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Targeting HIF-1 for cancer therapy

Key Points

  • Hypoxia-inducible factor 1 (HIF-1) is a heterodimeric protein that consists of two proteins — HIF-1α and HIF-1β. HIF-1 activates the transcription of many genes that code for proteins that are involved in angiogenesis, glucose metabolism, cell proliferation/survival and invasion/metastasis.

  • HIF-1α protein synthesis is regulated by activation of the phosphatidylinositol 3-kinase (PI3K) and ERK mitogen-activated protein kinase (MAPK) pathways. These pathways can be activated by signalling via receptor tyrosine kinases, non-receptor tyrosine kinases or G-protein-coupled receptors.

  • HIF-1α protein degradation is regulated by O2-dependent prolyl hydroxylation, which targets the protein for ubiquitylation by E3 ubiquitin-protein ligases. These ligases contain the von Hippel–Lindau tumour-suppressor protein (VHL), which binds specifically to hydroxylated HIF-1α. Ubiquitylated HIF-1α is rapidly degraded by the proteasome.

  • HIF-1α is overexpressed in human cancers as a result of intratumoral hypoxia as well as genetic alterations, such as gain-of-function mutations in oncogenes (for example, ERBB2) and loss-of-function mutations in tumour-suppressor genes (for example, VHL and PTEN). HIF-1α overexpression is associated with treatment failure and increased mortality.

  • In xenograft assays, manipulation of HIF-1 activity by genetic or pharmacological means has marked effects on tumour growth because of effects on angiogenesis, glucose metabolism and/or cell survival.

  • Screens are underway to identify small-molecule inhibitors of HIF-1 and to test their efficacy as anticancer agents. These drugs might represent an important component of novel combination therapies that are designed to target signalling molecules in cancer cells.

Abstract

Hypoxia-inducible factor 1 (HIF-1) activates the transcription of genes that are involved in crucial aspects of cancer biology, including angiogenesis, cell survival, glucose metabolism and invasion. Intratumoral hypoxia and genetic alterations can lead to HIF-1α overexpression, which has been associated with increased patient mortality in several cancer types. In preclinical studies, inhibition of HIF-1 activity has marked effects on tumour growth. Efforts are underway to identify inhibitors of HIF-1 and to test their efficacy as anticancer therapeutics.

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Figure 1: Regulation of HIF-1α protein synthesis.
Figure 2: O2-dependent regulation of HIF-1 activity.
Figure 3: Genes that are transcriptionally activated by HIF-1.
Figure 4: Mechanisms and consequences of HIF-1 activity in cancer cells.
Figure 5: HIF-1 target genes that encode invasion factors.
Figure 6: Involvement of HIF-1 in autocrine growth-factor stimulation of cancer cells.

References

  1. Semenza, G. L. & Wang, G. L. A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation. Mol. Cell. Biol. 12, 5447–5454 (1992).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

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

    CAS  Article  PubMed  Google Scholar 

  3. 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).

    CAS  Article  PubMed  Google Scholar 

  4. Harris, A. L. Hypoxia — a key regulatory factor in tumor growth. Nature Rev. Cancer 2, 38–46 (2001).

    Article  CAS  Google Scholar 

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

    CAS  Article  PubMed  Google Scholar 

  6. Iyer, N. V. et al. Cellular and developmental control of O2 homeostasis by hypoxia-inducible factor 1α. Genes Dev. 12, 149–162 (1998).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  7. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  8. Krishnamachary, B. et al. Regulation of colon carcinoma cell invasion by hypoxia-inducible factor 1. Cancer Res. 63, 1138–1143 (2003).

    CAS  PubMed  Google Scholar 

  9. Wykoff, C. C. et al. 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).

    CAS  Article  PubMed  Google Scholar 

  10. 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 

  11. Yu, J. et al. Identification and classification of p53-regulated genes. Proc. Natl Acad. Sci. USA 96, 14517–14522 (1999).

    CAS  Article  PubMed  Google Scholar 

  12. Ema, M. et al. A novel bHLH-PAS factor with close sequence similarity to hypoxia-inducible factor 1α regulates the VEGF expression and is potentially involved in lung and vascular development. Proc. Natl Acad. Sci. USA 94, 4273–4278 (1997).

    CAS  Article  PubMed  Google Scholar 

  13. Flamme, I. et al. HRF, a putative basic helix-loop-helix-PAS-domain transcription factor is closely related to hypoxia-inducible factor-1α and developmentally expressed in blood vessels. Mech. Dev. 63, 51–60 (1997).

    CAS  Article  PubMed  Google Scholar 

  14. Hogenesch, J. B. et al. Characterization of a subset of the basic-helix-loop-helix-PAS superfamily that interacts with components of the dioxin signaling pathway. J. Biol. Chem. 272, 8581–8593 (1997).

    CAS  Article  PubMed  Google Scholar 

  15. Tian, H., McKnight, S. L. & Russell, D. W. Endothelial PAS domain protein 1 (EPAS1), a transcription factor selectively expressed in endothelial cells. Genes Dev. 11, 72–82 (1997).

    CAS  Article  PubMed  Google Scholar 

  16. Brusselmans, K. et al. Hypoxia-inducible factor-2α (HIF-2α) is involved in the apoptotic response to hypoglycemia but not to hypoxia. J. Biol. Chem. 276, 39192–39196 (2001).

    CAS  Article  PubMed  Google Scholar 

  17. Makino, Y. et al. Inhibitory PAS domain protein (IPAS) is a hypoxia-inducible splicing variant of thehypoxia-inducible factor-3α locus. J. Biol. Chem. 277, 32405–32408 (2002).

    CAS  Article  PubMed  Google Scholar 

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

    CAS  Article  PubMed  Google Scholar 

  19. 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).

    CAS  Article  PubMed  Google Scholar 

  20. Ivan, M. et al. HIFα targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Science 292, 464–468 (2001).

    CAS  Article  PubMed  Google Scholar 

  21. 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).

    CAS  Article  PubMed  Google Scholar 

  22. Masson, N. et al. Independent function of two destruction domains in hypoxia-inducible factor-alpha chains activated by prolyl hydroxylation. EMBO J. 20, 5197–5206 (2001).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  23. Yu, F., White, S. B., Zhao, Q. & Lee, F. S. HIF-1α binding to VHL is regulated by stimulus-sensitive proline hydroxylation. Proc. Natl Acad. Sci. USA 98, 9630–9635 (2001).

    CAS  Article  PubMed  Google Scholar 

  24. 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).

    CAS  Article  PubMed  Google Scholar 

  25. Kamura, T. et al. Activation of HIF1α ubiquitination by a reconstituted von Hippel-Lindau (VHL) tumor suppressor complex. Proc. Natl Acad. Sci. USA 97, 10430–10435 (2000).

    CAS  Article  PubMed  Google Scholar 

  26. Maxwell, P. H. et al. The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 399, 271–275 (1999).

    CAS  Article  PubMed  Google Scholar 

  27. 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).

    CAS  Article  PubMed  Google Scholar 

  28. Tanimoto, K., Makino, Y., Pereira, T. & Poellinger, L. Mechanism of regulation of the hypoxia-inducible factor-1α by the von Hippel-Lindau tumor protein. EMBO J. 19, 4298–4309 (2000).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  29. Jiang, B. -H., Semenza, G. L., Bauer, C. & Marti, H. H. Hypoxia-inducible factor 1 levels vary exponentially over a physiologically relevant range of O2 tension. Am. J. Physiol. 271, C1172–C1180 (1996).

    CAS  Article  PubMed  Google Scholar 

  30. Jeong, J. W. et al. Regulation and destabilization of HIF-1α by ARD1-mediated acetylation. Cell 111, 709–720 (2002).

    CAS  Article  PubMed  Google Scholar 

  31. Jiang, B. -H. et al. Transactivation and inhibitory domains of hypoxia-inducible factor 1α: modulation of transcriptional activity by oxygen tension. J Biol. Chem. 272, 19253–19260 (1997).

    CAS  Article  PubMed  Google Scholar 

  32. Pugh, C. W. et al. Activation of hypoxia-inducible factor-1; definition of regulatory domains within the α subunit. J Biol. Chem. 272, 11205–11214 (1997).

    CAS  Article  PubMed  Google Scholar 

  33. Mahon, P. C., Hirota, K. & Semenza, G. L. FIH-1: a novel protein that interacts with HIF-1α and VHL to mediate repression of HIF-1 transcriptional activity. Genes Dev. 15, 2675–2686 (2001).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  34. Hewitson, K. S. et al. Hypoxia-inducible factor (HIF) asparagine hydroxylase is identical to factor inhibiting HIF (FIH) and is related to the cupin structural family. J. Biol. Chem. 277, 26351–26355 (2002).

    CAS  Article  PubMed  Google Scholar 

  35. Lando, D. et al. Asparagine hydroxylation of the HIF transactivation domain a hypoxic switch. Science 295, 858–861 (2002).

    CAS  Article  PubMed  Google Scholar 

  36. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  37. Dames, S. A. et al. Structural basis for HIF-1α/CBP recognition in the cellular hypoxic response. Proc. Natl Acad. Sci. USA 99, 5271–5276 (2002).

    CAS  Article  PubMed  Google Scholar 

  38. Freedman, S. J. et al. Structural basis for recruitment of CBP/p300 by hypoxia-inducible factor-1α. Proc. Natl Acad. Sci. USA 99, 5367–5372 (2002).

    CAS  Article  PubMed  Google Scholar 

  39. Hon, W. C. et al. Structural basis for the recognition of hydroxyproline in HIF-1α by pVHL. Nature 417, 975–978 (2002).

    CAS  Article  PubMed  Google Scholar 

  40. Min, J. H. et al. Structure of an HIF-1α-pVHL complex: hydroxyproline recognition in signaling. Science 296, 1886–1889 (2002).

    CAS  Article  PubMed  Google Scholar 

  41. Brand, K. A. & Hermfisse, U. Aerobic glycolysis by proliferating cells: a protective strategy against reactive oxygen species. FASEB J. 11, 388–395 (1997).

    CAS  Article  PubMed  Google Scholar 

  42. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  43. 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 

  44. 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).

    CAS  Article  PubMed  Google Scholar 

  45. Fukuda, R., Kelly, B. & Semenza, G. L. Vascular endothelial growth factor gene expression in colon cancer cells exposed to prostaglandin E2 is mediated by hypoxia-inducible factor 1. Cancer Res. 63, 2330–2334 (2003).

    CAS  PubMed  Google Scholar 

  46. Hellwig-Burgel, T., Stiehl, D. P. & Jelkmann, W. in Oxygen Sensing: Responses and Adaptation to Hypoxia (eds Lahiri, S., Semenza, G. L. & Prabhakar, N. R.) 95–108 (Marcel Dekker, Inc., New York, 2003).

    Google Scholar 

  47. Laughner, E. et al. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  48. Zhong, H. et al. Modulation of HIF-1α expression by the epidermal growth factor/phosphatidylinositol 3-kinase/PTEN/AKT/FRAP pathway in human prostate cancer cells: implications for tumor angiogenesis and therapeutic. Cancer Res. 60, 1541–1545 (2000).

    CAS  PubMed  Google Scholar 

  49. Zundel, W. et al. Loss of PTEN facilitates HIF-1-mediated gene expression. Genes Dev. 14, 391–396 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Richard, D. E. et al. 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).

    CAS  Article  PubMed  Google Scholar 

  51. 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 

  52. Sang, N. et al. MAPK signaling up-regulates the activity of hypoxia-inducible factors by its effects on p300. J. Biol. Chem. 278, 14013–14019 (2003).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  53. Hudson, C. C. et al. Regulation of hypoxia-inducible factor 1alpha expression and function by the mammalian target of rapamycin. Mol. Cell. Biol. 22, 7004–7014 (2002).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  54. Zhong, H. et al. Overexpression of hypoxia-inducible factor 1α in common human cancers and their metastases. Cancer Res. 59, 5830–5835 (1999).

    CAS  PubMed  Google Scholar 

  55. Feldser, D. et al. Reciprocal positive regulation of hypoxia-inducible factor 1α and insulin-like growth factor 2. Cancer Res. 59, 3915–3918 (1999).

    CAS  PubMed  Google Scholar 

  56. Talks, K. L. et al. The 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  57. Beasley, N. J. et al. Hypoxia-inducible factors HIF-1α and HIF-2α in head and neck cancer: relationship to tumor biology and treatment outcome in surgically resected patients. Cancer Res. 62, 2493–2497 (2002).

    CAS  PubMed  Google Scholar 

  58. Volm, M. & Koomagi, R. Hypoxia-inducible factor (HIF-1) and its relationship to apoptosis and proliferation in lung cancer. Anticancer Res. 20, 1527–1533 (2000).

    CAS  PubMed  Google Scholar 

  59. Giatromanolaki, A. et al. Relation of hypoxia inducible factor 1α and 2α in operable non-small cell lung cancer to angiogenic/molecular profile of tumours and survival. Br. J. Cancer 85, 881–890 (2001).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  60. Koukourakis, M. I. et al. Hypoxia-inducible factor (HIF1A and HIF2A), angiogenesis, and chemoradiotherapy outcome of squamous cell head-and-neck cancer. Int. J. Radiat. Oncol. Biol. Phys. 53, 1192–1202 (2002).

    CAS  Article  PubMed  Google Scholar 

  61. Birner, P. et al. Expression of hypoxia-inducible factor 1α in epithelial ovarian tumors: its impact on prognosis and on response to chemotherapy. Clin. Cancer Res. 7, 1661–1668 (2001).

    CAS  PubMed  Google Scholar 

  62. Koukourakis, M. I. et al. Hypoxia inducible factor (HIF-1α and HIF-2α) expression in early esophageal cancer and response to photodynamic therapy and radiotherapy. Cancer Res. 61, 1830–1832 (2001).

    CAS  PubMed  Google Scholar 

  63. 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).

    CAS  Article  PubMed  Google Scholar 

  64. 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 

  65. Unruh, A. et al. The hypoxia-inducible factor-1α is a negative factor for tumor therapy. Oncogene 22, 3213–3220 (2003).

    CAS  Article  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Akakura, N. et al. Constitutive expression of hypoxia-inducible factor 1α renders pancreatic cancer cells resistant to apoptosis induced by hypoxia and nutrient deprivation. Cancer Res. 61, 6548–6554 (2001).

    CAS  PubMed  Google Scholar 

  68. Jiang, B. H. et al. Dimerization, DNA binding, and transactivation properties of hypoxia-inducible factor 1. J. Biol. Chem. 271, 17771–17778 (1996).

    CAS  Article  PubMed  Google Scholar 

  69. Chen, J. et al. Dominant-negative hypoxia-inducible factor 1α reduces tumorigenicity of pancreatic cancer cells through the suppression of glucose metabolism. Am. J. Pathol. 1283–1291 (2003).

  70. Kung, A. L. et al. Suppression of tumor growth through disruption of hypoxia-inducible transcription. Nature Med. 6, 1335–1340 (2000).

    CAS  Article  PubMed  Google Scholar 

  71. Kondo, K. et al. Inhibition of HIF is necessary for tumor suppression by the von Hippel-Lindau protein. Cancer Cell 1, 237–246 (2002).

    CAS  Article  PubMed  Google Scholar 

  72. Maranchie, J. K. et al. The contribution of VHL substrate binding and HIF-1α to the phenotype of VHL loss in renal cell carcinoma. Cancer Cell 1, 247–255 (2002).

    CAS  Article  PubMed  Google Scholar 

  73. Mack, F. A. et al. Loss of pVHL is sufficient to cause HIF dysregulation in primary cells but does not promote tumor growth. Cancer Cell 3, 75–88 (2003).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  74. Bernards, R. & Weinberg, R. A. Metastasis genes: a progression puzzle. Nature 418, 823 (2002).

    CAS  Article  PubMed  Google Scholar 

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

    CAS  Article  PubMed  Google Scholar 

  76. 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).

    CAS  Article  PubMed  Google Scholar 

  77. Graeber, T. G. et al. Hypoxia-mediated selection of cells with diminished apoptotic potential in solid tumours. Nature 379, 88–91 (1996).

    CAS  Article  PubMed  Google Scholar 

  78. Bos, R. et al. Levels of hypoxia-inducible factor 1α during breast carcinogenesis. J. Natl Cancer Inst. 93, 309–314 (2001).

    CAS  Article  PubMed  Google Scholar 

  79. Semenza, G. L. Angiogenesis in ischemic and neoplastic disorders. Annu. Rev. Med. 54, 17–28 (2003).

    CAS  Article  PubMed  Google Scholar 

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

    CAS  Article  PubMed  Google Scholar 

  81. Aebersold, D. M. et al. Expression of hypoxia-inducible factor 1α: a novel predictive and prognostic parameter in the radiotherapy of oropharyngeal cancer. Cancer Res. 61, 2911–2916 (2001).

    CAS  PubMed  Google Scholar 

  82. Rapisarda, A. et al. Identification of small molecule inhibitors of hypoxia-inducible factor 1 transcriptional activation pathway. Cancer Res. 62, 4316–4324 (2002).

    CAS  PubMed  Google Scholar 

  83. Yeo, E. J. et al. YC-1: a potential anticancer drug targeting hypoxia-inducible factor 1. J. Natl Cancer Inst. 95, 516–525 (2003).

    CAS  Article  PubMed  Google Scholar 

  84. Isaacs, J. S. et al. Hsp90 regulates a von Hippel-Lindau-independent hypoxia-inducible factor-1α-degradative pathway. J. Biol. Chem. 277, 29936–29944 (2002).

    CAS  Article  PubMed  Google Scholar 

  85. Mabjeesh, N. J. et al. Geldanamycin induces degradation of hypoxia-inducible factor 1α protein via the proteosome pathway in prostate cancer cells. Cancer Res. 62, 2478–2482 (2002).

    CAS  PubMed  Google Scholar 

  86. Zagzag, D. et al. Geldanamycin inhibits migration of glioma cells in vitro: a potential role for hypoxia-inducible factor (HIF-1α) in glioma cell invasion. J. Cell. Physiol. 196, 394–402 (2003).

    CAS  Article  PubMed  Google Scholar 

  87. Welsh, S. J. et al. The thioredoxin redox inhibitors 1-methylpropyl 2-imidazolyl disulfide and pleurotin inhibit hypoxia-induced factor 1α and vascular endothelial growth factor formation. Mol. Cancer Ther. 2, 235–243 (2003).

    CAS  PubMed  Google Scholar 

  88. Mabjeesh, N. J. et al. 2ME2 inhibits tumor growth and angiogenesis by disrupting microtubules and dysregulating HIF. Cancer Cell 3, 363–375 (2003).

    CAS  Article  PubMed  Google Scholar 

  89. Mandriota, S. J. et al. HIF activation identifies early lesions in VHL kidneys: evidence for site-specific tumor suppressor function in the nephron. Cancer Cell 1, 459–468 (2002).

    CAS  Article  PubMed  Google Scholar 

  90. Zagzag, D. et al. Expression of hypoxia-inducible factor 1α in brain tumors: association with angiogenesis, invasion, and progression. Cancer 88, 2606–2618 (2000).

    CAS  Article  PubMed  Google Scholar 

  91. Price, J. E., Polyzos, A., Zhang, R. D. & Daniels, L. M. Tumorigenicity and metastasis of human breast carcinoma cell lines in nude mice. Cancer Res. 50, 717–721 (1990).

    CAS  PubMed  Google Scholar 

  92. Holland, E. C. Gliomagenesis: genetic alterations and mouse models. Nature Rev. Genet. 2, 120–129 (2001).

    CAS  Article  PubMed  Google Scholar 

  93. Van Dyke, T. & Jacks, T. Cancer modeling in the modern era: progress and challenges. Cell 108, 135–144 (2002).

    CAS  Article  PubMed  Google Scholar 

  94. Pomper, M. G. Can small animal imaging accelerate drug development? J. Cell. Biochem. 39 (Suppl.), 211–220 (2002).

    Article  CAS  Google Scholar 

  95. Artemov, D., Mori, N., Ravi, R. & Bhujwalla, Z. M. Magnetic resonance molecular imaging of the her-2/neu receptor. Cancer Res. 63, 2723–2727 (2003).

    CAS  PubMed  Google Scholar 

  96. Bhujwalla, Z. M. et al. Reduction of vascular and permeable regions in solid tumors detected by macromolecular contrast magnetic resonance imaging after treatment with antiangiogenic agent TNP-470. Clin. Cancer Res. 9, 355–362 (2003).

    CAS  PubMed  Google Scholar 

  97. Mankoff, D. A. et al. Blood flow and metabolism in locally advanced breast cancer: relationship to response to therapy. J. Nucl. Med. 43, 500–509 (2002).

    PubMed  Google Scholar 

  98. Liu, X. H. et al. Prostaglandin E2 induces hypoxia-inducible factor-1α stabilization and nuclear localization in a human prostate cancer cell line. J. Biol. Chem. 277, 50081–50086 (2002).

    CAS  Article  PubMed  Google Scholar 

  99. Fatyol, K. & Szalay, A. A. The p14ARF tumor suppressor protein facilitates nucleolar sequestration of HIF-1α and inhibits HIF-1 mediated transcription. J. Biol. Chem. 276, 28421–28429 (2001).

    CAS  Article  PubMed  Google Scholar 

  100. Iervolino, A. et al. Bcl-2 overexpression in human melanoma cells increases angiogenesis through VEGF mRNA stabilization and HIF-1-mediated transcriptional activity. FASEB J. 16, 1453–1455.

  101. Birner, P. et al. Overexpression of hypoxia-inducible factor 1α is a marker for an unfavorable prognosis in early-stage invasive cervical cancer. Cancer Res. 60, 4693–4696 (2000).

    CAS  PubMed  Google Scholar 

  102. Burri, P. et al. Significant correlation of hypoxia-inducible factor-1α with treatment outcome in cervical cancer treated with radical radiotherapy. Int. J. Radiat. Oncol. Biol. Phys. 56, 494–501 (2003).

    CAS  Article  PubMed  Google Scholar 

  103. Schindl, M. et al. Overexpression of hypoxia-inducible factor 1α is associated with an unfavorable prognosis in lymph node-positive breast cancer. Clin. Cancer Res. 8, 1831–1837 (2002).

    CAS  PubMed  Google Scholar 

  104. Bos, R. et al. Levels of hypoxia-inducible factor-1α independently predict prognosis in patients with lymph node negative breast carcinoma. Cancer 97, 1573–1581 (2003).

    Article  PubMed  Google Scholar 

  105. Birner, P. et al. Expression of hypoxia-inducible factor-1α in oligodendrogliomas: its impact on prognosis and on neoangiogenesis. Cancer 92, 165–171 (2001).

    CAS  Article  PubMed  Google Scholar 

  106. Sivridis, E. et al. Association of hypoxia-inducible factors 1α and 2α with activated angiogenic pathways and prognosis in patients with endometrial carcinoma. Cancer 95, 1055–1063 (2002).

    CAS  Article  PubMed  Google Scholar 

  107. Takahashi, R. et al. Hypoxia-inducible factor-1α expression and angiogenesis in gastrointestinal stromal tumor of the stomach. Oncol. Rep. 10, 797–802 (2003).

    CAS  PubMed  Google Scholar 

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DATABASES

Cancer.gov

brain cancer

breast cancer

cervical cancer

head and neck cancer

oesophageal cancer

oropharyngeal cancer

ovarian cancer

pancreatic cancer

prostate cancer

uterus

LocusLink

AKT

ARD1

BCL2

BNIP3

CBP

FIH-1

GLUT1

HIF-1α

HIF-2α

HIF-3α

HSP90

IGF2

mTOR

p53

p300

PDGF-β

PI3K

RAF

TGF-α

VEGF

VHL

OMIM

glioblastoma multiforme

Glossary

GLYCOLYTIC METABOLISM

Two molecules of ATP and NADH are generated by the conversion of one molecule of glucose to two molecules of pyruvate. The NADH is then used to reduce pyruvate to lactate.

OXIDATIVE METABOLISM

Glucose is converted to pyruvate, which is transported to the mitochondria, converted to acetyl coenzyme A and oxidized to CO2 in the citric-acid cycle. The NADH and FADH2 generated in this process provide electrons to respiratory cytochromes and, ultimately, to O2 in the inner mitochondrial membrane, generating ATP. The complete oxidation of one molecule of glucose results in the production of 36 molecules of ATP.

SV40 T-ANTIGEN

Large T-antigen — produced in the early stage following infection of cells with simian virus 40 —promotes transformation by binding to and inactivating the host p53 and RB (retinoblastoma gene product) proteins.

NCI DIVERSITY SET

A group of approximately 2,000 compounds that is representative of the complete chemical repository of the National Cancer Institute's Developmental Therapeutics Program.

TOPOISOMERASE I INHIBITORS

Drugs that inhibit an enzyme that relaxes supercoiled DNA by introducing a transient single-strand break.

PSEUDOPALISADING CELLS

Rows of viable cells surrounding areas of necrosis that are a histopathological characteristic of glioblastoma multiforme.

ORTHOTOPIC TRANSPLANTATION

The introduction of foreign tumour cells into another species at the site from which they were derived. For example, injection of human breast cancer cells into the mouse mammary fat pad.

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Semenza, G. Targeting HIF-1 for cancer therapy. Nat Rev Cancer 3, 721–732 (2003). https://doi.org/10.1038/nrc1187

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  • DOI: https://doi.org/10.1038/nrc1187

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