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Hypoxia signalling in cancer and approaches to enforce tumour regression

Nature volume 441, pages 437443 (25 May 2006) | Download Citation

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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.

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References

  1. 1.

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

  2. 2.

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

  3. 3.

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

  4. 4.

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

  5. 5.

    , , , & Ras GTPases: integrins' friends or foes? Nature Rev. Mol. Cell Biol. 4, 767–776 (2003).

  6. 6.

    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).

  7. 7.

    , & MAP kinases and hypoxia in the control of VEGF expression. Cancer Metastasis Rev. 19, 139–145 (2000).

  8. 8.

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

  9. 9.

    & Regulation of angiogenesis by hypoxia: role of the HIF system. Nature Med. 9, 677–684 (2003).

  10. 10.

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

  11. 11.

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

  12. 12.

    , , & Hypoxia-induced transcriptional activation and increased mRNA stability of vascular endothelial growth factor in C6 glioma cells. J. Biol. Chem. 270, 19761–19766 (1995).

  13. 13.

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

  14. 14.

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

  15. 15.

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

  16. 16.

    , & The biology of VEGF and its receptors. Nature Med. 9, 669–676 (2003).

  17. 17.

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

  18. 18.

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

  19. 19.

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

  20. 20.

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

  21. 21.

    , & 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).

  22. 22.

    , , , & 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).

  23. 23.

    , , , & Stress-activated protein kinases (JNK and p38/HOG) are essential for vascular endothelial growth factor mRNA stability. J. Biol. Chem. 275, 26484–26491 (2000).

  24. 24.

    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).

  25. 25.

    , & 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).

  26. 26.

    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).

  27. 27.

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

  28. 28.

    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).

  29. 29.

    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).

  30. 30.

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

  31. 31.

    , & Signalling via the hypoxia-inducible factor-1α requires multiple posttranslational modifications. Cell Signal. 17, 1–9 (2005).

  32. 32.

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

  33. 33.

    , & The hypoxia-inducible-factor hydroxylases bring fresh air into hypoxia signalling. EMBO Rep. 7, 41–45 (2006).

  34. 34.

    & A conserved family of prolyl-4-hydroxylases that modify HIF. Science 294, 1337–1340 (2001).

  35. 35.

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

  36. 36.

    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).

  37. 37.

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

  38. 38.

    , & Activation of the HIF pathway in cancer. Curr. Opin. Genet. Dev. 11, 293–299 (2001).

  39. 39.

    , , , & Regulation of the hypoxia-inducible transcription factor 1α by the ubiquitin–proteasome pathway. J. Biol. Chem. 274, 6519–6525 (1999).

  40. 40.

    , , & HIF-1-dependent transcriptional activity is required for oxygen-mediated HIF-1α degradation. FEBS Lett. 491, 85–90 (2001).

  41. 41.

    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).

  42. 42.

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

  43. 43.

    , , , & Identification of alternative spliced variants of human hypoxia-inducible factor-1α. J. Biol. Chem. 275, 6922–6927 (2000).

  44. 44.

    , , , & 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).

  45. 45.

    , , , & 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).

  46. 46.

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

  47. 47.

    , & BNip3 and signal-specific programmed death in the heart. J. Mol. Cell Cardiol. 38, 35–45 (2005).

  48. 48.

    & An expanding role for mTOR in cancer. Trends Mol. Med. 11, 353–361 (2005).

  49. 49.

    & 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).

  50. 50.

    & Dysregulation of HIF and VEGF is a unifying feature of the familial hamartoma syndromes. Cancer Cell 6, 7–10 (2004).

  51. 51.

    , , , & 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).

  52. 52.

    , , , & Phosphorylation and functional inactivation of TSC2 by Erk implications for tuberous sclerosis and cancer pathogenesis. Cell 121, 179–193 (2005).

  53. 53.

    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).

  54. 54.

    , & The immunosuppressant rapamycin mimics a starvation-like signal distinct from amino acid and glucose deprivation. Mol. Cell Biol. 22, 5575–5584 (2002).

  55. 55.

    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).

  56. 56.

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

  57. 57.

    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).

  58. 58.

    , , & AMP-activated protein kinase: ancient energy gauge provides clues to modern understanding of metabolism. Cell Metab. 1, 15–25 (2005).

  59. 59.

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

  60. 60.

    & 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).

  61. 61.

    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).

  62. 62.

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

  63. 63.

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

  64. 64.

    , & Silencing of the hypoxia-inducible cell death protein BNIP3 in pancreatic cancer. Cancer Res. 64, 5338–5346 (2004).

  65. 65.

    , & 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).

  66. 66.

    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).

  67. 67.

    & Role of VHL gene mutation in human cancer. J. Clin. Oncol. 22, 4991–5004 (2004).

  68. 68.

    , , & Regulation of phosphoglucose isomerase/autocrine motility factor expression by hypoxia. FASEB J. 19, 1422–1430 (2005).

  69. 69.

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

  70. 70.

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

  71. 71.

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

  72. 72.

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

  73. 73.

    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).

  74. 74.

    et al. Cancer Res. 66, 3567–3575 (2006).

  75. 75.

    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).

  76. 76.

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

  77. 77.

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

  78. 78.

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

  79. 79.

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

  80. 80.

    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).

  81. 81.

    , , , & Inhibition of HIF is necessary for tumor suppression by the von Hippel–Lindau protein. Cancer Cell 1, 237–46 (2002).

  82. 82.

    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).

  83. 83.

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

  84. 84.

    & Angiogenesis as a therapeutic target. Nature 438, 967–974 (2005).

  85. 85.

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

  86. 86.

    , , & 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).

  87. 87.

    , & The role of disturbed pH dynamics and the Na+/H+ exchanger in metastasis. Nature Rev. Cancer 5, 786–795 (2005).

  88. 88.

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

  89. 89.

    , & The SLC4 family of HCO3-transporters. Pflügers Arch. 447, 495–509 (2004).

  90. 90.

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

  91. 91.

    , & 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).

  92. 92.

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

  93. 93.

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

  94. 94.

    , & pHi, aerobic glycolysis and vascular endothelial growth factor in tumour growth. Novartis Found. Symp. 240, 186–196; Discussion 196–198 (2001).

  95. 95.

    , & Cytostatic potential of novel agents that inhibit the regulation of intracellular pH. Br. J. Cancer 87, 238–245 (2002).

  96. 96.

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

  97. 97.

    , & Autophagy in metazoans: cell survival in the land of plenty. Nature Rev. Mol. Cell Biol. 6, 439–448 (2005).

  98. 98.

    , , & The role of autophagy in cancer development and response to therapy. Nature Rev. Cancer 5, 726–734 (2005).

  99. 99.

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

  100. 100.

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

  101. 101.

    & Hypoxia-responsive transcription factors. Pflügers Arch. 450, 363–371 (2005).

  102. 102.

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

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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.

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  1. Institute of Signalling, Developmental Biology and Cancer Research, CNRS UMR-6543, University of Nice, Centre Antoine Lacassagne, 33 Avenue Valombrose, 06189 Nice, France.

    • Jacques Pouysségur
    • , Frédéric Dayan
    •  & Nathalie M. Mazure

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Correspondence to Jacques Pouysségur.

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