A conserved family of prolyl-4-hydroxylases that modify HIF. Science 294, 1337–1340 (2001).

    Article  ADS  CAS  PubMed  Google Scholar 

  35. Jaakkola, P. et al. Targeting of HIF-α to the von Hippel–Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science 292, 468–472 (2001).

    Article  ADS  CAS  PubMed  Google Scholar 

  36. Epstein, A. C. et al. C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation. Cell 107, 43–54 (2001).

    Article  CAS  PubMed  Google Scholar 

  37. Kaelin, W. G. Jr. The von Hippel–Lindau gene, kidney cancer, and oxygen sensing. J. Am. Soc. Nephrol. 14, 2703–2711 (2003).

    Article  PubMed  Google Scholar 

  38. Maxwell, P. H., Pugh, C. W. & Ratcliffe, P. J. Activation of the HIF pathway in cancer. Curr. Opin. Genet. Dev. 11, 293–299 (2001).

    Article  CAS  PubMed  Google Scholar 

  39. Kallio, P. J., Wilson, W. J., O'Brien, S., Makino, Y. & Poellinger, L. Regulation of the hypoxia-inducible transcription factor 1α by the ubiquitin–proteasome pathway. J. Biol. Chem. 274, 6519–6525 (1999).

    Article  CAS  PubMed  Google Scholar 

  40. Berra, E., Richard, D. E., Gothie, E. & Pouyssegur, J. HIF-1-dependent transcriptional activity is required for oxygen-mediated HIF-1α degradation. FEBS Lett. 491, 85–90 (2001).

    Article  CAS  PubMed  Google Scholar 

  41. Berra, E. et al. HIF prolyl-hydroxylase 2 is the key oxygen sensor setting low steady-state levels of HIF-1α in normoxia. EMBO J. 22, 4082–4090 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Lando, D. et al. FIH-1 is an asparaginyl hydroxylase enzyme that regulates the transcriptional activity of hypoxia-inducible factor. Genes Dev. 16, 1466–1471 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Gothie, E., Richard, D. E., Berra, E., Pages, G. & Pouyssegur, J. Identification of alternative spliced variants of human hypoxia-inducible factor-1α. J. Biol. Chem. 275, 6922–6927 (2000).

    Article  CAS  PubMed  Google Scholar 

  44. Koivunen, P., Hirsila, M., Gunzler, V., Kivirikko, K. I. & Myllyharju, J. Catalytic properties of the asparaginyl hydroxylase (FIH) in the oxygen sensing pathway are distinct from those of its prolyl 4-hydroxylases. J. Biol. Chem. 279, 9899–9904 (2004).

    Article  CAS  PubMed  Google Scholar 

  45. Dayan, F., Roux, D., Brahimi-Horn, C., Pouyssegur, J. & Mazure, N. The oxygen-sensor factor inhibiting HIF-1 (FIH) controls the expression of distinct genes through the bi-functional transcriptional character of HIF-1α. Cancer Res. 66, 3688–3698 (2006).

    Article  CAS  PubMed  Google Scholar 

  46. Bruick, R. K. Expression of the gene encoding the proapoptotic Nip3 protein is induced by hypoxia. Proc. Natl Acad. Sci. USA 97, 9082–9087 (2000).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  47. Webster, K. A., Graham, R. M. & Bishopric, N. H. BNip3 and signal-specific programmed death in the heart. J. Mol. Cell Cardiol. 38, 35–45 (2005).

    Article  CAS  PubMed  Google Scholar 

  48. Guertin, D. A. & Sabatini, D. M. An expanding role for mTOR in cancer. Trends Mol. Med. 11, 353–361 (2005).

    Article  CAS  PubMed  Google Scholar 

  49. Nobukini, T. & Thomas, G. The mTOR/S6K signalling pathway: the role of the TSC1/2 tumour suppressor complex and the proto-oncogene Rheb. Novartis Found. Symp. 262, 148–154; Discussion 154–159, 265–268 (2004).

    CAS  PubMed  Google Scholar 

  50. Brugarolas, J. & Kaelin, W. G. Jr. Dysregulation of HIF and VEGF is a unifying feature of the familial hamartoma syndromes. Cancer Cell 6, 7–10 (2004).

    Article  CAS  PubMed  Google Scholar 

  51. Tee, A. R., Manning, B. D., Roux, P. P., Cantley, L. C. & Blenis, J. Tuberous sclerosis complex gene products, Tuberin and Hamartin, control mTOR signaling by acting as a GTPase-activating protein complex toward Rheb. Curr. Biol. 13, 1259–1268 (2003).

    Article  CAS  PubMed  Google Scholar 

  52. Ma, L., Chen, Z., Erdjument-Bromage, H., Tempst, P. & Pandolfi, P. P. Phosphorylation and functional inactivation of TSC2 by Erk implications for tuberous sclerosis and cancer pathogenesis. Cell 121, 179–193 (2005).

    Article  CAS  PubMed  Google Scholar 

  53. Hara, K. et al. Amino acid sufficiency and mTOR regulate p70 S6 kinase and eIF-4E BP1 through a common effector mechanism. J. Biol. Chem. 273, 14484–14494 (1998).

    Article  CAS  PubMed  Google Scholar 

  54. Peng, T., Golub, T. R. & Sabatini, D. M. The immunosuppressant rapamycin mimics a starvation-like signal distinct from amino acid and glucose deprivation. Mol. Cell Biol. 22, 5575–5584 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Fukuda, R. et al. Insulin-like growth factor 1 induces hypoxia-inducible factor 1-mediated vascular endothelial growth factor expression, which is dependent on MAP kinase and phosphatidylinositol 3-kinase signaling in colon cancer cells. J. Biol. Chem. 277, 38205–38211 (2002).

    Article  CAS  PubMed  Google Scholar 

  56. Thomas, G. V. et al. Hypoxia-inducible factor determines sensitivity to inhibitors of mTOR in kidney cancer. Nature Med. 12, 122–127 (2006).

    Article  ADS  CAS  PubMed  Google Scholar 

  57. Shaw, R. J. et al. The tumor suppressor LKB1 kinase directly activates AMP-activated kinase and regulates apoptosis in response to energy stress. Proc. Natl Acad. Sci. USA 101, 3329–3335 (2004).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  59. Hardie, D. G. New roles for the LKB1–AMPK pathway. Curr. Opin. Cell Biol. 17, 167–173 (2005).

    Article  CAS  PubMed  Google Scholar 

  60. Reiling, J. H. & Hafen, E. The hypoxia-induced paralogs Scylla and Charybdis inhibit growth by down-regulating S6K activity upstream of TSC in Drosophila. Genes Dev. 18, 2879–2892 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Brugarolas, J. et al. Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex. Genes Dev. 18, 2893–2904 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Lum, J. J. et al. Growth factor regulation of autophagy and cell survival in the absence of apoptosis. Cell 120, 237–248 (2005).

    Article  CAS  PubMed  Google Scholar 

  63. Bacon, A. L. & Harris, A. L. Hypoxia-inducible factors and hypoxic cell death in tumour physiology. Ann. Med. 36, 530–539 (2004).

    Article  CAS  PubMed  Google Scholar 

  64. Okami, J., Simeone, D. M. & Logsdon, C. D. Silencing of the hypoxia-inducible cell death protein BNIP3 in pancreatic cancer. Cancer Res. 64, 5338–5346 (2004).

    Article  CAS  PubMed  Google Scholar 

  65. Manka, D., Spicer, Z. & Millhorn, D. E. Bcl-2/adenovirus E1B 19 kDa interacting protein-3 knockdown enables growth of breast cancer metastases in the lung, liver, and bone. Cancer Res. 65, 11689–11693 (2005).

    Article  CAS  PubMed  Google Scholar 

  66. Isaacs, J. S. et al. HIF overexpression correlates with biallelic loss of fumarate hydratase in renal cancer: novel role of fumarate in regulation of HIF stability. Cancer Cell 8, 143–53 (2005).

    Article  CAS  PubMed  Google Scholar 

  67. Kim, W. Y. & Kaelin, W. G. Role of VHL gene mutation in human cancer. J. Clin. Oncol. 22, 4991–5004 (2004).

    Article  CAS  PubMed  Google Scholar 

  68. Funasaka, T., Yanagawa, T., Hogan, V. & Raz, A. Regulation of phosphoglucose isomerase/autocrine motility factor expression by hypoxia. FASEB J. 19, 1422–1430 (2005).

    Article  CAS  PubMed  Google Scholar 

  69. Pennacchietti, S. et al. Hypoxia promotes invasive growth by transcriptional activation of the met protooncogene. Cancer Cell 3, 347–361 (2003).

    Article  PubMed  Google Scholar 

  70. Staller, P. et al. Chemokine receptor CXCR4 downregulated by von Hippel–Lindau tumour suppressor pVHL. Nature 425, 307–311 (2003).

    Article  ADS  CAS  PubMed  Google Scholar 

  71. Thiery, J. P. Epithelial–mesenchymal transitions in development and pathologies. Curr. Opin. Cell Biol. 15, 740–746 (2003).

    Article  CAS  PubMed  Google Scholar 

  72. Beavon, I. R. Regulation of E-cadherin: does hypoxia initiate the metastatic cascade? Mol. Pathol. 52, 179–188 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Imai, T. et al. Hypoxia attenuates the expression of E-cadherin via up-regulation of SNAIL in ovarian carcinoma cells. Am. J. Pathol. 163, 1437–1447 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Esteban, M. A. et al. Cancer Res. 66, 3567–3575 (2006).

    Article  CAS  PubMed  Google Scholar 

  75. Thomassin, L. et al. The Pro-regions of lysyl oxidase and lysyl oxidase-like 1 are required for deposition onto elastic fibers. J. Biol. Chem. 280, 42848–42855 (2005).

    Article  CAS  PubMed  Google Scholar 

  76. Peinado, H. et al. A molecular role for lysyl oxidase-like 2 enzyme in snail regulation and tumor progression. EMBO J. 24, 3446–3458 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Kirschmann, D. A. et al. A molecular role for lysyl oxidase in breast cancer invasion. Cancer Res. 62, 4478–4483 (2002).

    CAS  PubMed  Google Scholar 

  78. Erler, J. T. et al. Lysyl oxidase is essential for hypoxia-induced metastasis. Nature 440, 1222–1226 (2006).

  79. Denko, N. C. et al. Investigating hypoxic tumor physiology through gene expression patterns. Oncogene 22, 5907–5914 (2003).

    Article  CAS  PubMed  Google Scholar 

  80. Krishnamachary, B. et al. Hypoxia-inducible factor-1-dependent repression of E-cadherin in von Hippel–Lindau tumor suppressor-null renal cell carcinoma mediated by TCF3, ZFHX1A, and ZFHX1B. Cancer Res. 66, 2725–2731 (2006).

    Article  CAS  PubMed  Google Scholar 

  81. Kondo, K., Klco, J., Nakamura, E., Lechpammer, M. & Kaelin, W. G. Jr. Inhibition of HIF is necessary for tumor suppression by the von Hippel–Lindau protein. Cancer Cell 1, 237–46 (2002).

    Article  CAS  PubMed  Google Scholar 

  82. Covello, K. L. et al. HIF-2α regulates Oct-4: effects of hypoxia on stem cell function, embryonic development, and tumor growth. Genes Dev. 20, 557–570 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Kong, D. et al. Echinomycin, a small-molecule inhibitor of hypoxia-inducible factor-1 DNA-binding activity. Cancer Res. 65, 9047–9055 (2005).

    Article  CAS  PubMed  Google Scholar 

  84. Ferrara, N. & Kerbel, R. Angiogenesis as a therapeutic target. Nature 438, 967–974 (2005).

    Article  ADS  CAS  PubMed  Google Scholar 

  85. Oliner, J. et al. Suppression of angiogenesis and tumor growth by selective inhibition of angiopoietin-2. Cancer Cell 6, 507–516 (2004).

    Article  CAS  PubMed  Google Scholar 

  86. Newell, K., Franchi, A., Pouyssegur, J. & Tannock, I. Studies with glycolysis-deficient cells suggest that production of lactic acid is not the only cause of tumor acidity. Proc. Natl Acad. Sci. USA 90, 1127–1131 (1993).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  87. Cardone, R. A., Casavola, V. & Reshkin, S. J. The role of disturbed pH dynamics and the Na+/H+ exchanger in metastasis. Nature Rev. Cancer 5, 786–795 (2005).

    Article  CAS  Google Scholar 

  88. Potter, C. & Harris, A. L. Hypoxia inducible carbonic anhydrase IX, marker of tumour hypoxia, survival pathway and therapy target. Cell Cycle 3, 164–167 (2004).

    Article  CAS  PubMed  Google Scholar 

  89. Romero, M. F., Fulton, C. M. & Boron, W. F. The SLC4 family of HCO3-transporters. Pflügers Arch. 447, 495–509 (2004).

    Article  CAS  PubMed  Google Scholar 

  90. Halestrap, A. P. & Meredith, D. The SLC16 gene family-from monocarboxylate transporters (MCTs) to aromatic amino acid transporters and beyond. Pflügers Arch. 447, 619–628 (2004).

    Article  CAS  PubMed  Google Scholar 

  91. Ullah, M. S., Davies, A. J. & Halestrap, A. P. The plasma membrane lactate transporter MCT4, but not MCT1, is up-regulated by hypoxia through a HIF-1α dependent mechanism. J. Biol. Chem. 281, 9030–9037 (2006).

    Article  CAS  PubMed  Google Scholar 

  92. Sardet, C., Franchi, A. & Pouyssegur, J. Molecular cloning, primary structure, and expression of the human growth factor-activatable Na+/H+ antiporter. Cell 56, 271–280 (1989).

    Article  CAS  PubMed  Google Scholar 

  93. Counillon, L. & Pouyssegur, J. The expanding family of eucaryotic Na+/H+ exchangers. J. Biol. Chem. 275, 1–4 (2000).

    Article  CAS  PubMed  Google Scholar 

  94. Pouyssegur, J., Franchi, A. & Pages, G. pHi, aerobic glycolysis and vascular endothelial growth factor in tumour growth. Novartis Found. Symp. 240, 186–196; Discussion 196–198 (2001).

    CAS  PubMed  Google Scholar 

  95. Wong, P., Kleemann, H. W. & Tannock, I. F. Cytostatic potential of novel agents that inhibit the regulation of intracellular pH. Br. J. Cancer 87, 238–245 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Murray, C. M. et al. Monocarboxylate transporter MCT1 is a target for immunosuppression. Nature Chem. Biol. 1, 371–376 (2005).

    Article  CAS  Google Scholar 

  97. Lum, J. J., DeBerardinis, R. J. & Thompson, C. B. Autophagy in metazoans: cell survival in the land of plenty. Nature Rev. Mol. Cell Biol. 6, 439–448 (2005).

    Article  CAS  Google Scholar 

  98. Kondo, Y., Kanzawa, T., Sawaya, R. & Kondo, S. The role of autophagy in cancer development and response to therapy. Nature Rev. Cancer 5, 726–734 (2005).

    Article  CAS  Google Scholar 

  99. Vaupel, P. The role of hypoxia-induced factors in tumor progression. Oncologist 9 (suppl. 5), 10–17 (2004).

    Article  CAS  PubMed  Google Scholar 

  100. Cramer, T. et al. HIF-1α is essential for myeloid cell-mediated inflammation. Cell 112, 645–657 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Cummins, E. P. & Taylor, C. T. Hypoxia-responsive transcription factors. Pflügers Arch. 450, 363–371 (2005).

    Article  CAS  PubMed  Google Scholar 

  102. Gustafsson, M. V. et al. Hypoxia requires notch signaling to maintain the undifferentiated cell state. Dev. Cell 9, 617–628 (2005).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank all our laboratory members for their discussion and support, and particularly C. Brahimi-Horn for thoroughly reviewing and critically reading the manuscript. Because of space constraints, we apologize to the many research groups whose citations were omitted or cited indirectly. Financial support was from the Centre National de la Recherche Scientifique (CNRS), Centre A. Lacassagne, Ministère de l'Education, de la Recherche et de la Technologie, Ligue Nationale Contre le Cancer (Equipe labellisée), the GIP HMR (contract No. 1/9743B-A3) and Conseil Regional PACA.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Jacques Pouysségur.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Additional information

Author Information Reprints and permissions information is available at npg.nature.com/reprintsandpermissions.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Pouysségur, J., Dayan, F. & Mazure, N. Hypoxia signalling in cancer and approaches to enforce tumour regression. Nature 441, 437–443 (2006). https://doi.org/10.1038/nature04871

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature04871

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing