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.

Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response

A Corrigendum to this article was published on 03 July 2008

Key Points

  • This Review discusses four important and interrelated features of tumour hypoxia: the hypoxic response, the factors that influence tumour hypoxia, the role of hypoxia in the initiation of angiogenesis (angiogenic switch) and how hypoxia influences treatment responses.

  • The hypoxia response, driven primarily by the heterodimeric transcription factor hypoxia-inducible factor 1 (HIF1) influences cell survival, behaviour and angiogenesis.

  • Several pathophysiological factors contribute to the development of tumour hypoxia, which is typified by heterogeneity in oxygenation in space and in time.

  • Conflicting theories exist with respect to whether hypoxic stabilization of HIF1 is the primary feature of the angiogenic switch. There is clear evidence that HIF1 upregulation is associated with angiogenesis acceleration as opposed to angiogenesis initiation.

  • The appearance of perivascular (oxygenated regions) HIF1 expression during angiogenesis acceleration might be the result of increased levels of reactive oxygen species, associated with proliferation and/or instability in flow and hypoxia–reoxygenation injury.

  • Cytotoxic therapies, such as radiation therapy, improve tumour oxygenation but also increase HIF1 levels and transactivation of target genes through mechanisms associated with stress granule depolymerization and the production of free radicals. The upregulation of HIF1 in these circumstances protects tumour and endothelial cells from damage by the cytotoxic therapy.

Abstract

Hypoxia and free radicals, such as reactive oxygen and nitrogen species, can alter the function and/or activity of the transcription factor hypoxia-inducible factor 1 (HIF1). Interplay between free radicals, hypoxia and HIF1 activity is complex and can influence the earliest stages of tumour development. The hypoxic environment of tumours is heterogeneous, both spatially and temporally, and can change in response to cytotoxic therapy. Free radicals created by hypoxia, hypoxia–reoxygenation cycling and immune cell infiltration after cytotoxic therapy strongly influence HIF1 activity. HIF1 can then promote endothelial and tumour cell survival. As discussed here, a constant theme emerges: inhibition of HIF1 activity will have therapeutic benefit.

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

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Features of hypoxia-inducible factor (HIF1) regulation.
Figure 2: Seven points of regulation of tumour oxygenation.
Figure 3: Composite model for the effect of cycling tumour hypoxia on radial diffusion of oxygen.
Figure 4: Models for role of hypoxia in initiation and acceleration of angiogenesis.
Figure 5: Mechanisms for hypoxia-inducible factor 1 (HIF1) upregulation and consequences after radiation therapy.

References

  1. Virchow, R. Die Krankhaften Geschwulste (August Hirschwald, Berlin, 1863). The first report that vascular structures in tumours are abnormal.

    Google Scholar 

  2. Goldman, E. Growth of malignant disease in man and the lower animals with special reference to vascular system. Proc. R. Soc. Med. 1, 1 (1907).

    Google Scholar 

  3. Warren, B. A. in Tumor Blood Circulation: Angiogenesis, vascular morphology and blood flow of experimental and human tumors (ed. Peterson, H. I.) 1–48 (CRC Press, Boca Raton, 1979).

    Google Scholar 

  4. Folkman, J. Tumor angiogenesis: therapeutic implications. N. Engl. J. Med. 285, 1182–1186 (1971). The first to suggest that inhibition of tumour angiogenesis could have therapeutic benefit.

    CAS  PubMed  Article  Google Scholar 

  5. Vaupel, P., Thews, O., Kelleher, D. K. & Hoeckel, M. Oxygenation of human tumors: the Mainz experience. Strahlenther. Onkol. 174 (Suppl. 4), 6–12 (1998).

    PubMed  Google Scholar 

  6. Braun, R. D., Lanzen, J. L., Snyder, S. A. & Dewhirst, M. W. Comparison of tumor and normal tissue oxygen tension measurements using OxyLite or microelectrodes in rodents. Am. J. Physiol. Heart Circ. Physiol. 280, H2533–H2544 (2001).

    CAS  PubMed  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

  8. Wang, G. L. & Semenza, G. L. General involvement of hypoxia-inducible factor 1 in transcriptional response to hypoxia. Proc. Natl Acad. Sci. USA 90, 4304–4308 (1993).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  9. 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). Discovered that HIF1 is the oxygen-sensitive transcription factor that controls erythropoeitin synthesis.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  10. 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). The first to report that prolyl hydroxylation, which requires molecular oxygen, is the fundamental mechanism for stabilizing HIF1α under hypoxic conditions.

    CAS  PubMed  Article  Google Scholar 

  11. Ohh, M. et al. Ubiquitination of hypoxia-inducible factor requires direct binding to the beta-domain of the von Hippel-Lindau protein. Nature Cell Biol. 2, 423–427 (2000). The first to report that oxygen-dependent degradation of HIF1α occurs by recognition of the protein by the VHL complex

    CAS  PubMed  Article  Google Scholar 

  12. Thurman, R. G., Ji, S., Matsumura, T. & Lemasters, J. J. Is hypoxia involved in the mechanism of alcohol-induced liver injury? Fundam. Appl. Toxicol. 4, 125–133 (1984).

    CAS  PubMed  Article  Google Scholar 

  13. Wangsa-Wirawan, N. D. & Linsenmeier, R. A. Retinal oxygen: fundamental and clinical aspects. Arch Ophthalmol. 121, 547–557 (2003).

    PubMed  Article  Google Scholar 

  14. Haroon, Z. A., Raleigh, J. A., Greenberg, C. S. & Dewhirst, M. W. Early wound healing exhibits cytokine surge without evidence of hypoxia. Ann. Surg. 231, 137–147 (2000).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  15. Hale, L. P., Braun, R. D., Gwinn, W. M., Greer, P. K. & Dewhirst, M. W. Hypoxia in the thymus: role of oxygen tension in thymocyte survival. Am. J. Physiol. Heart. Circ. Physiol. 282, H1467–1477 (2002).

    CAS  PubMed  Article  Google Scholar 

  16. Samoszuk, M. K., Walter, J. & Mechetner, E. Improved immunohistochemical method for detecting hypoxia gradients in mouse tissues and tumors. J. Histochem. Cytochem. 52, 837–839 (2004).

    CAS  PubMed  Article  Google Scholar 

  17. Henquell, L., Odoroff, C. L. & Honig, C. R. Coronary intercapillary distance during growth: relation to PtO2 and aerobic capacity. Am J. Physiol. 231, 1852–1859 (1976).

    CAS  PubMed  Article  Google Scholar 

  18. Parmar, K., Mauch, P., Vergilio, J. A., Sackstein, R. & Down, J. D. Distribution of hematopoietic stem cells in the bone marrow according to regional hypoxia. Proc. Natl Acad. Sci. USA 104, 5431–5436 (2007).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  19. Arteel, G. E., Thurman, R. G., Yates, J. M. & Raleigh, J. A. Evidence that hypoxia markers detect oxygen gradients in liver: pimonidazole and retrograde perfusion of rat liver. Br. J. Cancer 72, 889–895 (1995).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  20. Laughlin, K. M. et al. Biodistribution of the nitroimidazole EF5 (2-[2-nitro-1H-imidazol-1-yl]-N-(2, 2, 3, 3, 3-pentafluoropropyl) acetamide) in mice bearing subcutaneous EMT6 tumors. J. Pharmacol. Exp. Ther. 277, 1049–1057 (1996).

    CAS  PubMed  Google Scholar 

  21. Rosmorduc, O. et al. Hepatocellular hypoxia-induced vascular endothelial growth factor expression and angiogenesis in experimental biliary cirrhosis. Am. J. Pathol. 155, 1065–1073 (1999).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  22. Houck, K. A., Leung, D. W., Rowland, A. M., Winer, J. & Ferrara, N. Dual regulation of vascular endothelial growth factor bioavailability by genetic and proteolytic mechanisms. J. Biol. Chem. 267, 26031–26037 (1992).

    CAS  PubMed  Google Scholar 

  23. Fannon, M. et al. Binding inhibition of angiogenic factors by heparan sulfate proteoglycans in aqueous humor: potential mechanism for maintenance of an avascular environment. FASEB J. 17, 902–904 (2003).

    CAS  PubMed  Article  Google Scholar 

  24. Chou, S. C., Azuma, Y., Varia, M. A. & Raleigh, J. A. Evidence that involucrin, a marker for differentiation, is oxygen regulated in human squamous cell carcinomas. Br. J. Cancer 90, 728–735 (2004).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  25. Zhu, Y. et al. Hypoxia upregulates osteopontin expression in NIH-3T3 cells via a Ras-activated enhancer. Oncogene 24, 6555–6563 (2005).

    CAS  PubMed  Article  Google Scholar 

  26. Huang, J. H. et al. Requirements for T lymphocyte migration in explanted lymph nodes. J. Immunol. 178, 7747–7755 (2007).

    CAS  PubMed  Article  Google Scholar 

  27. Li, F. et al. Regulation of HIF-1α stability through S-nitrosylation. Mol. Cell 26, 63–74 (2007). This paper proved that nitrosylation of a cysteine residue in the oxygen-dependent degradation domain of HIF1α can prevent its degradation under aerobic conditions.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  28. 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). The first report suggesting that reactive oxygen species may be responsible for stabilizing HIF1α under hypoxic conditions.

    CAS  Article  PubMed  Google Scholar 

  29. Guzy, R. D. et al. Mitochondrial complex III is required for hypoxia-induced ROS production and cellular oxygen sensing. Cell Metab. 1, 401–408 (2005).

    CAS  PubMed  Article  Google Scholar 

  30. Bell, E. L. et al. The Qo site of the mitochondrial complex III is required for the transduction of hypoxic signaling via reactive oxygen species production. J. Cell Biol. 177, 1029–1036 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  31. Ignarro, L. J. Nitric oxide as a unique signaling molecule in the vascular system: a historical overview. J. Physiol. Pharmacol. 53, 503–514 (2002).

    CAS  PubMed  Google Scholar 

  32. Pryor, W. A. et al. Free radical biology and medicine: it's a gas, man! Am. J. Physiol. Regul. Integr. Comp. Physiol. 291, R491–511 (2006).

    CAS  PubMed  Article  Google Scholar 

  33. Moncada, S. & Higgs, E. A. The discovery of nitric oxide and its role in vascular biology. Br. J. Pharmacol. 147 (Suppl. 1), S193–S201 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Tozer, G. M. & Everett, S. A. Nitric oxide in tumor biology and cancer therapy. Part 2: Therapeutic implications. Clin. Oncol. (R. Coll. Radiol.) 9, 357–364 (1997).

    CAS  Article  Google Scholar 

  35. Tozer, G. M. & Everett, S. A. Nitric oxide in tumour biology and cancer therapy. Part 1: Physiological aspects. Clin. Oncol. (R. Coll. Radiol.) 9, 282–293 (1997).

    CAS  Article  Google Scholar 

  36. BelAiba, R. S. et al. Redox-sensitive regulation of the HIF pathway under non-hypoxic conditions in pulmonary artery smooth muscle cells. Biol. Chem. 385, 249–257 (2004).

    CAS  PubMed  Article  Google Scholar 

  37. Page, E. L., Chan, D. A., Giaccia, A. J., Levine, M. & Richard, D. E. Hypoxia-inducible factor-1α stabilization in nonhypoxic conditions: role of oxidation and intracellular ascorbate depletion. Mol. Biol. Cell 19, 86–94 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  38. Mateo, J., Garcia-Lecea, M., Cadenas, S., Hernandez, C. & Moncada, S. Regulation of hypoxia-inducible factor-1α by nitric oxide through mitochondria-dependent and -independent pathways. Biochem. J. 376, 537–544 (2003).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  39. Sumbayev, V. V., Budde, A., Zhou, J. & Brune, B. HIF-1 α protein as a target for S-nitrosation. FEBS Lett. 535, 106–112 (2003).

    CAS  PubMed  Article  Google Scholar 

  40. Kimura, H. et al. Identification of hypoxia-inducible factor 1 ancillary sequence and its function in vascular endothelial growth factor gene induction by hypoxia and nitric oxide. J. Biol. Chem. 276, 2292–2298 (2001).

    CAS  PubMed  Article  Google Scholar 

  41. Sandau, K. B., Faus, H. G. & Brune, B. Induction of hypoxia-inducible-factor 1 by nitric oxide is mediated via the PI 3K pathway. Biochem. Biophys. Res. Commun. 278, 263–267 (2000).

    CAS  PubMed  Article  Google Scholar 

  42. Kasuno, K. et al. Nitric oxide induces hypoxia-inducible factor 1 activation that is dependent on MAPK and phosphatidylinositol 3-kinase signaling. J. Biol. Chem. 279, 2550–2558 (2004).

    CAS  PubMed  Article  Google Scholar 

  43. Mansfield, K. D. et al. Mitochondrial dysfunction resulting from loss of cytochrome c impairs cellular oxygen sensing and hypoxic HIF-α activation. Cell Metab. 1, 393–399 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  44. Venkataraman, S. et al. Manganese superoxide dismutase overexpression inhibits the growth of androgen-independent prostate cancer cells. Oncogene 24, 77–89 (2005).

    CAS  PubMed  Article  Google Scholar 

  45. Wang, M. et al. Manganese superoxide dismutase suppresses hypoxic induction of hypoxia-inducible factor-1α and vascular endothelial growth factor. Oncogene 24, 8154–8166 (2005).

    CAS  PubMed  Article  Google Scholar 

  46. Liu, Y. et al. Carbon monoxide and nitric oxide suppress the hypoxic induction of vascular endothelial growth factor gene via the 5′ enhancer. J. Biol. Chem. 273, 15257–15262 (1998).

    CAS  PubMed  Article  Google Scholar 

  47. Huang, L. E., Willmore, W. G., Gu, J., Goldberg, M. A. & Bunn, H. F. Inhibition of hypoxia-inducible factor 1 activation by carbon monoxide and nitric oxide. Implications for oxygen sensing and signaling. J. Biol. Chem. 274, 9038–9044 (1999).

    CAS  PubMed  Article  Google Scholar 

  48. Hagen, T., Taylor, C. T., Lam, F. & Moncada, S. Redistribution of intracellular oxygen in hypoxia by nitric oxide: effect on HIF1α. Science 302, 1975–1978 (2003).

    CAS  Article  PubMed  Google Scholar 

  49. Berchner-Pfannschmidt, U., Yamac, H., Trinidad, B. & Fandrey, J. Nitric oxide modulates oxygen sensing by hypoxia-inducible factor 1-dependent induction of prolyl hydroxylase 2. J. Biol. Chem. 282, 1788–1796 (2007).

    CAS  PubMed  Article  Google Scholar 

  50. Jankovic, B. et al. Comparison between pimonidazole binding, oxygen electrode measurements, and expression of endogenous hypoxia markers in cancer of the uterine cervix. Cytometry B Clin. Cytom. 70, 45–55 (2006).

    CAS  PubMed  Article  Google Scholar 

  51. Raleigh, J. A. et al. Hypoxia and vascular endothelial growth factor expression in human squamous cell carcinomas using pimonidazole as a hypoxia marker. Cancer Res. 58, 3765–3768 (1998).

    CAS  PubMed  Google Scholar 

  52. Vordermark, D. & Brown, J. M. Evaluation of hypoxia-inducible factor-1α (HIF-1α) as an intrinsic marker of tumor hypoxia in U87 MG human glioblastoma: in vitro and xenograft studies. Int. J. Radiat. Oncol. Biol. Phys. 56, 1184–1193 (2003).

    CAS  PubMed  Article  Google Scholar 

  53. Janssen, H. L. et al. HIF-1A, pimonidazole, and iododeoxyuridine to estimate hypoxia and perfusion in human head-and-neck tumors. Int. J. Radiat. Oncol. Biol. Phys. 54, 1537–1549 (2002).

    CAS  PubMed  Article  Google Scholar 

  54. Quintero, M., Brennan, P. A., Thomas, G. J. & Moncada, S. Nitric oxide is a factor in the stabilization of hypoxia-inducible factor-1α in cancer: role of free radical formation. Cancer Res. 66, 770–774 (2006).

    CAS  PubMed  Article  Google Scholar 

  55. Brown, J. M. & Wilson, W. R. Exploiting tumour hypoxia in cancer treatment. Nature Rev. Cancer 4, 437–447 (2004).

    CAS  Article  Google Scholar 

  56. Ljungkvist, A. S., Bussink, J., Kaanders, J. H. & van der Kogel, A. J. Dynamics of tumor hypoxia measured with bioreductive hypoxic cell markers. Radiat. Res. 167, 127–145 (2007).

    CAS  PubMed  Article  Google Scholar 

  57. Vaupel, P. & Harrison, L. Tumor hypoxia: causative factors, compensatory mechanisms, and cellular response. Oncologist 9 (Suppl. 5), 4–9 (2004).

    PubMed  Article  Google Scholar 

  58. Dewhirst, M. W. et al. Quantification of longitudinal tissue pO2 gradients in window chamber tumours: impact on tumour hypoxia. Br. J. Cancer 79, 1717–1722 (1999).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  59. Secomb, T. W., Hsu, R., Dewhirst, M. W., Klitzman, B. & Gross, J. F. Analysis of oxygen transport to tumor tissue by microvascular networks. Int. J. Radiat. Oncol. Biol. Phys. 25, 481–489 (1993).

    CAS  PubMed  Article  Google Scholar 

  60. Secomb, T. W., Hsu, R., Park, E. Y. & Dewhirst, M. W. Green's function methods for analysis of oxygen delivery to tissue by microvascular networks. Ann. Biomed. Eng. 32, 1519–1529 (2004).

    PubMed  Article  Google Scholar 

  61. Dewhirst, M. W. et al. Microvascular studies on the origins of perfusion-limited hypoxia. Br. J. Cancer Suppl. 27, S247–251 (1996). The first report to demonstrate that arteriolar vasomotion can be involved in intermittent hypoxia.

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Erickson, K. et al. Effect of longitudinal oxygen gradients on effectiveness of manipulation of tumor oxygenation. Cancer Res. 63, 4705–4712 (2003).

    CAS  PubMed  Google Scholar 

  63. Sorg, B. S., Moeller, B. J., Donovan, O., Cao, Y. & Dewhirst, M. W. Hyperspectral imaging of hemoglobin saturation in tumor microvasculature and tumor hypoxia development. J. Biomed. Opt. 10, 44004 (2005).

    PubMed  Article  CAS  Google Scholar 

  64. Ljungkvist, A. S. et al. Vascular architecture, hypoxia, and proliferation in first-generation xenografts of human head-and-neck squamous cell carcinomas. Int. J. Radiat. Oncol. Biol. Phys. 54, 215–228 (2002).

    PubMed  Article  Google Scholar 

  65. Devasahayam, N. et al. Strategies for improved temporal and spectral resolution in in vivo oximetric imaging using time-domain EPR. Magn. Reson. Med. 57, 776–783 (2007).

    PubMed  Article  Google Scholar 

  66. Wijffels, K. I. et al. Vascular architecture and hypoxic profiles in human head and neck squamous cell carcinomas. Br. J. Cancer 83, 674–683 (2000).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  67. Brown, J. M. Evidence for acutely hypoxic cells in mouse tumours, and a possible mechanism of reoxygenation. Br. J. Radiol 52, 650–656 (1979). The first report that intermittent hypoxia that is radiobiologically important can be found in tumours.

    CAS  PubMed  Article  Google Scholar 

  68. Reinhold, H. S., Blachiwiecz, B. & Blok, A. Oxygenation and reoxygenation in 'sandwich' tumours. Bibl. Anat, 270–272 (1977).

  69. Yamaura, H. & Matsuzawa, T. Tumor regrowth after irradiation; an experimental approach. Int. J. Radiat. Biol. Relat. Stud. Phys. Chem. Med. 35, 201–219 (1979).

    CAS  PubMed  Article  Google Scholar 

  70. Dewhirst, M. W. Intermittent hypoxia furthers the rationale for hypoxia-inducible factor-1 targeting. Cancer Res. 67, 854–855 (2007).

    CAS  PubMed  Article  Google Scholar 

  71. Durand, R. E. & Aquino-Parsons, C. Clinical relevance of intermittent tumour blood flow. Acta Oncol. 40, 929–936 (2001).

    CAS  PubMed  Article  Google Scholar 

  72. Chaplin, D. J., Olive, P. L. & Durand, R. E. Intermittent blood flow in a murine tumor: radiobiological effects. Cancer Res. 47, 597–601 (1987).

    CAS  PubMed  Google Scholar 

  73. Chaplin, D. J., Trotter, M. J., Durand, R. E., Olive, P. L. & Minchinton, A. I. Evidence for intermittent radiobiological hypoxia in experimental tumour systems. Biomed. Biochim. Acta 48, S255–259 (1989).

    CAS  PubMed  Google Scholar 

  74. Minchinton, A. I., Durand, R. E. & Chaplin, D. J. Intermittent blood flow in the KHT sarcoma — flow cytometry studies using Hoechst 33342. Br. J. Cancer 62, 195–200 (1990).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  75. Thomas, C. D., Stern, S., Chaplin, D. J. & Guichard, M. Transient perfusion and radiosensitizing effect after nicotinamide, carbogen, and perflubron emulsion administration. Radiother. Oncol. 39, 235–241 (1996).

    CAS  PubMed  Article  Google Scholar 

  76. Trotter, M. J., Chaplin, D. J. & Olive, P. L. Effect of angiotensin II on intermittent tumour blood flow and acute hypoxia in the murine SCCVII carcinoma. Eur. J. Cancer 27, 887–893 (1991).

    CAS  PubMed  Article  Google Scholar 

  77. Chaplin, D. J., Durand, R. E. & Olive, P. L. Acute hypoxia in tumors: implications for modifiers of radiation effects. Int. J. Radiat. Oncol. Biol. Phys. 12, 1279–1282 (1986).

    CAS  PubMed  Article  Google Scholar 

  78. Durand, R. E. Intermittent blood flow in solid tumours — an under-appreciated source of 'drug resistance'. Cancer Metastasis Rev. 20, 57–61 (2001).

    CAS  PubMed  Article  Google Scholar 

  79. Durand, R. E. & Aquino-Parsons, C. Non-constant tumour blood flow — implications for therapy. Acta Oncol. 40, 862–869 (2001).

    CAS  PubMed  Article  Google Scholar 

  80. Kimura, H. et al. Fluctuations in red cell flux in tumor microvessels can lead to transient hypoxia and reoxygenation in tumor parenchyma. Cancer Res. 56, 5522–5528 (1996). The first report to show that intermittent hypoxia can be caused by instabilities in tumour microvessel red cell flux and that vascular stasis is not required for this effect.

    CAS  PubMed  Google Scholar 

  81. Lanzen, J. et al. Direct demonstration of instabilities in oxygen concentrations within the extravascular compartment of an experimental tumor. Cancer Res. 66, 2219–2223 (2006).

    CAS  PubMed  Article  Google Scholar 

  82. Braun, R. D., Lanzen, J. L. & Dewhirst, M. W. Fourier analysis of fluctuations of oxygen tension and blood flow in R3230Ac tumors and muscle in rats. Am. J. Physiol. 277, H551–568 (1999).

    CAS  PubMed  Google Scholar 

  83. Brurberg, K. G., Skogmo, H. K., Graff, B. A., Olsen, D. R. & Rofstad, E. K. Fluctuations in pO2 in poorly and well-oxygenated spontaneous canine tumors before and during fractionated radiation therapy. Radiother. Oncol. 77, 220–226 (2005). The first report that intermittent hypoxia can occur in clinically-relevant canine tumours.

    PubMed  Article  Google Scholar 

  84. Cardenas-Navia, L. I. et al. Tumor-dependent kinetics of partial pressure of oxygen fluctuations during air and oxygen breathing. Cancer Res. 64, 6010–6017 (2004).

    CAS  PubMed  Article  Google Scholar 

  85. Pigott, K. H., Hill, S. A., Chaplin, D. J. & Saunders, M. I. Microregional fluctuations in perfusion within human tumours detected using laser Doppler flowmetry. Radiother. Oncol. 40, 45–50 (1996).

    CAS  PubMed  Article  Google Scholar 

  86. Bennewith, K. L., Raleigh, J. A. & Durand, R. E. Orally administered pimonidazole to label hypoxic tumor cells. Cancer Res. 62, 6827–6830 (2002).

    CAS  PubMed  Google Scholar 

  87. Cardenas-Navia, L. I. et al. The pervasive presence of fluctuating oxygenation in tumors. Cancer Res. (in the press).

  88. Sorg, B. S., Hardee, M. E., Agarwal, N., Moeller, B. J. & Dewhirst, M. W. Spectral imaging facilitates visualization and measurements of unstable and abnormal microvascular oxygen transport in tumors. J. Biomed. Opt. 13, 014026 (2008).

    PubMed  Article  CAS  Google Scholar 

  89. Baudelet, C. et al. Physiological noise in murine solid tumours using T2*-weighted gradient-echo imaging: a marker of tumour acute hypoxia? Phys. Med. Biol. 49, 3389–3411 (2004).

    PubMed  Article  Google Scholar 

  90. Brurberg, K. G., Benjaminsen, I. C., Dorum, L. M. & Rofstad, E. K. Fluctuations in tumor blood perfusion assessed by dynamic contrast-enhanced MRI. Magn. Reson. Med. 58, 473–481 (2007).

    PubMed  Article  Google Scholar 

  91. Baudelet, C. et al. The role of vessel maturation and vessel functionality in spontaneous fluctuations of T2*-weighted GRE signal within tumors. NMR Biomed. 19, 69–76 (2006).

    PubMed  Article  Google Scholar 

  92. Patan, S., Munn, L. L. & Jain, R. K. Intussusceptive microvascular growth in a human colon adenocarcinoma xenograft: a novel mechanism of tumor angiogenesis. Microvasc. Res. 51, 260–272 (1996). This paper is the first to connect the concept of vascular remodelling as a putative mechanism for intermittent hypoxia.

    CAS  PubMed  Article  Google Scholar 

  93. Chien, S., Usami, S. & Skalak, R. in Handbook of Physiology (eds Renkin, E. M., Michel, C. & Geiger, S. R.) 217–251 (American Physiological Society, Bethesda, 1984).

    Google Scholar 

  94. Kiani, M. F., Pries, A. R., Hsu, L. L., Sarelius, I. H. & Cokelet, G. R. Fluctuations in microvascular blood flow parameters caused by hemodynamic mechanisms. Am. J. Physiol. 266, H1822–H1828 (1994).

    CAS  PubMed  Google Scholar 

  95. Pries, A. R., Schonfeld, D., Gaehtgens, P., Kiani, M. F. & Cokelet, G. R. Diameter variability and microvascular flow resistance. Am. J. Physiol. 272, H2716–H2725 (1997).

    CAS  PubMed  Google Scholar 

  96. Kavanagh, B. D., Coffey, B. E., Needham, D., Hochmuth, R. M. & Dewhirst, M. W. The effect of flunarizine on erythrocyte suspension viscosity under conditions of extreme hypoxia, low pH, and lactate treatment. Br. J. Cancer 67, 734–741 (1993).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  97. Cao, Y. et al. Observation of incipient tumor angiogenesis that is independent of hypoxia and hypoxia inducible factor-1 activation. Cancer Res. 65, 5498–5505 (2005). This paper provides evidence in a preclinical model that hypoxia is not a prerequisite for the initiation of tumour angiogenesis.

    CAS  PubMed  Article  Google Scholar 

  98. Nehmeh, S. A. et al. Reproducibility of intratumor distribution of 18F-fluoromisonidazole in head and neck cancer. Int. J. Radiat. Oncol. Biol. Phys. 70, 235–242 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  99. Peng, Y. J. et al. Heterozygous HIF-1α deficiency impairs carotid body-mediated systemic responses and reactive oxygen species generation in mice exposed to intermittent hypoxia. J. Physiol. 577, 705–716 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  100. Yuan, G., Nanduri, J., Bhasker, C. R., Semenza, G. L. & Prabhakar, N. R. Ca2+/calmodulin kinase-dependent activation of hypoxia inducible factor 1 transcriptional activity in cells subjected to intermittent hypoxia. J. Biol. Chem. 280, 4321–4328 (2005).

    CAS  PubMed  Article  Google Scholar 

  101. Semenza, G. L. & Prabhakar, N. R. HIF-1-dependent respiratory, cardiovascular, and redox responses to chronic intermittent hypoxia. Antioxid. Redox Signal. 9, 1391–1396 (2007).

    CAS  PubMed  Article  Google Scholar 

  102. Toffoli, S., Feron, O., Raes, M. & Michiels, C. Intermittent hypoxia changes HIF-1α phosphorylation pattern in endothelial cells: unravelling of a new PKA-dependent regulation of HIF-1α. Biochim. Biophys. Acta 1773, 1558–1571 (2007).

    CAS  PubMed  Article  Google Scholar 

  103. Martinive, P. et al. Preconditioning of the tumor vasculature and tumor cells by intermittent hypoxia: implications for anticancer therapies. Cancer Res. 66, 11736–11744 (2006). This report shows that HIF1 upregulation is more strongly induced by repeated exposures to hypoxia–reoxygenation than by chronic hypoxia.

    CAS  PubMed  Article  Google Scholar 

  104. Sioussat, T. M., Dvorak, H. F., Brock, T. A. & Senger, D. R. Inhibition of vascular permeability factor (vascular endothelial growth factor) with antipeptide antibodies. Arch. Biochem. Biophys. 301, 15–20 (1993).

    CAS  PubMed  Article  Google Scholar 

  105. Senger, D. R., Perruzzi, C. A., Feder, J. & Dvorak, H. F. A highly conserved vascular permeability factor secreted by a variety of human and rodent tumor cell lines. Cancer Res. 46, 5629–5632 (1986).

    CAS  PubMed  Google Scholar 

  106. Ferrara, N. & Henzel, W. J. Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells. Biochem. Biophys. Res. Commun 161, 851–858 (1989). This is the first report that VEGF is a mitogen for endothelial cells.

    CAS  PubMed  Article  Google Scholar 

  107. Leung, D. W., Cachianes, G., Kuang, W. J., Goeddel, D. V. & Ferrara, N. Vascular endothelial growth factor is a secreted angiogenic mitogen. Science 246, 1306–1309 (1989).

    CAS  PubMed  Article  Google Scholar 

  108. Yuan, F. et al. Time-dependent vascular regression and permeability changes in established human tumor xenografts induced by an anti-vascular endothelial growth factor/vascular permeability factor antibody. Proc. Natl Acad. Sci. USA 93, 14765–14770 (1996).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  109. Holash, J. et al. Vessel cooption, regression, and growth in tumors mediated by angiopoietins and VEGF. Science 284, 1994–1998 (1999). This report is the first to theorize that a hypoxic crisis, mediated by regression of coopted host microvasculature, may be required for tumour angiogenesis initiation.

    CAS  PubMed  Article  Google Scholar 

  110. Holash, J., Wiegand, S. J. & Yancopoulos, G. D. New model of tumor angiogenesis: dynamic balance between vessel regression and growth mediated by angiopoietins and VEGF. Oncogene 18, 5356–5362 (1999).

    CAS  PubMed  Article  Google Scholar 

  111. Lin, P. et al. Inhibition of tumor angiogenesis using a soluble receptor establishes a role for Tie2 in pathologic vascular growth. J. Clin. Invest. 100, 2072–2078 (1997). This is the first paper demonstrating the importance of TIE2, the receptor for angiopoietins, as a pro-angiogenic endothelial cell receptor in tumours.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  112. Peters, K. G. et al. Functional significance of Tie2 signaling in the adult vasculature. Recent Prog. Horm. Res. 59, 51–71 (2004).

    CAS  PubMed  Article  Google Scholar 

  113. Winkles, J. A. et al. Human vascular smooth muscle cells both express and respond to heparin-binding growth factor I (endothelial cell growth factor). Proc. Natl Acad. Sci. USA 84, 7124–7128 (1987).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  114. Soker, S., Takashima, S., Miao, H. Q., Neufeld, G. & Klagsbrun, M. Neuropilin-1 is expressed by endothelial and tumor cells as an isoform-specific receptor for vascular endothelial growth factor. Cell 92, 735–745 (1998).

    CAS  PubMed  Article  Google Scholar 

  115. Mazure, N. M., Chen, E. Y., Yeh, P., Laderoute, K. R. & Giaccia, A. J. Oncogenic transformation and hypoxia synergistically act to modulate vascular endothelial growth factor expression. Cancer Res. 56, 3436–3440 (1996).

    CAS  PubMed  Google Scholar 

  116. Diaz-Gonzalez, J. A., Russell, J., Rouzaut, A., Gil-Bazo, I. & Montuenga, L. Targeting hypoxia and angiogenesis through HIF-1α inhibition. Cancer Biol. Ther. 4, 1055–1062 (2005).

    CAS  PubMed  Article  Google Scholar 

  117. Laderoute, K. R. et al. Opposing effects of hypoxia on expression of the angiogenic inhibitor thrombospondin 1 and the angiogenic inducer vascular endothelial growth factor. Clin. Cancer Res. 6, 2941–2950 (2000).

    CAS  PubMed  Google Scholar 

  118. Steinman, S., Wang, J., Bourne, P., Yang, Q. & Tang, P. Expression of cytokeratin markers, ER-α, PR, HER-2/neu, and EGFR in pure ductal carcinoma in situ (DCIS) and DCIS with co-existing invasive ductal carcinoma (IDC) of the breast. Ann. Clin. Lab. Sci. 37, 127–134 (2007).

    CAS  PubMed  Google Scholar 

  119. Dabbs, D. J., Chivukula, M., Carter, G. & Bhargava, R. Basal phenotype of ductal carcinoma in situ: recognition and immunohistologic profile. Mod. Pathol. 19, 1506–1511 (2006).

    CAS  PubMed  Article  Google Scholar 

  120. Kamat, C. D. et al. Mutant p53 facilitates pro-angiogenic, hyperproliferative phenotype in response to chronic relative hypoxia. Cancer Lett. 249, 209–219 (2007).

    CAS  PubMed  Article  Google Scholar 

  121. Zhou, S. et al. Frequency and phenotypic implications of mitochondrial DNA mutations in human squamous cell cancers of the head and neck. Proc. Natl Acad. Sci. USA 104, 7540–7545 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  122. Feldkamp, M. M., Lau, N., Rak, J., Kerbel, R. S. & Guha, A. Normoxic and hypoxic regulation of vascular endothelial growth factor (VEGF) by astrocytoma cells is mediated by Ras. Int. J. Cancer 81, 118–124 (1999).

    CAS  PubMed  Article  Google Scholar 

  123. Jiang, B. H. & Liu, L. Z. AKT signaling in regulating angiogenesis. Curr. Cancer Drug Targets 8, 19–26 (2008).

    CAS  PubMed  Article  Google Scholar 

  124. Naumov, G. N. et al. A model of human tumor dormancy: an angiogenic switch from the nonangiogenic phenotype. J. Natl Cancer Inst. 98, 316–325 (2006).

    PubMed  Article  Google Scholar 

  125. Stessels, F. et al. Breast adenocarcinoma liver metastases, in contrast to colorectal cancer liver metastases, display a non-angiogenic growth pattern that preserves the stroma and lacks hypoxia. Br. J. Cancer 90, 1429–1436 (2004). The first report that vessel cooption can occur in human cancer.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  126. Colpaert, C. G. et al. Cutaneous breast cancer deposits show distinct growth patterns with different degrees of angiogenesis, hypoxia and fibrin deposition. Histopathology 42, 530–540 (2003).

    CAS  PubMed  Article  Google Scholar 

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

    CAS  PubMed  Article  Google Scholar 

  128. Zakrzewicz, A., Secomb, T. W. & Pries, A. R. Angioadaptation: keeping the vascular system in shape. News Physiol. Sci. 17, 197–201 (2002).

    PubMed  Google Scholar 

  129. Gregoire, V., Hittelman, W. N., Rosier, J. F. & Milas, L. Chemo-radiotherapy: radiosensitizing nucleoside analogues (review). Oncol. Rep. 6, 949–957 (1999).

    CAS  PubMed  Google Scholar 

  130. Bussink, J., Kaanders, J. H., Rijken, P. F., Raleigh, J. A. & van der Kogel, A. J. Changes in blood perfusion and hypoxia after irradiation of a human squamous cell carcinoma xenograft tumor line. Radiat. Res. 153, 398–404 (2000).

    CAS  PubMed  Article  Google Scholar 

  131. Milas, L., Milross, C. G. & Mason, K. A. Cytotoxic treatments and tumor oxygenation. Cancer J. Sci. Am. 2, 59–60; author reply 60–61 (1996).

    CAS  PubMed  Google Scholar 

  132. Milas, L. et al. Role of reoxygenation in induction of enhancement of tumor radioresponse by paclitaxel. Cancer Res. 55, 3564–3568 (1995).

    CAS  PubMed  Google Scholar 

  133. Milas, L., Hunter, N., Mason, K. A., Milross, C. & Peters, L. J. Tumor reoxygenation as a mechanism of taxol-induced enhancement of tumor radioresponse. Acta Oncol. 34, 409–412 (1995).

    CAS  PubMed  Article  Google Scholar 

  134. Rubin, P. & Casarett, G. Microcirculation of tumors. II. The supervascularized state of irradiated regressing tumors. Clin. Radiol. 17, 346–355 (1966). This paper was the first to suggest that radiation therapy induced a change in tumour vascular density that would favour increased oxygenation.

    CAS  PubMed  Article  Google Scholar 

  135. Dewhirst, M. W. et al. Heterogeneity in tumor microvascular response to radiation. Int. J. Radiat. Oncol. Biol. Phys 18, 559–568 (1990).

    CAS  PubMed  Article  Google Scholar 

  136. Moeller, B. J., Cao, Y., Li, C. Y. & Dewhirst, M. W. Radiation activates HIF-1 to regulate vascular radiosensitivity in tumors: role of reoxygenation, free radicals, and stress granules. Cancer Cell 5, 429–441 (2004). This paper demonstrated that tumour reoxygenation after radiotherapy paradoxically led to an increase in HIF1 activity through mechanisms involving free radical generation and stress granule disaggregation.

    CAS  PubMed  Article  Google Scholar 

  137. Moeller, B. J. et al. A manganese porphyrin superoxide dismutase mimetic enhances tumor radioresponsiveness. Int. J. Radiat. Oncol. Biol. Phys. 63, 545–552 (2005).

    CAS  PubMed  Article  Google Scholar 

  138. Moeller, B. J. et al. Pleiotropic effects of HIF-1 blockade on tumor radiosensitivity. Cancer Cell 8, 99–110 (2005).

    CAS  PubMed  Article  Google Scholar 

  139. Williams, K. J. et al. Enhanced response to radiotherapy in tumours deficient in the function of hypoxia-inducible factor-1. Radiother. Oncol. 75, 89–98 (2005).

    CAS  PubMed  Article  Google Scholar 

  140. Kedersha, N. L., Gupta, M., Li, W., Miller, I. & Anderson, P. RNA-binding proteins TIA-1 and TIAR link the phosphorylation of eIF-2 α to the assembly of mammalian stress granules. J. Cell Biol. 147, 1431–1442 (1999).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  141. Magnon, C. et al. Radiation and inhibition of angiogenesis by canstatin synergize to induce HIF-1α-mediated tumor apoptotic switch. J. Clin. Invest. 117, 1844–1855 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  142. Tatum, J. L. et al. Hypoxia: importance in tumor biology, noninvasive measurement by imaging, and value of its measurement in the management of cancer therapy. Int. J. Radiat. Biol. 82, 699–757 (2006).

    CAS  Article  PubMed  Google Scholar 

  143. Manzoor, A. A., Yuan, H., Palmer, G. M., Viglianti, B. L. & Dewhirst, M. W. in Molecular Imaging: Principles and Practice (eds Weissleder, R., Gambhir, S. S., Ross, B. D. & Rehemtulla, A.) (BC Decker, Ontario, 2008).

    Google Scholar 

  144. Raleigh, J. A., Dewhirst, M. W. & Thrall, D. E. Measuring tumor hypoxia. Semin. Radiat. Oncol. 6, 37–45 (1996).

    CAS  PubMed  Article  Google Scholar 

  145. Khan, N., Williams, B. B., Hou, H., Li, H. & Swartz, H. M. Repetitive tissue pO2 measurements by electron paramagnetic resonance oximetry: current status and future potential for experimental and clinical studies. Antioxid. Redox Signal. 9, 1169–1182 (2007).

    CAS  PubMed  Article  Google Scholar 

  146. Srinivasan, S. et al. Developments in quantitative oxygen-saturation imaging of breast tissue in vivo using multispectral near-infrared tomography. Antioxid. Redox Signal. 9, 1143–1156 (2007).

    CAS  PubMed  Article  Google Scholar 

  147. Matsumoto, K., Subramanian, S., Murugesan, R., Mitchell, J. B. & Krishna, M. C. Spatially resolved biologic information from in vivo EPRI, OMRI, and MRI. Antioxid. Redox Signal. 9, 1125–1141 (2007).

    CAS  PubMed  Article  Google Scholar 

  148. Koch, C. J. Measurement of absolute oxygen levels in cells and tissues using oxygen sensors and 2-nitroimidazole EF5. Methods Enzymol. 352, 3–31 (2002).

    CAS  PubMed  Article  Google Scholar 

  149. Koch, C. J., Evans, S. M. & Lord, E. M. Oxygen dependence of cellular uptake of EF5 [2-(2-nitro-1H-imidazol-1-yl)-N-(2, 2, 3, 3, 3-pentafluoropropyl)acetamide]: analysis of drug adducts by fluorescent antibodies vs bound radioactivity. Br. J. Cancer 72, 869–874 (1995).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  150. Koch, C. J. & Evans, S. M. Non-invasive PET and SPECT imaging of tissue hypoxia using isotopically labeled 2-nitroimidazoles. Adv. Exp. Med. Biol. 510, 285–292 (2003).

    CAS  PubMed  Article  Google Scholar 

  151. Padhani, A. R., Krohn, K. A., Lewis, J. S. & Alber, M. Imaging oxygenation of human tumours. Eur. Radiol. 17, 861–872 (2007).

    PubMed  Article  Google Scholar 

  152. Moon, E. J., Brizel, D. M., Chi, J. T. & Dewhirst, M. W. The potential role of intrinsic hypoxia markers as prognostic variables in cancer. Antioxid. Redox Signal. 9, 1237–1294 (2007).

    CAS  PubMed  Article  Google Scholar 

  153. Le, Q. T. et al. Expression and prognostic significance of a panel of tissue hypoxia markers in head-and-neck squamous cell carcinomas. Int. J. Radiat. Oncol. Biol. Phys. 69, 167–175 (2007).

    CAS  PubMed  Article  Google Scholar 

  154. Vaupel, P., Hockel, M. & Mayer, A. Detection and characterization of tumor hypoxia using pO2 histography. Antioxid. Redox Signal. 9, 1221–1235 (2007).

    CAS  PubMed  Article  Google Scholar 

  155. Secomb, T. W., Hsu, R., Ong, E. T., Gross, J. F. & Dewhirst, M. W. Analysis of the effects of oxygen supply and demand on hypoxic fraction in tumors. Acta Oncol. 34, 313–316 (1995).

    CAS  PubMed  Article  Google Scholar 

  156. Dewhirst, M. W., Cao, Y., Li, C. Y. & Moeller, B. Exploring the role of HIF-1 in early angiogenesis and response to radiotherapy. Radiother. Oncol. 83, 249–255 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

Download references

Acknowledgements

The authors acknowledge the helpful discussions with I. Cardenas-Navia, T. Schroeder, E. Moon and A. Manzoor in the preparation of this manuscript. B. Sorg's contributions to the laboratory form important bases for the concepts presented. Two decades of collaboration with T. Secomb led to many of the insights provided in this Review. The authors also acknowledge the support of I. Fridovich, B. Haberle and Z. Vujaskovic for introducing them to SOD mimetics that were used to test important hypotheses regarding the role of reactive oxygen species in HIF1α regulation and angiogenesis. Supported by grants from the NIH CA40355 and the Duke SPORE for Breast Cancer.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Mark W. Dewhirst.

Supplementary information

Supplementary information S1 (movie)

Phosphorescence lifetime imaging was performed to image vascular oxygen concentration in 2x3 mm regions of skin fold window chamber tumors of Fischer rats. The windows contained either the 9L glioma (movie 1) or a fibrosarcoma (movie 2). Oxygen measurements were made every 2.5 min for 60-90 min. The movies depict changes in pO2 that are >5 mmHg from the immediately preceding image. Red indicates an increase, Blue indicates a decrease and yellow indicates no changes >5mmHg. Note that in both examples there are a significant number of pixels showing this behavior, with the fibrosarcoma showing more of a tendency to exhibit contiguous regions of similar behaviour. (AVI 8525 kb)

Supplementary information S2 (movie)

Phosphorescence lifetime imaging was performed to image vascular oxygen concentration in 2x3 mm regions of skin fold window chamber tumors of Fischer rats. The windows contained either the 9L glioma (movie 1) or a fibrosarcoma (movie 2). Oxygen measurements were made every 2.5 min for 60-90 min. The movies depict changes in pO2 that are >5 mmHg from the immediately preceding image. Red indicates an increase, Blue indicates a decrease and yellow indicates no changes >5mmHg. Note that in both examples there are a significant number of pixels showing this behavior, with the fibrosarcoma showing more of a tendency to exhibit contiguous regions of similar behaviour. (AVI 12787 kb)

Supplementary information S3 (figure)

Expression of HIF-1 reporter protein (Green fluorescence protein; GFP) during angiogenesis initiation and acceleration. (PDF 793 kb)

Related links

Related links

DATABASES

National Cancer Institute

breast cancer

cervical cancer

colorectal cancer

glioma

head and neck cancer

National Cancer Institute Drug Dictionary

tirapazamine

FURTHER INFORMATION

M. W. Dewhirst's homepage

Glossary

Microangiography

This method permits visualization of microvessels in a tissue following injection of an X-ray contrast agent and exposure to X-rays; X-ray film or digital imaging are used to visualize the vessels.

Vascular casting

With this method, a cast of microvessels as they actually exist in tissues is preserved to permit visualization. Vasculature is filled with a polymer that sets inside the vessels. The tissue is then digested away to leave just the cast of the microvessels.

Shunt vessels

These are large-diameter vessels that directly connect between feeding and draining vessels at the periphery of a tumour. These can shunt flow around the main body of the tumour, thereby starving the tumour of nutrients.

Redox ratio

This ratio, which is derived from the relative abundance of two naturally fluorescent coenzymes, FAD and NADH, is related to the metabolic activity of a tissue.

Hypoxic cytotoxin

Hypoxic cytotoxins are drugs that are selectively toxic to hypoxic cells.

Laser Doppler flowmetry

This method measures velocity of red blood cells in tissue. When a laser illuminates tissue the light strikes red blood cells that are moving. The reflected light undergoes a detectable change in shift in frequency (Doppler shift) that is related to red blood cell velocity.

Blood oxygen level detection magnetic resonance imaging

(BOLD MRI.) This is an MRI method that is sensitive to the difference in magnetic properties of deoxyhaemoglobin versus oxyhaemoglobin.

Dynamic contrast enhanced MRI

(DCE MRI.) This is a method to measure perfusion/permeability of an MR contrast agent as it enters and leaves a tissue following bolus intravenous injection. Kinetic analysis permits derivation of parameters related to vascular permeability and perfusion.

Vasomotion

Arterioles in the peripheral circulation exhibit fluctuations in diameter that control perfusion of dependent tissues.

Bifurcation point

This term refers to a branch point in the microcirculation, in which flow splits from one vessel to two or more daughter vessels.

Carotid body

The carotid body is a collection of pH-, partial pressure of O2 (pO2)- and pCO2-sensitive chemoreceptor cells located on the carotid artery wall. When stimulated they send signals to the central nervous system to regulate respiratory and heart rates.

Dormancy

This is a state of tumour growth at a time when cell loss is equal to cell proliferation and before the onset of angiogenesis.

Stress granules

Cell stress initiators, such as nutritional deprivation or hypoxia, cause a general downregulation of protein translation, involving prevention of mRNA entry into ribosomes, forming stress granules (in complex with RNA-binding proteins) in the cytoplasm. Stress granules rapidly disaggregate upon removal of stress, permitting subsequent protein translation.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Dewhirst, M., Cao, Y. & Moeller, B. Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response. Nat Rev Cancer 8, 425–437 (2008). https://doi.org/10.1038/nrc2397

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrc2397

Further reading

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