Location via proxy:   [ UP ]  
[Report a bug]   [Manage cookies]                
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 — a key regulatory factor in tumour growth

Nature Reviews Cancer volume 2, pages 38–47 (2002)Cite this article

Key Points

  • Hypoxia is a reduction in the normal level of tissue oxygen tension, and occurs during acute and chronic vascular disease, pulmonary disease and cancer. It induces a transcription programme that promotes an aggressive tumour phenotype.

  • Hypoxia is associated with resistance to radiation therapy and chemotherapy, but is also associated with poor outcome regardless of treatment modality, indicating that it might be an important therapeutic target.

  • Hypoxia-inducible factor-1α (HIF-1α) is a key transcription factor that is induced by hypoxia and regulated by a proline hydroxylase.

  • Pathways that are regulated by hypoxia include angiogenesis, glycolysis, growth-factor signalling, immortalization, genetic instability, tissue invasion and metastasis, apoptosis and pH regulation.

  • Most of the hypoxia-induced pathways promote tumour growth, but apoptosis is also induced by hypoxia. The balance of these pathways might be critical for the effects of hypoxia on tumour growth.

  • Drugs that inhibit HIF-1α expression antagonize HIF-1α interaction with CBP/p300 or block downstream function of genes such as vascular endothelial growth factor and cyclooxygenase-2 have potentially important roles in tumour therapy. Hypoxia can also be used to activate therapeutic gene delivery to specific areas of tissue.

Abstract

Cells undergo a variety of biological responses when placed in hypoxic conditions, including activation of signalling pathways that regulate proliferation, angiogenesis and death. Cancer cells have adapted these pathways, allowing tumours to survive and even grow under hypoxic conditions, and tumour hypoxia is associated with poor prognosis and resistance to radiation therapy. Many elements of the hypoxia-response pathway are therefore good candidates for therapeutic targeting.

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

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

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

Figure 1: HIF-1 pathway.
Figure 2: Other factors involved in HIF-1 activation of hypoxia-response genes.
Figure 3: Hypoxia regulation of cell-death pathways.

Similar content being viewed by others

References

  1. Thomlinson, R. & Gray, L. The histological structure of some human lung cancers and the possible implications for radiotherapy. Br. J. Canc. 9, 539–549 (1955).

    Article  CAS  Google Scholar 

  2. Brown, J. M. & Giaccia, A. J. The unique physiology of solid tumors: opportunities (and problems) for cancer therapy. Cancer Res. 58, 1408–1416 (1998).

    CAS  PubMed  Google Scholar 

  3. Prabhakar, N. R. Oxygen sensing during intermittent hypoxia: cellular and molecular mechanisms. J. Appl. Physiol. 90, 1986–1994 (2001).

    Article  CAS  PubMed  Google Scholar 

  4. Wouters, B. G. & Brown, J. M. Cells at intermediate oxygen levels can be more important than the hypoxic fraction in determining tumor response to fractionated radiotherapy. Radiat. Res. 147, 541–550 (1997).

    Article  CAS  PubMed  Google Scholar 

  5. Hockel, M. & Vaupel, P. Tumor hypoxia: definitions and current clinical, biologic, and molecular aspects. J. Natl Cancer Inst. 93, 266–276 (2001).

    Article  CAS  PubMed  Google Scholar 

  6. Hockel, M., Schlenger, K., Hockel, S. & Vaupel, P. Hypoxic cervical cancers with low apoptotic index are highly aggressive. Cancer Res. 59, 4525–4528 (1999).

    CAS  PubMed  Google Scholar 

  7. Dang, C. V. & Semenza, G. L. Oncogenic alterations of metabolism. Trends Biochem. Sci. 24, 68–72 (1999).

    Article  CAS  PubMed  Google Scholar 

  8. Wang, G. L., Jiang, B. H., Rue, E. A. & Semenza, G. L. Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc. Natl Acad. Sci. USA 92, 5510–5514 (1995)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Carrero, P. et al. Redox-regulated recruitment of the transcriptional coactivators CREB-binding protein and SRC-1 to hypoxia-inducible factor-1α. Mol. Cell Biol. 20, 402–415 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Lando, D., Pongratz, I., Poellingers, L. & Whitelaw, M. L. A redox mechanism controls differential DNA binding activities of hypoxia-inducible factor (HIF)-1α and the HIF-like factor. J. Biol. Chem. 275, 4618–4627 (2000).

    Article  CAS  PubMed  Google Scholar 

  11. Cockman, M. E. et al. Hypoxia inducible factor-α binding and ubiquitylation by the von Hippel–Lindau tumor suppressor protein. J. Biol. Chem. 275, 25733–25741 (2000).

    Article  CAS  PubMed  Google Scholar 

  12. Ohh, M. et al. Ubiquitination of hypoxia-inducible factor requires direct binding to the β-domain of the von Hippel–Lindau protein. Nature Cell Biol. 2, 423–427 (2000).

    Article  CAS  PubMed  Google Scholar 

  13. Kamura, T. et al. Activation of HIF-1α ubiquitination by a reconstituted von Hippel–Lindau (VHL) tumor suppressor complex. Proc. Natl Acad. Sci. USA 97, 10430–10435 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Tanimoto, K., Makino, Y., Pereira, T. & Poellinger, L. Mechanism of regulation of the hypoxia-inducible factor-1α by the von Hippel–Lindau tumor suppressor protein. EMBO J. 19, 4298–4309 (2000).References 11–14 report that VHL protein modifies HIF-1α by ubiquitylation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Maxwell, P. H. et al. The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 399, 271–275 (1999).The first to show that mutations in VHL caused upregulation of HIF-1α, coupling a tumour-suppressor pathway to HIF-1 signalling.

    Article  CAS  PubMed  Google Scholar 

  16. Stebbins, C. E., Kaelin, W. G. Jr & Pavletich, N. P. Structure of the VHL–elongin-C–elongin-B complex: implications for VHL tumor suppressor function. Science 284, 455–461 (1999).

    Article  CAS  PubMed  Google Scholar 

  17. 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  CAS  PubMed  Google Scholar 

  18. Ivan, M. et al. HIF-α targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Science 292, 464–468 (2001).References 17 and 18 were the first descriptions of an enzyme that covalently modifies HIF-1α in an oxygen-dependent manner.

    Article  CAS  PubMed  Google Scholar 

  19. Masson, N., Willam, C., Maxwell, P. H., Pugh, C. W. & Ratcliffe, P. J. Independent function of two destruction domains in hypoxia-inducible factor-α chains activated by prolyl hydroxylation. EMBO J. 20, 5197–5206 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Chandel, N. S. et al. Reactive oxygen species generated at mitochondrial complex III stabilize hypoxia-inducible factor-1α during hypoxia: a mechanism of O2 sensing. J. Biol. Chem. 275, 25130–25138 (2000).

    Article  CAS  PubMed  Google Scholar 

  21. Srinivas, V. et al. Oxygen sensing and HIF-1 activation does not require an active mitochondrial respiratory chain electron-transfer pathway. J. Biol. Chem. 276, 21995–21998 (2001).

    Article  CAS  PubMed  Google Scholar 

  22. Vaux, E. C., Metzen, E., Yeates, K. M. & Ratcliffe, P. J. Regulation of hypoxia-inducible factor is preserved in the absence of a functioning mitochondrial respiratory chain. Blood 98, 296–302 (2001).

    Article  CAS  PubMed  Google Scholar 

  23. 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 

  24. Bruick, R. K. & McKnight, S. L. A conserved family of prolyl-4-hydroxylases that modify HIF. Science 294, 1337–1340 (2001).References 23 and 24 describe the characterization of three enzymes that act as oxygen sensors, using HIF-1α as a substrate and requiring oxygen.

    Article  CAS  PubMed  Google Scholar 

  25. Ryan, H. E., Lo, J. & Johnson, R. S. HIF-1α is required for solid tumor formation and embryonic vascularization. EMBO J. 17, 3005–3015 (1998).This study, along with references 28 and 44 , shows that HIF-1α has a significant role in tumour growth in vivo.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Tian, H., Hammer, R. E., Matsumoto, A. M., Russell, D. W. & McKnight, S. L. The hypoxia-responsive transcription factor EPAS1 is essential for catecholamine homeostasis and protection against heart failure during embryonic development. Genes Dev. 12, 3320–3324 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Peng, J., Zhang, L., Drysdale, L. & Fong, G. H. The transcription factor EPAS-1/hypoxia-inducible factor-2α plays an important role in vascular remodeling. Proc. Natl Acad. Sci. USA 97, 8386–8391 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Maxwell, P. H. et al. Hypoxia-inducible factor-1 modulates gene expression in solid tumors and influences both angiogenesis and tumor growth. Proc. Natl Acad. Sci. USA 94, 8104–8109 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Talks, K. L. et al. Expression and distribution of the hypoxia-inducible factors HIF-1α and HIF-2α in normal human tissues, cancers, and tumor-associated macrophages. Am. J. Pathol. 157, 411–421 (2000).The authors used a monoclonal antibody against HIF-1α to examine its expression and distribution in a variety of solid tumours. They observed nuclear localization of HIF-1α and -2α in subsets of the tumour cells, and reported that HIF-2α was also strongly expressed by subsets of tumour-associated macrophages.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Zhong, H. et al. Overexpression of hypoxia-inducible factor-1α in common human cancers and their metastases. Cancer Res. 59, 5830–5835 (1999).HIF-1α expression was analysed by immuno-histochemistry in 179 tumour specimens, and found to be overexpressed in a variety of tumour types. HIF-1α expression was also correlated with aberrant p53 accumulation and cell proliferation. These results provided the first clinical data indicating that HIF-1α was important for human cancer progression.

    CAS  PubMed  Google Scholar 

  31. Elson, D. A., Ryan, H. E., Snow, J. W., Johnson, R. & Arbeit, J. M. Coordinate up-regulation of hypoxia inducible factor (HIF)-1α and HIF-1 target genes during multi-stage epidermal carcinogenesis and wound healing. Cancer Res. 60, 6189–6195 (2000).

    CAS  PubMed  Google Scholar 

  32. Krieg, M. et al. Up-regulation of hypoxia-inducible factors HIF-1α and HIF-2α under normoxic conditions in renal carcinoma cells by von Hippel–Lindau tumor suppressor gene loss of function. Oncogene 19, 5435–5443 (2000).

    Article  CAS  PubMed  Google Scholar 

  33. Hanahan, D. & Weinberg, R. A. The hallmarks of cancer. Cell 100, 57–70 (2000).

    Article  CAS  PubMed  Google Scholar 

  34. Denko, N. et al. Epigenetic regulation of gene expression in cervical cancer cells by the tumor microenvironment. Clin. Cancer Res. 6, 480–487 (2000).

    CAS  PubMed  Google Scholar 

  35. Koong, A. C. et al. Candidate genes for the hypoxic tumor phenotype. Cancer Res. 60, 883–887 (2000).

    CAS  PubMed  Google Scholar 

  36. Wykoff, C. C., Pugh, C. W., Maxwell, P. H., Harris, A. L. & Ratcliffe, P. J. Identification of novel hypoxia dependent and independent target genes of the von Hippel–Lindau (VHL) tumour suppressor by mRNA differential expression profiling. Oncogene 19, 6297–6305 (2000).

    Article  CAS  PubMed  Google Scholar 

  37. Lal, A. et al. Transcriptional response to hypoxia in human tumors. J. Natl Cancer Inst. 93, 1337–1343 (2001).References 35–37 described a large number of hypoxia-regulated genes, among which there are many proangiogenic pathways.

    Article  CAS  PubMed  Google Scholar 

  38. Berra, E. et al. Signaling angiogenesis via p42/p44 MAP kinase and hypoxia. Biochem. Pharmacol. 60, 1171–1178 (2000).

    Article  CAS  PubMed  Google Scholar 

  39. Conrad, P. W., Beitner-Johnson, D. & Millhorn, D. E. EPAS1 trans-activation during hypoxia requires p42/p44 MAPK. J. Biol. Chem. 274, 33709–33713 (1999).

    Article  CAS  PubMed  Google Scholar 

  40. Chen, E. Y., Mazure, N. M., Cooper, J. A. & Giaccia, A. J. Hypoxia activates a platelet-derived growth factor receptor/phosphatidylinositol 3-kinase/AKT pathway that results in glycogen synthase kinase-3 inactivation. Cancer Res. 61, 2429–2433 (2001).

    CAS  PubMed  Google Scholar 

  41. Zundel, W. et al. Loss of PTEN facilitates HIF-1-mediated gene expression. Genes Dev. 14, 391–396 (2000).One of several papers showing that the PI3K pathway regulates HIF through a hypoxia-independent pathway.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Ryan, H. E. et al. Hypoxia-inducible factor-1α is a positive factor in solid tumor growth. Cancer Res. 60, 4010–4015 (2000).

    CAS  PubMed  Google Scholar 

  43. Mazurek, S., Boschek, C. B. & Eigenbrodt, E. The role of phosphometabolites in cell proliferation, energy metabolism, and tumor therapy. J. Bioenerg. Biomembr. 29, 315–330 (1997).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  45. Yu, J. L. et al. Heterogeneous vascular dependence of tumor cell populations. Am. J. Pathol. 158, 1325–1334 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Kung, A. L., Wang, S., Klco, J. M., Kaelin, W. G. & Livingston, D. M. Suppression of tumor growth through disruption of hypoxia-inducible transcription. Nature Med. 6, 1335–1340 (2000).Revealed that blockade of HIF-1 signalling by a peptide can completely inhibit tumour growth in vivo.

    Article  CAS  PubMed  Google Scholar 

  47. de Fraipont, F., Nicholson, A. C., Feige, J. J. & Van Meir, E. G. Thrombospondins and tumor angiogenesis. Trends Mol. Med. 7, 401–407 (2001).

    Article  CAS  PubMed  Google Scholar 

  48. Seagroves, T. N. et al. Transcription factor HIF-1 is a necessary mediator of the pasteur effect in mammalian cells. Mol. Cell Biol. 21, 3436–3444 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Chen, C. H., Pore, N., Behrooz, A., Ismail, B.-F. & Maity, A. Regulation of GLUT1 mRNA by hypoxia-inducible factor-1: interaction between H-ras and hypoxia. J. Biol. Chem. 276, 9519–9525 (2001).

    Article  CAS  PubMed  Google Scholar 

  50. Seimiya, H. et al. Hypoxia up-regulates telomerase activity via mitogen-activated protein kinase signaling in human solid tumor cells. Biochem. Biophys. Res. Commun. 260, 365–370 (1999).

    Article  CAS  PubMed  Google Scholar 

  51. Coquelle, A., Toledo, F., Stern, S., Bieth, A. & Debatisse, M. A new role for hypoxia in tumor progression: induction of fragile site triggering genomic rearrangements and formation of complex DMs and HSRs. Mol. Cell 2, 259–265 (1998).

    Article  CAS  PubMed  Google Scholar 

  52. Yuan, J., Narayanan, L., Rockwell, S. & Glazer, P. M. Diminished DNA repair and elevated mutagenesis in mammalian cells exposed to hypoxia and low pH. Cancer Res. 60, 4372–4376 (2000).

    CAS  PubMed  Google Scholar 

  53. Kim, M. S. et al. Histone deacetylases induce angiogenesis by negative regulation of tumor suppressor genes. Nature Med. 7, 437–443 (2001).

    Article  PubMed  Google Scholar 

  54. 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  CAS  PubMed  PubMed Central  Google Scholar 

  55. Vande Velde, C. et al. BNIP3 and genetic control of necrosis-like cell death through the mitochondrial permeability transition pore. Mol. Cell Biol. 20, 5454–5468 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Sowter, H. M., Ratcliffe, P. J., Watson, P., Greenberg, A. H. & Harris, A. L. HIF-1-dependent regulation of hypoxic induction of the cell death factors BNIP3 and NIX in human tumors. Cancer Res. 61, 6669–6673 (2001).

    CAS  PubMed  Google Scholar 

  57. Suzuki, H., Tomida, A. & Tsuruo, T. Dephosphorylated hypoxia-inducible factor-1α as a mediator of p53-dependent apoptosis during hypoxia. Oncogene 20, 5779–5788 (2001).

    Article  CAS  PubMed  Google Scholar 

  58. Graeber, T. G. et al. Hypoxia-mediated selection of cells with diminished apoptotic potential in solid tumors. Nature 379, 88–91 (1996).Shows that hypoxia selects for a more aggressive tumour phenotype in vivo.

    Article  CAS  PubMed  Google Scholar 

  59. Koumenis, C. et al. Regulation of p53 by hypoxia: dissociation of transcriptional repression and apoptosis from p53-dependent transactivation. Mol. Cell Biol. 21, 1297–1310 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Soengas, M. S. et al. Apaf-1 and caspase-9 in p53-dependent apoptosis and tumor inhibition. Science 284, 156–159 (1999).Defines the key pathways of hypoxia-induced apoptosis.

    Article  CAS  PubMed  Google Scholar 

  61. An, W. G. et al. Stabilization of wild-type p53 by hypoxia-inducible factor-1α. Nature 392, 405–408 (1998).

    Article  CAS  PubMed  Google Scholar 

  62. Ravi, R. et al. Regulation of tumor angiogenesis by p53-induced degradation of hypoxia-inducible factor-1α. Genes Dev. 14, 34–44 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Dong, Z. et al. Up-regulation of apoptosis inhibitory protein IAP-2 by hypoxia. HIF-1-independent mechanisms. J. Biol. Chem. 276, 18702–18709 (2001).Reports non-HIF-1 pathways that are important for cell survival that is regulated by hypoxia.

    Article  CAS  PubMed  Google Scholar 

  64. Ivanov, S. V. et al. Down-regulation of transmembrane carbonic anhydrases in renal cell carcinoma cell lines by wild-type von Hippel–Lindau transgenes. Proc. Natl Acad. Sci. USA 95, 12596–12601 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Wykoff, C. C. et al. Hypoxia-inducible expression of tumor-associated carbonic anhydrases. Cancer Res. 60, 7075–7083 (2000).Shows that acid pH in tumours might be determined by novel hypoxia-regulated pathways.

    CAS  PubMed  Google Scholar 

  66. Loncaster, J. A. et al. Carbonic anhydrase (CA IX) expression, a potential new intrinsic marker of hypoxia: correlations with tumor oxygen measurements and prognosis in locally advanced carcinoma of the cervix. Cancer Res. 61, 6394–6399 (2001).

    CAS  PubMed  Google Scholar 

  67. Chia, S. K. et al. Prognostic significance of a novel hypoxia-regulated marker, carbonic anhydrase IX, in invasive breast carcinoma. J. Clin. Oncol. 19, 3660–3668 (2001).

    Article  CAS  PubMed  Google Scholar 

  68. Yamagata, M., Hasuda, K., Stamato, T. & Tannock, I. F. The contribution of lactic acid to acidification of tumours: studies of variant cells lacking lactate dehydrogenase. Br. J. Cancer 77, 1726–1731 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Gardner, L. B. et al. Hypoxia inhibits G1/S transition through regulation of p27 expression. J. Biol. Chem. 276, 7919–7926 (2001).

    Article  CAS  PubMed  Google Scholar 

  70. Green, S. L., Freiberg, R. A. & Giaccia, A. J. p21(Cip1) and p27(Kip1) regulate cell cycle reentry after hypoxic stress but are not necessary for hypoxia-induced arrest. Mol. Cell Biol. 21, 1196–1206 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Raleigh, J. A. et al. A clinical study of hypoxia and metallothionein protein expression in squamous cell carcinomas. Clin. Cancer Res. 6, 855–862 (2000).

    CAS  PubMed  Google Scholar 

  72. Taylor, C. T., Furuta, G. T., Synnestvedt, K. & Colgan, S. P. Phosphorylation-dependent targeting of cAMP response element binding protein to the ubiquitin/proteasome pathway in hypoxia. Proc. Natl Acad. Sci. USA 97, 12091–12096 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Schmedtje, J. F. Jr, Ji, Y. S., Liu, W. L., DuBois, R. N. & Runge, M. S. Hypoxia induces cyclooxygenase-2 via the NF-κB p65 transcription factor in human vascular endothelial cells. J. Biol. Chem. 272, 601–608 (1997).

    Article  CAS  PubMed  Google Scholar 

  74. Yan, S. F. et al. Hypoxia-associated induction of early growth response-1 gene expression. J. Biol. Chem. 274, 15030–15040 (1999).

    Article  CAS  PubMed  Google Scholar 

  75. Yan, S. F., Pinsky, D. J. & Stern, D. M. A pathway leading to hypoxia-induced vascular fibrin deposition. Semin. Thromb. Hemost. 26, 479–483 (2000).

    Article  CAS  PubMed  Google Scholar 

  76. Murphy, B. J. et al. Activation of metallothionein gene expression by hypoxia involves metal response elements and metal transcription factor-1. Cancer Res. 59, 1315–1322 (1999).

    CAS  PubMed  Google Scholar 

  77. Carmeliet, P. et al. Synergism between vascular endothelial growth factor and placental growth factor contributes to angiogenesis and plasma extravasation in pathological conditions. Nature Med. 7, 575–583 (2001).

    Article  CAS  PubMed  Google Scholar 

  78. Littlewood, T. J. The impact of hemoglobin levels on treatment outcomes in patients with cancer. Semin. Oncol. 28, 49–53 (2001).

    Article  CAS  PubMed  Google Scholar 

  79. Littlewood, T. J., Bajetta, E., Nortier, J. W., Vercammen, E. & Rapoport, B. Effects of epoetin alfa on hematologic parameters and quality of life in cancer patients receiving nonplatinum chemotherapy: results of a randomized, double-blind, placebo-controlled trial. J. Clin. Oncol. 19, 2865–2874 (2001).

    Article  CAS  PubMed  Google Scholar 

  80. Bernier, J. et al. ARCON: accelerated radiotherapy with carbogen and nicotinamide in head and neck squamous cell carcinomas. The experience of the Co-operative group of radiotherapy of the european organization for research and treatment of cancer (EORTC). Radiother. Oncol. 55, 111–119 (2000).

    Article  CAS  PubMed  Google Scholar 

  81. Cohen, J.-E. et al. The farnesyltransferase inhibitor L744,832 reduces hypoxia in tumors expressing activated H-ras. Cancer Res. 61, 2289–2293 (2001).

    Google Scholar 

  82. Wardman, P. Electron transfer and oxidative stress as key factors in the design of drugs selectively active in hypoxia. Curr. Med. Chem. 8, 739–761 (2001).

    Article  CAS  PubMed  Google Scholar 

  83. von Pawel, J. et al. Tirapazamine plus cisplatin versus cisplatin in advanced non-small-cell lung cancer: a report of the international CATAPULT I study group. Cisplatin and tirapazamine in subjects with advanced previously untreated non-small-cell lung tumors. J. Clin. Oncol. 18, 1351–1359 (2000).

    Article  CAS  PubMed  Google Scholar 

  84. Lewis, J. S. & Welch, M. J. PET imaging of hypoxia. J. Nucl. Med. Allied Sci. 45, 183–188 (2001).

    CAS  Google Scholar 

  85. Sun, X. et al. Gene transfer of antisense hypoxia inducible factor-1α enhances the therapeutic efficacy of cancer immunotherapy. Gene Ther. 8, 638–645 (2001).Describes how the synergy between anti-HIF-1 therapy and immunotherapy might be an important model for future clinical trials.

    Article  CAS  PubMed  Google Scholar 

  86. Bhattacharya, S. et al. Functional role of p35srj, a novel p300/CBP binding protein, during transactivation by HIF-1. Genes Dev. 13, 64–75 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Gleadle, J. M., Ebert, B. L. & Ratcliffe, P. J. Diphenylene iodonium inhibits the induction of erythropoietin and other mammalian genes by hypoxia. Implications for the mechanism of oxygen sensing. Eur. J. Biochem. 234, 92–99 (1995).

    Article  CAS  PubMed  Google Scholar 

  88. Dachs, G. U. et al. Targeting gene expression to hypoxic tumor cells. Nature Med. 3, 515–520 (1997).Shows that the HIF-1 pathway can be manipulated to activate therapeutic genes at specific oxygen tensions in vivo.

    Article  CAS  PubMed  Google Scholar 

  89. Lemmon, M. J. et al. Anaerobic bacteria as a gene delivery system that is controlled by the tumor microenvironment. Gene Ther. 4, 791–796 (1997).

    Article  CAS  PubMed  Google Scholar 

  90. Dang, L. H., Bettegowda, C., Huso, D. L., Kinzler, K. W. & Vogelstein, B. Combination bacteriolytic therapy for the treatment of experimental tumours. Proc. Natl Acad. Sci. USA 2001 Nov 27; [epub ahead of print].

  91. Griffiths, L. et al. The macrophage: a novel system to deliver gene therapy to pathological hypoxia. Gene Ther. 7, 255–262 (2000).

    Article  CAS  PubMed  Google Scholar 

  92. Koshikawa, N., Takenaga, K., Tagawa, M. & Sakiyama, S. Therapeutic efficacy of the suicide gene driven by the promoter of vascular endothelial growth factor gene against hypoxic tumor cells. Cancer Res. 60, 2936–2941 (2000).

    CAS  PubMed  Google Scholar 

  93. Pioli, P. A. & Rigby, W. F. The von Hippel–Lindau protein interacts with heteronuclear ribonucleoprotein a2 and regulates its expression. J. Biol. Chem. 276, 40346–40352 (2001).Discusses the role of RNA stabilization in hypoxia gene regulation, particularly the direct role of VHL.

    Article  CAS  PubMed  Google Scholar 

  94. Ohh, M. The von Hippel–Lindau tumor suppressor protein is required for proper assembly of an extracellular fibronectin matrix. Mol. Cell 7, 959–968 (1998).

    Article  Google Scholar 

  95. Okuda, H. et al. Direct interaction of the β-domain of VHL tumor suppressor protein with the regulatory domain of atypical PKC isotypes. Biochem. Biophys. Res. Commun. 263, 491–497 (1999).

    Article  CAS  PubMed  Google Scholar 

  96. Kamura, T., Conrad, M. N., Yan, Q., Conaway, R. C. & Conaway, J. W. The Rbx1 subunit of SCF and VHL E3 ubiquitin ligase activates Rub1 modification of cullins Cdc53 and Cul2. Genes Dev. 13, 2928–2933 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Yamashita, K., Discher, D. J., Hu, J., Bishopric, N. H. & Webster, K. A. Molecular regulation of the endothelin-1 gene by hypoxia. Contributions of hypoxia-inducible factor-1, activator protein-1, GATA-2, and p300/CBP. J. Biol. Chem. 276, 12645–12653 (2001).

    Article  CAS  PubMed  Google Scholar 

  98. Maltepe, E., Keith, B., Arsham, A. M., Brorson, J. R. & Simon, M. C. The role of ARNT2 in tumor angiogenesis and the neural response to hypoxia. Biochem. Biophys. Res. Commun. 273, 231–238 (2000).

    Article  CAS  PubMed  Google Scholar 

  99. Hogenesch, J. B., Gu, Y. Z., Jain, S. & Bradfield, C. A. The basic helix–loop–helix–PAS orphan MOP3 forms transcriptionally active complexes with circadian and hypoxia factors. Proc. Natl Acad. Sci. USA 95, 5474–5479 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Thrash-Bingham, C. A. & Tartof, K. D. αHIF: a natural antisense transcript overexpressed in human renal cancer and during hypoxia. J. Natl Cancer Inst. 91, 143–151 (1999).

    Article  CAS  PubMed  Google Scholar 

  101. Levy, N. S., Chung, S., Furneaux, H. & Levy, A. P. Hypoxic stabilization of vascular endothelial growth factor mRNA by the RNA-binding protein HuR. J. Biol. Chem. 273, 6417–6423 (1998).

    Article  CAS  PubMed  Google Scholar 

  102. Levy, N. S., Goldberg, M. A. & Levy, A. P. Sequencing of the human vascular endothelial growth factor (VEGF) 3′ untranslated region (UTR): conservation of five hypoxia-inducible RNA-protein binding sites. Biochim. Biophys. Acta 1352, 167–173 (1997).

    Article  CAS  PubMed  Google Scholar 

  103. Palmer, L. A., Semenza, G. L., Stoler, M. H. & Johns, R. A. Hypoxia induces type II NOS gene expression in pulmonary artery endothelial cells via HIF-1. Am. J. Physiol. 274, L212–L219 (1998).

    CAS  PubMed  Google Scholar 

  104. Zelzer, E. et al. Insulin induces transcription of target genes through the hypoxia-inducible factor HIF-1α/ARNT. EMBO J. 17, 5085–5094 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Richard, D. E., Berra, E. & Pouyssegur, J. Nonhypoxic pathway mediates the induction of hypoxia-inducible factor-1α in vascular smooth muscle cells. J. Biol. Chem. 275, 26765–26771 (2000).

    Article  CAS  PubMed  Google Scholar 

  106. Laughner, E., Taghavi, P., Chiles, K., Mahon, P. C. & Semenza, G. L. HER2 (neu) signaling increases the rate of hypoxia-inducible factor-1α (HIF-1α) synthesis: novel mechanism for HIF-1-mediated vascular endothelial growth factor expression. Mol. Cell Biol. 21, 3995–4004 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Sodhi, A. et al. The Kaposi's sarcoma-associated herpes virus G protein-coupled receptor up-regulates vascular endothelial growth factor expression and secretion through mitogen-activated protein kinase and p38 pathways acting on hypoxia-inducible factor-1α. Cancer Res. 60, 4873–4880 (2000).

    CAS  PubMed  Google Scholar 

  108. Hirota, K. & Semenza, G. L. Rac1 activity is required for the activation of hypoxia-inducible factor-1. J. Biol. Chem. 276, 21166–21172 (2001).

    Article  CAS  PubMed  Google Scholar 

  109. Jiang, B. H., Agani, F., Passaniti, A. & Semenza, G. L. v-SRC induces expression of hypoxia-inducible factor-1 (HIF-1) and transcription of genes encoding vascular endothelial growth factor and enolase 1: involvement of HIF-1 in tumor progression. Cancer Res. 57, 5328–5335 (1997).

    CAS  PubMed  Google Scholar 

  110. Aragones, J. et al. Evidence for the involvement of diacylglycerol kinase in the activation of hypoxia-inducible transcription factor-1 by low oxygen tension. J. Biol. Chem. 276, 10548–10555 (2001).

    Article  CAS  PubMed  Google Scholar 

  111. Lee, S. W. et al. Human hepatitis B virus X protein is a possible mediator of hypoxia-induced angiogenesis in hepatocarcinogenesis. Biochem. Biophys. Res. Commun. 268, 456–461 (2000).

    Article  CAS  PubMed  Google Scholar 

  112. Wang, G. L., Jiang, B. H. & Semenza, G. L. Effect of protein kinase and phosphatase inhibitors on expression of hypoxia-inducible factor-1. Biochem. Biophys. Res. Commun. 216, 669–675 (1995).

    Article  CAS  PubMed  Google Scholar 

  113. Blancher, C., Moore, J. W., Talks, K. L., Houlbrook, S. & Harris, A. L. Relationship of hypoxia-inducible factor (HIF)-1α and HIF-2α expression to vascular endothelial growth factor induction and hypoxia survival in human breast cancer cell lines. Cancer Res. 60, 7106–7113 (2000).

    CAS  PubMed  Google Scholar 

  114. Hur, E., Chang, K. Y., Lee, E., Lee, S. K. & Park, H. Mitogen-activated protein kinase kinase inhibitor PD98059 blocks the transactivation but not the stabilization or DNA binding ability of hypoxia-inducible factor-1α. Mol. Pharmacol. 59, 1216–1224 (2001).

    Article  CAS  PubMed  Google Scholar 

  115. Zhong, H. et al. Modulation of hypoxia-inducible factor-1α expression by the epidermal growth factor/phosphatidylinositol 3-kinase/PTEN/AKT/FRAP pathway in human prostate cancer cells: implications for tumor angiogenesis and therapeutics. Cancer Res. 60, 1541–1545 (2000).Reports that oncogenic signalling pathways regulate HIF-1α, independently of hypoxia. Inhibitors of these pathways also block hypoxia-induced HIF-1 signalling.

    CAS  PubMed  Google Scholar 

  116. Board, M., Colquhoun, A. & Newsholme, E. A. High Km glucose-phosphorylating (glucokinase) activities in a range of tumour cell lines and inhibition of rates of tumour growth by the specific enzyme inhibitor mannoheptulose. Cancer Res. 55, 3278–3285 (1995).

    CAS  PubMed  Google Scholar 

  117. Schmaltz, C., Hardenbergh, P. H., Wells, A. & Fisher, D. E. Regulation of proliferation-survival decisions during tumor cell hypoxia. Mol. Cell. Biol. 18, 2845–2854 (1998).Shows that cell death in hypoxia might be mediated by low pH rather than low oxygen.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

I thank I. Stratford and C. West for their helpful comments, and L. Richards for administrative assistance.

Author information

Authors and Affiliations

  1. Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, OX3 9DS, UK

    Adrian L. Harris

Authors
  1. Adrian L. Harris
    View author publications

    You can also search for this author in PubMed Google Scholar

Supplementary information

Related links

Related links

DATABASES

CancerNet:

breast cancer

cervical cancer

colon carcinoma

endometrial tumours

gastric carcinoma

glioblastoma

head and neck tumours

oesophageal cancer

ovarian cancer

pancreatic carcinoma

prostate carcinoma

renal cancer

skin carcinoma

 GenBank:

HSV-TK

LocusLink

α-integrin

α-adrenergic receptor

acetoacetyl CoA thiolase

adenylate kinase-3

adrenomedullin

AKT

angiopoietin-2

annexin V

APAF-1

ARNT

ARNT2

BAD

BAX

carbonic anhydrase-9

caspase-3

caspase-9

CBP

CD99

ceruloplasmin

collagen-5α1

CREB

CUL2

cyclin G2

cyclooxygenase-2

cytochrome c

DEC1

EGR-1

elongin-B

elongin-C

endothelin-1

endothelin-2

enolase-1

epidermal growth factor receptor

ERBB2

erythtopoietin

ETS

ferritin light chain

fibroblast growth factor-3

fibronectin

FOS

GADD153

GLUT1

GLUT3

glyceraldehyde-3-phosphate dehydrogenase

HAP-1

heat-shock factor

heme oxygenase-1

hepatocyte growth factor

hexokinase-1

hexokinase-2

Hif-1α

HIF-1α

Hif-2α

HIF-2α

hnRNP

IAP2

IGF-1

IGF-2

IGF binding protein-1

IGF binding protein-2

IGF binding protein-3

IGF-1R

interleukin-6

interleukin-8

intestinal trefoil factor

JUN

Ku70

Ku80

KIP1

lactate dehydrogenase-A

L1CAM

lipocortin

low-density lipoprotein receptor-related protein

macrophage inhibitory factor

matrix metalloproteinase-13

MDM2

metal-regulatory transcription factor-1

metalloproteinases

metallothionein

monocyte chemotactic protein-1

MOP3

NF-κB

NIP3

nitric oxide synthase

NIX

osteopontin

p300

p44 mitogen-activated kinase

p53

phosphoglycerate kinase-1

phosphoribosyl pyrophosphate synthetase

PI3K

placental growth factor

plasminogen activator inhibitor-1

platelet-derived growth factor

platelet-derived growth factor-B

proline-4 hydroxylase

PTEN

pyruvate kinase-M

RBX1

spermidine N1-acetyl transferase

SRC

TGF-α

TGF-β1

TGF-β3

thioredoxin

Tie-2

transferrin

transferrin receptor

transgelin

transglutaminse-2

tyrosine hydroxylase

urokinase receptor

VEGF

VEGFR1

VEGFR2

VHL

vimentin

WAF1

FURTHER INFORMATION

SRI web site on hypoxia in cancer

LINKS

Lactate dehydrogenase

Glossary

ERYTHROPOIETIN

A renal hormone that is induced by anaemia and that activates haemoglobin synthesis by bone-marrow red-cell precursors.

CEREBELLAR HAEMANGIOGBLASTOMAS

Non-malignant proliferations of vascular stromal cells in the central nervous system.

THROMBOSPONDINS

A multigene family of extracellular proteins that inhibit angiogenesis through several mechanisms, including upregulation of TGF-β and decreasing the cellular response to VEGF.

TELOMERASE

A ribonucleoprotein that maintains telomere length. Telomerase activity is repressed in most normal adult human somatic tissues, limiting replicative capacity. Reactivation of telomerase is believed to be a necessary event for the sustained growth of most human tumours.

FRAGILE SITE

A site in a chromosome that is susceptible to chromosome breakage and fusion with other chromosomes.

CARBONIC ANHYDRASES

Enzymes that convert carbon dioxide to carbonic acid and then to protons and bicarbonate ions.

INVOLUCRIN

A cytoskeletal protein in squamous cells that is involved in their terminal differentiation.

DEEP-VEIN THROMBOSIS

The process of clot formation in the venous circulation, usually in the lower limbs or pelvis.

PULMONARY EMBOLISM THROMBOSIS

The occlusion of pulmonary veins by clots dislodged from peripheral deep veins, usually from the lower extremities.

ACCELERATED RADIOTHERAPY WITH CARBOGEN AND NICOTINAMIDE

Experimental technique to improve blood flow and oxygen delivery to tumours.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Harris, A. Hypoxia — a key regulatory factor in tumour growth. Nat Rev Cancer 2, 38–47 (2002). https://doi.org/10.1038/nrc704

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrc704

This article is cited by

Search

Advanced 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