Skip to main content

Abstract

Radiation is a very effective form of cancer therapy but its effectiveness is significantly influenced by changes in the levels of oxygen, nutrients and pH in the tumor microenvironment. Radiation dose is also limited by normal tissue toxicity, which can manifest itself both in early effects as well as in late effects. Therefore, approaches aimed at improving the therapeutic window for radiotherapy should consider both the effects of the tumor microenvironment such as hypoxia, and also target pathways that may reduce radiation-induced normal tissue toxicity. With these concepts in mind, we review the biological consequences of tumor hypoxia and the effects of hypoxia/HIF on tumor radiation sensitivity as well as the effects of targeting the HIF/PHD axis for normal tissue radioprotection.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Ward JF. DNA damage produced by ionizing radiation in mammalian cells: identities, mechanisms of formation, and reparability. Prog Nucleic Acid Res Mol Biol. 1988;35:95–125.

    Article  CAS  PubMed  Google Scholar 

  2. Hammond EM, Olcina M, Giaccia AJ. Hypoxia and modulation of cellular radiation response. New York: Springer; 2011.

    Book  Google Scholar 

  3. Barker HE, Paget JTE, Khan AA, Harrington KJ. The tumour microenvironment after radiotherapy: mechanisms of resistance and recurrence. [Internet]. Nat Rev Cancer. 2015;15(7):409–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Masson N, Ratcliffe PJ. Hypoxia signaling pathways in cancer metabolism: the importance of co-selecting interconnected physiological pathways. [Internet]. Cancer Metab. 2014;2(1):3.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Dendy PP, Wardman P. Hypoxia in biology and medicine: the legacy of L H Gray [Internet]. Br J Radiol. 2006;79(943):545–9.

    Article  CAS  PubMed  Google Scholar 

  6. Gray LH, Conger AD, Ebert M, Hornsey S, Scott OC. The concentration of oxygen dissolved in tissues at the time of irradiation as a factor in radiotherapy. [Internet]. Br J Radiol. 1953;26(312):638–48.

    Article  CAS  PubMed  Google Scholar 

  7. Crabtree HG, Cramer W. The action of radium on cancer cells. II.—some factors determining the susceptibility of cancer cells to radium. [Internet]. Proc R Soc London B Biol Sci. 1933;113(782):238–50.

    Article  CAS  Google Scholar 

  8. Thomlinson RH, Gray LH. The histological structure of some human lung cancers and the possible implications for radio-therapy. Br J Cancer. 1955;9(4):539–49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Reinhold HS, Blachiewicz B, Berg-Blok A. Reoxygenation of tumours in “sandwich” chambers. Eur J Cancer. 1979;15(4):481–9. doi:10.1016/0014-2964(79)90083-5.

    Article  CAS  PubMed  Google Scholar 

  10. Brown JM. Evidence for acutely hypoxic cells in mouse tumours, and a possible mechanism of reoxygenation. [Internet]. Br J Radiol. 1979;52(620):650–6.

    Article  CAS  PubMed  Google Scholar 

  11. Schofield CJ, Ratcliffe PJ. Oxygen sensing by HIF hydroxylases. [Internet]. Nat Rev Mol Cell Biol. 2004;5(5):343–54.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  13. Baumann M, et al. Radiation oncology in the era of precision medicine. [Internet]. Nat Rev Cancer. 2016;16(4):234–49.

    Article  CAS  PubMed  Google Scholar 

  14. Bentzen SM. Preventing or reducing late side effects of radiation therapy: radiobiology meets molecular pathology. [Internet]. Nat Rev Cancer. 2006;6(9):702–13.

    Article  CAS  PubMed  Google Scholar 

  15. Olcina MM, Giaccia AJ. Reducing radiation-induced gastrointestinal toxicity—the role of the PHD/HIF axis. J Clin Invest. 2016. doi:10.1172/JCI84432.

    Google Scholar 

  16. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–74.

    Article  CAS  PubMed  Google Scholar 

  17. Nordsmark M, Overgaard M, Overgaard J. Pretreatment oxygenation predicts radiation response in advanced squamous cell carcinoma of the head and neck. Radiother Oncol. 1996;41(96):31–9.

    Article  CAS  PubMed  Google Scholar 

  18. Aebersold DM, et al. Expression of hypoxia-inducible factor-1alpha: a novel predictive and prognostic parameter in the radiotherapy of oropharyngeal cancer. [Internet]. Cancer Res. 2001;61:2911–6.

    CAS  PubMed  Google Scholar 

  19. Brown JM, Wilson WR. Exploiting tumour hypoxia in cancer treatment. [Internet]. Nat Rev Cancer. 2004;4(6):437–47.

    Article  CAS  PubMed  Google Scholar 

  20. Höckel M, Vaupel P. Tumor hypoxia: definitions and current clinical, biologic, and molecular aspects. J Natl Cancer Inst. 2001;93(4):266–76.

    Article  PubMed  Google Scholar 

  21. Greer SN, Metcalf JL, Wang Y, Ohh M. The updated biology of hypoxia-inducible factor. [Internet]. EMBO J. 2012;31(11):2448–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Yoshimura M, Itasaka S, Harada H, Hiraoka M. Microenvironment and radiation therapy. Biomed Res Int. 2013;2013:685308. doi:10.1155/2013/685308.

    Article  PubMed  Google Scholar 

  23. Vaupel P, Kallinowski F, Okunieff P. Blood flow, oxygen and nutrient supply, and metabolic microenvironment of human tumors: a review. Cancer Res. 1989;49(23):6449–65.

    CAS  PubMed  Google Scholar 

  24. Folkman J. What is the evidence that tumors are angiogenesis dependent? J Natl Cancer Inst. 1990;82(1):4–6.

    Article  CAS  PubMed  Google Scholar 

  25. Vaupel P. The role of hypoxia-induced factors in tumor progression. Oncologist. 2004;9 Suppl 5:10–7.

    Article  CAS  PubMed  Google Scholar 

  26. Kizaka-Kondoh S, Inoue M, Harada H, Hiraoka M. Tumor hypoxia: a target for selective cancer therapy. Cancer Sci. 2003;94(12):1021–8.

    Article  CAS  PubMed  Google Scholar 

  27. Held KD. Radiobiology for the Radiologist, 6th ed., by Eric J. Hall and Amato J. Giaccia. Radiat Res. 2006;166:816–7.

    Article  CAS  Google Scholar 

  28. Wang GL, Semenza GL. Purification and characterization of hypoxia-inducible factor 1. [Internet]. J Biol Chem. 1995;270(3):1230–7.

    Article  CAS  PubMed  Google Scholar 

  29. Jaakkola P, et al. Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. [Internet]. Science. 2001;292(5516):468–72.

    Article  CAS  PubMed  Google Scholar 

  30. Ivan M, et al. HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. [Internet]. Science. 2001;292(5516):464–8.

    Article  CAS  PubMed  Google Scholar 

  31. Maxwell PH, et al. The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature. 1999;399(6733):271–5.

    Article  CAS  PubMed  Google Scholar 

  32. Wenger RH, et al. Integration of oxygen signaling at the consensus HRE. Sci STKE. 2005;2005(306):re12.

    PubMed  Google Scholar 

  33. Kaelin WG, Ratcliffe PJ. Oxygen sensing by Metazoans: the central role of the HIF hydroxylase pathway. Mol Cell. 2008;30(4):393–402.

    Article  CAS  PubMed  Google Scholar 

  34. Finley LWS, et al. SIRT3 opposes reprogramming of cancer cell metabolism through HIF1α destabilization. Cancer Cell. 2011;19(3):416–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Zundel W, et al. Loss of PTEN facilitates HIF-1-mediated gene expression. Genes Dev. 2000;14(4):391–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Hudson CC, et al. Regulation of hypoxia-inducible factor 1alpha expression and function by the mammalian target of rapamycin. [Internet]. Mol Cell Biol. 2002;22(20):7004–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Giaccia A. Hypoxic stress proteins: survival of the Fittest. [Internet]. Semin Radiat Oncol. 1996;6(1):46–58.

    Article  PubMed  Google Scholar 

  38. Semenza GL. Regulation of hypoxia-induced angiogenesis: a chaperone escorts VEGF to the dance. J Clin Invest. 2001;108(1):39–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Leibovich SJ, et al. Macrophage-induced angiogenesis is mediated by tumour necrosis factor-alpha. [Internet]. Nature. 1987;329(6140):630–2.

    Article  CAS  PubMed  Google Scholar 

  40. Leek RD, et al. Macrophage infiltration is associated with VEGF and EGFR expression in breast cancer. J Pathol. 2000;190(4):430–6.

    Article  CAS  PubMed  Google Scholar 

  41. Goonewardene TI, Sowter HM, Harris AL. Hypoxia-induced pathways in breast cancer. Microsc Res Tech. 2002;59(1):41–8.

    Article  CAS  PubMed  Google Scholar 

  42. Semenza GL, Roth PH, Fang HM, Wang GL. Transcriptional regulation of genes encoding glycolytic enzymes by hypoxia-inducible factor 1. [Internet]. J Biol Chem. 1994;269(38):23757–63.

    CAS  PubMed  Google Scholar 

  43. Semenza GL, et al. Hypoxia response elements in the aldolase A, enolase 1, and lactate dehydrogenase a gene promoters contain essential binding sites for hypoxia-inducible factor 1. J Biol Chem. 1996;271(51):32529–37.

    Article  CAS  PubMed  Google Scholar 

  44. Vaupel P, Thews O, Hoeckel M. Treatment resistance of solid tumors: role of hypoxia and anemia. Med Oncol. 2001;18(4):243–59.

    Article  CAS  PubMed  Google Scholar 

  45. Rofstad EK. Microenvironment-induced cancer metastasis. [Internet]. Int J Radiat Biol. 2000;76(5):589–605.

    Article  CAS  PubMed  Google Scholar 

  46. Cheng KC, Cahill DS, Kasai H, Nishimura S, Loeb LA. 8-Hydroxyguanine, an abundant form of oxidative DNA damage, causes G—T and A—C substitutions. J Biol Chem. 1992;267(1):166–72.

    CAS  PubMed  Google Scholar 

  47. Olinski R, et al. Oxidative DNA damage: assessment of the role in carcinogenesis, atherosclerosis, and acquired immunodeficiency syndrome. Free Radic Biol Med. 2002;33(2):192–200.

    Article  CAS  PubMed  Google Scholar 

  48. Reynolds TY, Rockwell S, Glazer PM. Genetic instability induced by the tumor microenvironment. Cancer Res. 1996;56(24):5754–7.

    CAS  PubMed  Google Scholar 

  49. Hammond EM, Giaccia AJ. The role of p53 in hypoxia-induced apoptosis. Biochem Biophys Res Commun. 2005;331(3):718–25.

    Article  CAS  PubMed  Google Scholar 

  50. Olcina MM, et al. H3K9me3 facilitates hypoxia-induced p53-dependent apoptosis through repression of APAK. Oncogene. 2016;35(6):793–9. doi:10.1038/onc.2015.134.

    Article  CAS  PubMed  Google Scholar 

  51. Graeber TG, et al. Hypoxia induces accumulation of p53 protein, but activation of a G1-phase checkpoint by low-oxygen conditions is independent of p53 status. [Internet]. Mol Cell Biol. 1994;14(9):6264–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Hammond EM, Denko NC, Dorie MJ, Abraham RT, Giaccia AJ. Hypoxia links ATR and p53 through replication arrest. [Internet]. Mol Cell Biol. 2002;22(6):1834–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Olcina MM, et al. Replication stress and chromatin context link ATM activation to a role in DNA replication. Mol Cell. 2013;52(5):758–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Soengas MS, et al. Apaf-1 and caspase-9 in p53-dependent apoptosis and tumor inhibition. [Internet]. Science. 1999;284(5411):156–9.

    Article  CAS  PubMed  Google Scholar 

  55. Leszczynska KB, et al. Hypoxia-induced p53 modulates both apoptosis and radiosensitivity via AKT. [Internet]. J Clin Invest. 2015;125(6):2385–98.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Bussink J, Kaanders JHAM, Van Der Kogel AJ. Tumor hypoxia at the micro-regional level: clinical relevance and predictive value of exogenous and endogenous hypoxic cell markers. Radiother Oncol. 2003;67(1):3–15.

    Article  PubMed  Google Scholar 

  57. Moon EJ, Brizel DM, Chi J-TA, Dewhirst MW. The potential role of intrinsic hypoxia markers as prognostic variables in cancer. Antioxid Redox Signal. 2007;9(8):1237–94.

    Article  CAS  PubMed  Google Scholar 

  58. Moeller BJ, et al. Pleiotropic effects of HIF-1 blockade on tumor radiosensitivity. Cancer Cell. 2005;8(2):99–110.

    Article  CAS  PubMed  Google Scholar 

  59. Moeller BJ, Dewhirst MW. HIF-1 and tumour radiosensitivity. Br J Cancer. 2006;95(1):1–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Cam H, Easton JB, High A, Houghton PJ. mTORC1 signaling under hypoxic conditions is controlled by atm-dependent phosphorylation of HIF-1α. Mol Cell. 2010;40(4):509–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Pires IM, et al. Targeting radiation-resistant hypoxic tumour cells through ATR inhibition. [Internet]. Br J Cancer. 2012;107(2):291–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Fallone F, Britton S, Nieto L, Salles B, Muller C. ATR controls cellular adaptation to hypoxia through positive regulation of hypoxia-inducible factor 1 (HIF-1) expression. [Internet]. Oncogene. 2012;32(37):4387–96.

    Article  PubMed  Google Scholar 

  63. Moeller BJ, Cao Y, Li CY, Dewhirst MW. Radiation activates HIF-1 to regulate vascular radiosensitivity in tumors: role of reoxygenation, free radicals, and stress granules. Cancer Cell. 2004;5(5):429–41.

    Article  CAS  PubMed  Google Scholar 

  64. Harada H, et al. Cancer cells that survive radiation therapy acquire HIF-1 activity and translocate towards tumour blood vessels. [Internet]. Nat Commun. 2012;3:783.

    Article  PubMed  PubMed Central  Google Scholar 

  65. Kim WY, Oh SH, Woo JK, Hong WK, Lee HY. Targeting heat shock protein 90 overrides the resistance of lung cancer cells by blocking radiation-induced stabilization of hypoxia-inducible factor-1α. Cancer Res. 2009;69(4):1624–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Bertout JA, et al. HIF2α inhibition promotes p53 pathway activity, tumor cell death, and radiation responses. [Internet]. Proc Natl Acad Sci. 2009;106(34):14391–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. ClinicalTrials.gov. No Title. [Internet]. 2016. https://clinicaltrials.gov/ct2/results?term=Proline+hydroxylase&Search=Search.

  68. Taniguchi CM, et al. PHD inhibition mitigates and protects against radiation-induced gastrointestinal toxicity via HIF2. [Internet]. Sci Transl Med. 2014;6(236):236ra64.

    Article  PubMed  PubMed Central  Google Scholar 

  69. Pugh CW, Ratcliffe PJ. Regulation of angiogenesis by hypoxia: role of the HIF system. Nat Med. 2003;9(6):677–84.

    Article  CAS  PubMed  Google Scholar 

  70. Bertout JA, Patel SA, Simon MC. The impact of O2 availability on human cancer. Nat Rev Cancer. 2008;8(12):967–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Wilson WR, Hay MP. Targeting hypoxia in cancer therapy. [Internet]. Nat Rev Cancer. 2011;11(6):393–410.

    Article  CAS  PubMed  Google Scholar 

  72. Henke M, et al. Erythropoietin to treat head and neck cancer patients with anaemia undergoing radiotherapy: randomised, double-blind, placebo-controlled trial. Lancet. 2003;362(9392):1255–60.

    Article  CAS  PubMed  Google Scholar 

  73. Fletcher GH, Lindberg RD, Caderao JB, Wharton JT. Hyperbaric oxygen as a radiotherapeutic adjuvant in advanced cancer of the uterine cervix. Preliminary results of a randomized trial. [Internet]. Cancer. 1977;39(2):617–23.

    Article  CAS  PubMed  Google Scholar 

  74. Hoskin PJ, Saunders MI, Dische S. Hypoxic radiosensitizers in radical radiotherapy for patients with bladder carcinoma: hyperbaric oxygen, misonidazole, and accelerated radiotherapy, carbogen, and nicotinamide. Cancer. 1999;86(7):1322–8.

    Article  CAS  PubMed  Google Scholar 

  75. Overgaard J. Hypoxic modification of radiotherapy in squamous cell carcinoma of the head and neck—a systematic review and meta-analysis. Radiother Oncol. 2011;100(1):22–32.

    Article  PubMed  Google Scholar 

  76. Hoskin PJ, Rojas AM, Saunders MI, Bentzen SM, Motohashi KJ. Carbogen and nicotinamide in locally advanced bladder cancer: early results of a phase-III randomized trial. [Internet]. Radiother Oncol. 2009;91(1):120–5.

    Article  CAS  PubMed  Google Scholar 

  77. Janssens GO, et al. Accelerated radiotherapy with carbogen and nicotinamide for laryngeal cancer: results of a phase III randomized trial. [Internet]. J Clin Oncol. 2012;30(15):1777–83.

    Article  CAS  PubMed  Google Scholar 

  78. Janssens GO, et al. Improved recurrence-free survival with ARCON for anemic patients with laryngeal cancer. Clin Cancer Res. 2014;20(5):1345–54.

    Article  CAS  PubMed  Google Scholar 

  79. Baillet F, Housset M, Dessard-Diana B, Boisserie G. Positive clinical experience with misonidazole in brachytherapy and external radiotherapy. Int J Radiat Oncol Biol Phys. 1989;16(4):1073–5.

    Article  CAS  PubMed  Google Scholar 

  80. Minsky BD, Leibel SA. The treatment of hepatic metastases from colorectal cancer with radiation therapy alone or combined with chemotherapy or misonidazole. [Internet]. Cancer Treat Rev. 1989;16(4):213–9.

    Article  CAS  PubMed  Google Scholar 

  81. Simpson JR, et al. Radiation therapy alone or combined with misonidazole in the treatment of locally advanced non-oat cell lung cancer: report of an RTOG prospective randomized trial. [Internet]. Int J Radiat Oncol Biol Phys Chem Chem Phys. 1989;16(6):1483–91.

    CAS  Google Scholar 

  82. Timothy AR, Overgaard J, Overgaard M. A phase I clinical study of nimorazole as a hypoxic radiosensitizer. Int J Radiat Oncol Biol Phys. 1984;10(9):1765–8.

    Article  CAS  PubMed  Google Scholar 

  83. Brown JM. SR 4233 (tirapazamine): a new anticancer drug exploiting hypoxia in solid tumours. [Internet]. Br J Cancer. 1993;67(6):1163–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Rischin D, et al. Phase I trial of concurrent tirapazamine, cisplatin, and radiotherapy in patients with advanced head and neck cancer. J Clin Oncol. 2001;19(2):535–42.

    CAS  PubMed  Google Scholar 

  85. Weiss GJ, et al. Phase 1 study of the safety, tolerability, and pharmacokinetics of TH-302, a hypoxia-activated prodrug, in patients with advanced solid malignancies. Clin Cancer Res. 2011;17(9):2997–3004.

    Article  CAS  PubMed  Google Scholar 

  86. François A, Milliat F, Guipaud O, Benderitter M. Inflammation and immunity in radiation damage to the gut mucosa. [Internet]. Biomed Res Int. 2013;2013:123241.

    PubMed  PubMed Central  Google Scholar 

  87. Citrin D, et al. Radioprotectors and mitigators of radiation-induced normal tissue injury. [Internet]. Oncologist. 2010;15(4):360–71.

    Article  PubMed  PubMed Central  Google Scholar 

  88. Palazon A, Goldrath AW, Nizet V, Johnson RS. HIF transcription factors, inflammation, and immunity. [Internet]. Immunity. 2014;41(4):518–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Hauer-Jensen M, Denham JW, Andreyev HJN. Radiation enteropathy—pathogenesis, treatment and prevention. [Internet]. Nat Rev Gastroenterol Hepatol. 2014;11(8):470–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Seiwert TY, Salama JK, Vokes EE. The concurrent chemoradiation paradigm—general principles. Nat Clin Pract Oncol. 2007;4(2):86–100.

    Article  CAS  PubMed  Google Scholar 

  91. Maes C, Carmeliet G, Schipani E. Hypoxia-driven pathways in bone development, regeneration and disease. [Internet]. Nat Rev Rheumatol. 2012;8(6):358–66.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Amato J. Giaccia .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2016 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Olcina, M.M., Kim, R., Giaccia, A.J. (2016). The Role of Hypoxia in Radiation Response. In: Anscher, M., Valerie, K. (eds) Strategies to Enhance the Therapeutic Ratio of Radiation as a Cancer Treatment. Springer, Cham. https://doi.org/10.1007/978-3-319-45594-5_2

Download citation

Publish with us

Policies and ethics