Advertisement

The Clinical Impact of Hypoxia in Head and Neck Squamous Cell Carcinoma

  • Annette M. Lim
  • Quynh-Thu Le
  • Danny Rischin
Chapter
Part of the Current Cancer Research book series (CUCR)

Abstract

Hypoxia commonly occurs in head and neck squamous cell carcinomas and is associated with treatment resistance and poor patient outcome. The presence of tumor hypoxia can contribute to the protection of cancer cells from DNA damage induced by ionizing radiation and chemotherapy, with hypoxia also promoting alterations in tumor biology that enhance malignant progression. Significant effort has been devoted to abrogating the effects of hypoxia through approaches that include the modification of tumor oxygenation and the tumor vasculature. Recent approaches to improve therapeutic response have explored agents that can sensitize hypoxic cancer cells to chemoradiation or directly cause hypoxic cell death. However, these approaches have had limited success. There is significant clinical need to identify an appropriate predictive biomarker to select patients with tumor hypoxia that will benefit from hypoxia-modifying approaches.

Keywords

Head and neck Squamous cell carcinoma HNSCC Hypoxia Radiation resistance Oxygen enhancement ratio Nitroimidazole Nimorazole Tirapazamine Pimonidazole FMISO FAZA HIF HIF-1 Osteopontin 

References

  1. 1.
    Shield KD, Ferlay J, Jemal A, Sankaranarayanan R, Chaturvedi AK, Bray F, et al. The global incidence of lip, oral cavity, and pharyngeal cancers by subsite in 2012. CA Cancer J Clin. 2017;67(1):51–64.CrossRefPubMedGoogle Scholar
  2. 2.
    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(1):31–9.CrossRefPubMedGoogle Scholar
  3. 3.
    Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin. 2005;55(2):74–108.CrossRefPubMedGoogle Scholar
  4. 4.
    Ang KK, Harris J, Wheeler R, Weber R, Rosenthal DI, Nguyen-Tan PF, et al. Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med. 2010;363(1):24–35.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Rischin D, Peters LJ, O'Sullivan B, Giralt J, Fisher R, Yuen K, et al. Tirapazamine, cisplatin, and radiation versus cisplatin and radiation for advanced squamous cell carcinoma of the head and neck (TROG 02.02, HeadSTART): a phase III trial of the Trans-Tasman Radiation Oncology Group. J Clin Oncol: official journal of the American Society of Clinical Oncology. 2010;28(18):2989–95.CrossRefGoogle Scholar
  6. 6.
    Vermorken JB, Mesia R, Rivera F, Remenar E, Kawecki A, Rottey S, et al. Platinum-based chemotherapy plus cetuximab in head and neck ancer. N Engl J Med. 2008;359(11):1116–27.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Vermorken JB, Stohlmacher-Williams J, Davidenko I, Licitra L, Winquist E, Villanueva C, et al. Cisplatin and fluorouracil with or without panitumumab in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck (SPECTRUM): an open-label phase 3 randomised trial. Lancet Oncol. 2013;14(8):697–710.CrossRefPubMedGoogle Scholar
  8. 8.
    Ferris RL, Blumenschein G Jr, Fayette J, Guigay J, Colevas AD, Licitra L, et al. Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N Engl J Med. 2016;375(19):1856–67.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Gillison ML, Koch WM, Capone RB, Spafford M, Westra WH, Wu L, et al. Evidence for a causal association between human papillomavirus and a subset of head and neck cancers. J Natl Cancer Inst. 2000;92(9):709–20.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Gillison ML, D'Souza G, Westra W, Sugar E, Xiao W, Begum S, et al. Distinct risk factor profiles for human papillomavirus type 16-positive and human papillomavirus type 16-negative head and neck cancers. J Natl Cancer Inst. 2008;100(6):407–20.CrossRefPubMedGoogle Scholar
  11. 11.
    Gillison ML. HPV and prognosis for patients with oropharynx cancer. Eur J Cancer. 2009;45(Suppl 1):383–5.CrossRefPubMedGoogle Scholar
  12. 12.
    Lassen P, Eriksen JG, Hamilton-Dutoit S, Tramm T, Alsner J, Overgaard J. Effect of HPV-associated p16INK4A expression on response to radiotherapy and survival in squamous cell carcinoma of the head and neck. J Clin Oncol: official journal of the American Society of Clinical Oncology. 2009;27(12):1992–8.CrossRefGoogle Scholar
  13. 13.
    Rischin D, Young RJ, Fisher R, Fox SB, Le QT, Peters LJ, et al. Prognostic significance of p16INK4A and human papillomavirus in patients with oropharyngeal cancer treated on TROG 02.02 phase III trial. J Clin Oncol: official journal of the American Society of Clinical Oncology. 2010;28(27):4142–8.CrossRefGoogle Scholar
  14. 14.
    Licitra L, Perrone F, Bossi P, Suardi S, Mariani L, Artusi R, et al. High-risk human papillomavirus affects prognosis in patients with surgically treated oropharyngeal squamous cell carcinoma. J Clin Oncol: official journal of the American Society of Clinical Oncology. 2006;24(36):5630–6.CrossRefGoogle Scholar
  15. 15.
    Vaupel P, Kelleher DK, Hockel M. Oxygen status of malignant tumors: pathogenesis of hypoxia and significance for tumor therapy. Semin Oncol. 2001;28(2 Suppl 8):29–35.CrossRefPubMedGoogle Scholar
  16. 16.
    Nordsmark M, Bentzen SM, Rudat V, Brizel D, Lartigau E, Stadler P, et al. Prognostic value of tumor oxygenation in 397 head and neck tumors after primary radiation therapy. An international multi-center study. Radiother Oncol. 2005;77(1):18–24.CrossRefPubMedGoogle Scholar
  17. 17.
    Overgaard J, Horsman MR. Modification of hypoxia-induced radioresistance in tumors by the use of oxygen and sensitizers. Semin Radiat Oncol. 1996;6(1):10–21.CrossRefPubMedGoogle Scholar
  18. 18.
    Gray LH, Conger AD, Ebert M, Hornsey S, Scott OC. Concentration of oxygen dissolved in tissues at the time of irradiation as a factor in radiotherapy. Br J Radiol. 1953;26:638–48.CrossRefPubMedGoogle Scholar
  19. 19.
    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.CrossRefPubMedGoogle Scholar
  20. 20.
    Shannon AM, Bouchier-Hayes DJ, Condron CM, Toomey D. Tumour hypoxia, chemotherapeutic resistance and hypoxia-related therapies. Cancer Treat Rev. 2003;29(4):297–307.CrossRefPubMedGoogle Scholar
  21. 21.
    Becker A, Hansgen G, Bloching M, Weigel C, Lautenschlager C, Dunst J. Oxygenation of squamous cell carcinoma of the head and neck: comparison of primary tumors, neck node metastases, and normal tissue. Int J Radiat Oncol Biol Phys. 1998;42(1):35–41.CrossRefPubMedGoogle Scholar
  22. 22.
    Monti E, Gariboldi MB. HIF-1 as a target for cancer chemotherapy, chemosensitization and chemoprevention. Curr Mol Pharmacol. 2011;4(1):62–77.CrossRefPubMedGoogle Scholar
  23. 23.
    Henk JM, Kunkler PB, Smith CW. Radiotherapy and hyperbaric oxygen in head and neck cancer. Final report of first controlled clinical trial. Lancet. 1977;2(8029):101–3.CrossRefPubMedGoogle Scholar
  24. 24.
    Henk JM. Late results of a trial of hyperbaric oxygen and radiotherapy in head and neck cancer: a rationale for hypoxic cell sensitizers? Int J Radiat Oncol Biol Phys. 1986;12(8):1339–41.CrossRefPubMedGoogle Scholar
  25. 25.
    Overgaard J, Hansen HS, Overgaard M, Bastholt L, Berthelsen A, Specht L, et al. A randomized double-blind phase III study of nimorazole as a hypoxic radiosensitizer of primary radiotherapy in supraglottic larynx and pharynx carcinoma. Results of the Danish Head and Neck Cancer Study (DAHANCA) Protocol 5-85. Radiother Oncol. 1998;46(2):135–46.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Brown JM. Tumor microenvironment and the response to anticancer therapy. Cancer Biol Ther. 2002;1(5):453–8.CrossRefPubMedGoogle Scholar
  27. 27.
    Rademakers SE, Span PN, Kaanders JH, Sweep FC, van der Kogel AJ, Bussink J. Molecular aspects of tumour hypoxia. Mol Oncol. 2008;2(1):41–53.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Bredell MG, Ernst J, El-Kochairi I, Dahlem Y, Ikenberg K, Schumann DM. Current relevance of hypoxia in head and neck cancer. Oncotarget. 2016;7(31):50781–804.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Rockwell S, Dobrucki IT, Kim EY, Marrison ST, Vu VT. Hypoxia and radiation therapy: past history, ongoing research, and future promise. Curr Mol Med. 2009;9(4):442–58.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Pignon JP, le Maitre A, Maillard E, Bourhis J. Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): an update on 93 randomised trials and 17,346 patients. Radiother Oncol. 2009;92(1):4–14.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Henk JM, Kunkler PB, Shah NK, Smith CW, Sutherland WH, Wassif SB. Hyperbaric oxygen in radiotherapy of head and neck carcinoma. Clin Radiol. 1970;21(3):223–31.CrossRefPubMedGoogle Scholar
  32. 32.
    Churchill-Davidson I, Sanger C, Thomlinson RH. II. Clinical application. Br J Radiol. 1957;30(356):406–22.CrossRefPubMedGoogle Scholar
  33. 33.
    Brizel DM, Sibley GS, Prosnitz LR, Scher RL, Dewhirst MW. Tumor hypoxia adversely affects the prognosis of carcinoma of the head and neck. Int J Radiat Oncol Biol Phys. 1997;38(2):285–189.CrossRefPubMedGoogle Scholar
  34. 34.
    Rudat V, Stadler P, Becker A, Vanselow B, Dietz A, Wannenmacher M, et al. Predictive value of the tumor oxygenation by means of pO2 histography in patients with advanced head and neck cancer. Strahlenther Onkol. 2001;177(9):462–8.CrossRefPubMedGoogle Scholar
  35. 35.
    Nordsmark M, Bentzen SM, Overgaard J. Measurement of human tumour oxygenation status by a polarographic needle electrode. An analysis of inter- and intratumour heterogeneity. Acta Oncol. 1994;33(4):383–9.CrossRefPubMedGoogle Scholar
  36. 36.
    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(1):31–9.CrossRefPubMedGoogle Scholar
  37. 37.
    Koukourakis MI, Bentzen SM, Giatromanolaki A, Wilson GD, Daley FM, Saunders MI, et al. Endogenous markers of two separate hypoxia response pathways (hypoxia inducible factor 2 alpha and carbonic anhydrase 9) are associated with radiotherapy failure in head and neck cancer patients recruited in the CHART randomized trial. J Clin Oncol: official journal of the American Society of Clinical Oncology. 2006;24(5):727–35.CrossRefGoogle Scholar
  38. 38.
    Ferreira MB, De Souza JA, Cohen EE. Role of molecular markers in the management of head and neck cancers. Curr Opin Oncol. 2011;23(3):259–64.CrossRefPubMedGoogle Scholar
  39. 39.
    Zips D, Zophel K, Abolmaali N, Perrin R, Abramyuk A, Haase R, et al. Exploratory prospective trial of hypoxia-specific PET imaging during radiochemotherapy in patients with locally advanced head-and-neck cancer. Radiother Oncol. 2012;Google Scholar
  40. 40.
    Kikuchi M, Yamane T, Shinohara S, Fujiwara K, Hori SY, Tona Y, et al. 18F-fluoromisonidazole positron emission tomography before treatment is a predictor of radiotherapy outcome and survival prognosis in patients with head and neck squamous cell carcinoma. Ann Nucl Med. 2011;25(9):625–33.CrossRefPubMedGoogle Scholar
  41. 41.
    Kaanders JH, Wijffels KI, Marres HA, Ljungkvist AS, Pop LA, van den Hoogen FJ, et al. Pimonidazole binding and tumor vascularity predict for treatment outcome in head and neck cancer. Cancer Res. 2002;62(23):7066–74.PubMedGoogle Scholar
  42. 42.
    Swartz JE, Pothen AJ, Stegeman I, Willems SM, Grolman W. Clinical implications of hypoxia biomarker expression in head and neck squamous cell carcinoma: a systematic review. Cancer Med. 2015;4(7):1101–16.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Bache M, Kappler M, Said HM, Staab A, Vordermark D. Detection and specific targeting of hypoxic regions within solid tumors: current preclinical and clinical strategies. Curr Med Chem. 2008;15(4):322–38.CrossRefPubMedGoogle Scholar
  44. 44.
    Karam PA, Leslie SA, Anbar A. The effects of changing atmospheric oxygen concentrations and background radiation levels on radiogenic DNA damage rates. Health Phys. 2001;81(5):545–53.CrossRefPubMedGoogle Scholar
  45. 45.
    Moulder JE, Rockwell S. Hypoxic fractions of solid tumors: experimental techniques, methods of analysis, and a survey of existing data. Int J Radiat Oncol Biol Phys. 1984;10(5):695–712.CrossRefPubMedGoogle Scholar
  46. 46.
    Rockwell S, Moulder JE. Hypoxic fractions of human tumors xenografted into mice: a review. Int J Radiat Oncol Biol Phys. 1990;19(1):197–202.CrossRefPubMedGoogle Scholar
  47. 47.
    Wenzl T, Wilkens JJ. Modelling of the oxygen enhancement ratio for ion beam radiation therapy. Phys Med Biol. 2011;56(11):3251–68.CrossRefPubMedGoogle Scholar
  48. 48.
    Shannon AM, Bouchier-Hayes DJ, Condron CM, Toomey D. Tumour hypoxia, chemotherapeutic resistance and hypoxia-related therapies. Cancer Treat Rev. 29(4):297–307.Google Scholar
  49. 49.
    Teicher BA, Lazo JS, Sartorelli AC. Classification of antineoplastic agents by their selective toxicities toward oxygenated and hypoxic tumor cells. Cancer Res. 1981;41(1):73–81.PubMedGoogle Scholar
  50. 50.
    Wozniak AJ, Ross WE. DNA damage as a basis for 4'-demethylepipodophyllotoxin-9-(4,6-O-ethylidene-beta-D-glucopyranoside) (etoposide) cytotoxicity. Cancer Res. 1983;43(1):120–4.PubMedPubMedCentralGoogle Scholar
  51. 51.
    Wozniak AJ, Glisson BS, Hande KR, Ross WE. Inhibition of etoposide-induced DNA damage and cytotoxicity in L1210 cells by dehydrogenase inhibitors and other agents. Cancer Res. 1984;44(2):626–32.PubMedPubMedCentralGoogle Scholar
  52. 52.
    Walker LJ, Craig RB, Harris AL, Hickson ID. A role for the human DNA repair enzyme HAP1 in cellular protection against DNA damaging agents and hypoxic stress. Nucleic Acids Res. 1994;22(23):4884–9.CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Graeber TG, Osmanian C, Jacks T, Housman DE, Koch CJ, Lowe SW, et al. Hypoxia-mediated selection of cells with diminished apoptotic potential in solid tumours. Nature. 1996;379(6560):88–91.CrossRefPubMedGoogle Scholar
  54. 54.
    Le QT, Denko NC, Giaccia AJ. Hypoxic gene expression and metastasis. Cancer Metastasis Rev. 2004;23(3-4):293–310.CrossRefPubMedGoogle Scholar
  55. 55.
    Semenza GL. Hypoxia-inducible factor 1 (HIF-1) pathway. Sci STKE: signal transduction knowledge environment. 2007;2007(407):cm8.CrossRefPubMedGoogle Scholar
  56. 56.
    Takenaga K. Angiogenic signaling aberrantly induced by tumor hypoxia. Front Biosci: a journal and virtual library. 2011;16:31–48.CrossRefGoogle Scholar
  57. 57.
    Harris AL. Hypoxia--a key regulatory factor in tumour growth. Nat Rev Cancer. 2002;2(1):38–47.CrossRefPubMedGoogle Scholar
  58. 58.
    Li DW, Dong P, Wang F, Chen XW, Xu CZ, Zhou L. Hypoxia induced multidrug resistance of laryngeal cancer cells via hypoxia-inducible factor-1α. Asian Pac J Cancer Prev. 2013;14(8):4853–8.CrossRefPubMedGoogle Scholar
  59. 59.
    Hsu DS, Lan HY, Huang CH, Tai SK, Chang SY, Tsai TL, et al. Regulation of excision repair cross-complementation group 1 by Snail contributes to cisplatin resistance in head and neck cancer. Clin Cancer Res. 2010;16(18):4561–71.CrossRefPubMedGoogle Scholar
  60. 60.
    Gammon L, Mackenzie IC. Roles of hypoxia, stem cells and epithelial–mesenchymal transition in the spread and treatment resistance of head and neck cancer. J Oral Pathol Med. 2016;45(2):77–82.CrossRefPubMedGoogle Scholar
  61. 61.
    Comerford KM, Wallace TJ, Karhausen J, Louis NA, Montalto MC, Colgan SP. Hypoxia-inducible factor-1-dependent regulation of the multidrug resistance (MDR1) gene. Cancer Res. 2002;62(12):3387–94.PubMedPubMedCentralGoogle Scholar
  62. 62.
    Krishnamurthy P, Ross DD, Nakanishi T, Bailey-Dell K, Zhou S, Mercer KE, et al. The stem cell marker Bcrp/ABCG2 enhances hypoxic cell survival through interactions with heme. J Biol Chem. 2004;279(23):24218–25.CrossRefPubMedGoogle Scholar
  63. 63.
    Zeng L, Kizaka-Kondoh S, Itasaka S, Xie X, Inoue M, Tanimoto K, et al. Hypoxia inducible factor-1 influences sensitivity to paclitaxel of human lung cancer cell lines under normoxic conditions. Cancer Sci. 2007;98(9):1394–401.CrossRefPubMedGoogle Scholar
  64. 64.
    Greijer AE, de Jong MC, Scheffer GL, Shvarts A, van Diest PJ, van der Wall E. Hypoxia-induced acidification causes mitoxantrone resistance not mediated by drug transporters in human breast cancer cells. Cell Oncol: the official journal of the International Society for Cellular Oncology 2005;27(1):43-49.Google Scholar
  65. 65.
    Wykoff CC, Beasley NJ, Watson PH, Turner KJ, Pastorek J, Sibtain A, et al. Hypoxia-inducible expression of tumor-associated carbonic anhydrases. Cancer Res. 2000;60(24):7075–83.PubMedGoogle Scholar
  66. 66.
    Warburg O, Wind F, Negelein E. The metabolism of tumors in the body. J Gen Physiol. 1927;8(6):519–30.CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Vaupel P. Tumor microenvironmental physiology and its implications for radiation oncology. Semin Radiat Oncol. 2004;14(3):198–206.CrossRefPubMedGoogle Scholar
  68. 68.
    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.PubMedPubMedCentralGoogle Scholar
  69. 69.
    Moncharmont C, Levy A, Gilormini M, Bertrand G, Chargari C, Alphonse G, et al. Targeting a cornerstone of radiation resistance: cancer stem cell. Cancer Lett. 2012;322(2):139–47.CrossRefPubMedGoogle Scholar
  70. 70.
    Sermeus A, Michiels C. Reciprocal influence of the p53 and the hypoxic pathways. Cell Death Dis. 2011;2:e164.CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Vaupel P, Schlenger K, Knoop C, Hockel M. Oxygenation of human tumors: evaluation of tissue oxygen distribution in breast cancers by computerized O2 tension measurements. Cancer Res. 1991;51(12):3316–22.PubMedGoogle Scholar
  72. 72.
    Hockel M, Schlenger K, Knoop C, Vaupel P. Oxygenation of carcinomas of the uterine cervix: evaluation by computerized O2 tension measurements. Cancer Res. 1991;51(22):6098–102.PubMedGoogle Scholar
  73. 73.
    Nordsmark M, Overgaard J. A confirmatory prognostic study on oxygenation status and loco-regional control in advanced head and neck squamous cell carcinoma treated by radiation therapy. Radiother Oncol. 2000;57(1):39–43.CrossRefPubMedGoogle Scholar
  74. 74.
    Le QT, Sutphin PD, Raychaudhuri S, Yu SC, Terris DJ, Lin HS, et al. Identification of osteopontin as a prognostic plasma marker for head and neck squamous cell carcinomas. Clin Cancer Res. 2003;9(1):59–67.PubMedGoogle Scholar
  75. 75.
    Nordsmark M, Eriksen JG, Gebski V, Alsner J, Horsman MR, Overgaard J. Differential risk assessments from five hypoxia specific assays: the basis for biologically adapted individualized radiotherapy in advanced head and neck cancer patients. Radiother Oncol. 2007;83(3):389–97.CrossRefPubMedGoogle Scholar
  76. 76.
    Rudat V, Vanselow B, Wollensack P, Bettscheider C, Osman-Ahmet S, Eble MJ, et al. Repeatability and prognostic impact of the pretreatment pO(2) histography in patients with advanced head and neck cancer. Radiother Oncol. 2000;57(1):31–7.CrossRefPubMedGoogle Scholar
  77. 77.
    Nozue M, Lee I, Yuan F, Teicher BA, Brizel DM, Dewhirst MW, et al. Interlaboratory variation in oxygen tension measurement by Eppendorf "Histograph" and comparison with hypoxic marker. J Surg Oncol. 1997;66(1):30–8.CrossRefPubMedGoogle Scholar
  78. 78.
    Wiesener MS, Jürgensen JS, Rosenberger C, Scholze C, Hörstrup JH, Warnecke C, et al. Widespread, hypoxia-inducible expression of HIF-2α in distinct cell populations of different organs. FASEB J. 2002;17:271–3.Google Scholar
  79. 79.
    Unwith S, Zhao H, Hennah L, Ma D. The potential role of HIF on tumour progression and dissemination. Int J Cancer. 2015;136(11):2491–503.CrossRefPubMedGoogle Scholar
  80. 80.
    Semenza GL. Targeting HIF-1 for cancer therapy. Nat Rev Cancer. 2003;3(10):721–32.CrossRefPubMedGoogle Scholar
  81. 81.
    Denko NC. Hypoxia, HIF1 and glucose metabolism in the solid tumour. Nat Rev Cancer. 2008;8(9):705–13.CrossRefPubMedGoogle Scholar
  82. 82.
    Semenza GL, Wang GL. 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. 1992;12(12):5447–54.CrossRefPubMedPubMedCentralGoogle Scholar
  83. 83.
    Wang GL, Jiang BH, Rue EA, Semenza GL. Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci U S A. 1995;92(12):5510–4.CrossRefPubMedPubMedCentralGoogle Scholar
  84. 84.
    Nordsmark MAJ, Eriksen JG, et al. The prognostic value of serum osteopontin, HIF-1alpha and pO2 measurements in advanced head and neck tumors treated by radiotherapy. Eur J Cancer Suppl. 2003;1:S145.CrossRefGoogle Scholar
  85. 85.
    Peridis S, Pilgrim G, Athanasopoulos I, Parpounas K. Carbonic anhydrase-9 expression in head and neck cancer: a meta-analysis. Eur Arch Oto Rhino Laryngol: official journal of the European Federation of Oto-Rhino-Laryngological Societies. 2011;268(5):661–70.CrossRefGoogle Scholar
  86. 86.
    Li J, Zhang G, Wang X, Li X-F. Is carbonic anhydrase IX a validated target for molecular imaging of cancer and hypoxia? Future Oncol. 2015;11(10):1531–41.CrossRefPubMedPubMedCentralGoogle Scholar
  87. 87.
    Wykoff CC, Beasley NJP, Watson PH, Turner KJ, Pastorek J, Sibtain A, et al. Hypoxia-inducible expression of tumor-associated carbonic anhydrases. Cancer Res. 2000;60(24):7075–83.PubMedGoogle Scholar
  88. 88.
    Forsythe JA, Jiang BH, Iyer NV, Agani F, Leung SW, Koos RD, et al. Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. Mol Cell Biol. 1996;16(9):4604–13.CrossRefPubMedPubMedCentralGoogle Scholar
  89. 89.
    Macheda ML, Rogers S, Best JD. Molecular and cellular regulation of glucose transporter (GLUT) proteins in cancer. J Cell Physiol. 2005;202(3):654–62.CrossRefPubMedGoogle Scholar
  90. 90.
    Kimura H, Weisz A, Kurashima Y, Hashimoto K, Ogura T, D'Acquisto F, et al. Hypoxia response element of the human vascular endothelial growth factor gene mediates transcriptional regulation by nitric oxide: control of hypoxia-inducible factor-1 activity by nitric oxide. Blood. 2000;95(1):189–97.PubMedPubMedCentralGoogle Scholar
  91. 91.
    Shih SC, Claffey KP. Role of AP-1 and HIF-1 transcription factors in TGF-beta activation of VEGF expression. Growth Factors. 2001;19(1):19–34.CrossRefPubMedGoogle Scholar
  92. 92.
    Anavi S, Hahn-Obercyger M, Madar Z, Tirosh O. Mechanism for HIF-1 activation by cholesterol under normoxia: a redox signaling pathway for liver damage. Free Radic Biol Med. 2014;71:61–9.CrossRefPubMedGoogle Scholar
  93. 93.
    Fukuda R, Hirota K, Fan F, Jung YD, Ellis LM, Semenza GL. 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. 2002;277(41):38205–11.CrossRefPubMedGoogle Scholar
  94. 94.
    Richard DE, Berra E, Gothie E, Roux D, Pouyssegur J. p42/p44 mitogen-activated protein kinases phosphorylate hypoxia-inducible factor 1alpha (HIF-1alpha) and enhance the transcriptional activity of HIF-1. J Biol Chem. 1999;274(46):32631–7.CrossRefPubMedGoogle Scholar
  95. 95.
    Nakamura M, Bodily JM, Beglin M, Kyo S, Inoue M, Laimins LA. Hypoxia-specific stabilization of HIF-1alpha by human papillomaviruses. Virology. 2009;387(2):442–8.CrossRefPubMedPubMedCentralGoogle Scholar
  96. 96.
    Guo Y, Meng X, Ma J, Zheng Y, Wang Q, Wang Y, et al. Human papillomavirus 16 E6 contributes HIF-1alpha induced Warburg effect by attenuating the VHL-HIF-1alpha interaction. Int J Mol Sci. 2014;15(5):7974–86.CrossRefPubMedPubMedCentralGoogle Scholar
  97. 97.
    Gong L, Zhang W, Zhou J, Lu J, Xiong H, Shi X, et al. Prognostic value of HIFs expression in head and neck cancer: a systematic review. PLoS One. 2013;8(9):e75094.CrossRefPubMedPubMedCentralGoogle Scholar
  98. 98.
    Hoogsteen IJ, Marres HA, Bussink J, van der Kogel AJ, Kaanders JH. Tumor microenvironment in head and neck squamous cell carcinomas: predictive value and clinical relevance of hypoxic markers. A review. Head Neck. 2007;29(6):591–604.CrossRefPubMedGoogle Scholar
  99. 99.
    Bussink J, Kaanders JH, 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.CrossRefPubMedGoogle Scholar
  100. 100.
    PO DEL, Jorge CC, Oliveira DT, Pereira MC. Hypoxic condition and prognosis in oral squamous cell carcinoma. Anticancer Res. 2014;34(2):605–12.Google Scholar
  101. 101.
    Qian J, Wenguang X, Zhiyong W, Yuntao Z, Wei H. Hypoxia inducible factor: a potential prognostic biomarker in oral squamous cell carcinoma. Tumor Biol. 2016;37(8):10815–20.CrossRefGoogle Scholar
  102. 102.
    van Kuijk SJA, Yaromina A, Houben R, Niemans R, Lambin P, Dubois LJ. Prognostic significance of carbonic anhydrase IX expression in cancer patients: a meta-analysis. Front Oncol. 2016;6(69)Google Scholar
  103. 103.
    Kaluz S, Kaluzova M, Chrastina A, Olive PL, Pastorekova S, Pastorek J, et al. Lowered oxygen tension induces expression of the hypoxia marker MN/carbonic anhydrase IX in the absence of hypoxia-inducible factor 1 alpha stabilization: a role for phosphatidylinositol 3'-kinase. Cancer Res. 2002;62(15):4469–77.PubMedGoogle Scholar
  104. 104.
    Mayer A, Hockel M, Vaupel P. Carbonic anhydrase IX expression and tumor oxygenation status do not correlate at the microregional level in locally advanced cancers of the uterine cervix. Clin Cancer Res. 2005;11(20):7220–5.CrossRefPubMedGoogle Scholar
  105. 105.
    Li XF, Carlin S, Urano M, Russell J, Ling CC, O'Donoghue JA. Visualization of hypoxia in microscopic tumors by immunofluorescent microscopy. Cancer Res. 2007;67(16):7646–53.CrossRefPubMedGoogle Scholar
  106. 106.
    Zelzer E, Levy Y, Kahana C, Shilo BZ, Rubinstein M, Cohen B. Insulin induces transcription of target genes through the hypoxia-inducible factor HIF-1alpha/ARNT. EMBO J. 1998;17(17):5085–94.CrossRefPubMedPubMedCentralGoogle Scholar
  107. 107.
    Okino ST, Chichester CH, Whitlock JP Jr. Hypoxia-inducible mammalian gene expression analyzed in vivo at a TATA-driven promoter and at an initiator-driven promoter. J Biol Chem. 1998;273(37):23837–43.CrossRefPubMedGoogle Scholar
  108. 108.
    Rivenzon-Segal D, Boldin-Adamsky S, Seger D, Seger R, Degani H. Glycolysis and glucose transporter 1 as markers of response to hormonal therapy in breast cancer. Int J Cancer. 2003;107(2):177–82.CrossRefPubMedGoogle Scholar
  109. 109.
    Brands RC, Köhler O, Rauthe S, Hartmann S, Ebhardt H, Seher A, et al. The prognostic value of GLUT-1 staining in the detection of malignant transformation in oral mucosa. Clin Oral Investig. 2016:1–7.Google Scholar
  110. 110.
    Li C-X, Sun J-L, Gong Z-C, Lin Z-Q, Liu H. Prognostic value of GLUT-1 expression in oral squamous cell carcinoma: a prisma-compliant meta-analysis. Medicine. 2016;95(45):e5324.CrossRefPubMedPubMedCentralGoogle Scholar
  111. 111.
    Vassilakopoulou M, Psyrri A, Argiris A. Targeting angiogenesis in head and neck cancer. Oral Oncol. 2015;51(5):409–15.CrossRefPubMedPubMedCentralGoogle Scholar
  112. 112.
    Glück AA, Aebersold DM, Zimmer Y, Medová M. Interplay between receptor tyrosine kinases and hypoxia signaling in cancer. Int J Biochem Cell Biol. 2015;62:101–14.CrossRefPubMedPubMedCentralGoogle Scholar
  113. 113.
    Kowanetz M, Ferrara N. Vascular endothelial growth factor signaling pathways: therapeutic perspective. Clin Cancer Res. 2006;12(17):5018–22.CrossRefPubMedPubMedCentralGoogle Scholar
  114. 114.
    Kyzas PA, Cunha IW, Ioannidis JP. Prognostic significance of vascular endothelial growth factor immunohistochemical expression in head and neck squamous cell carcinoma: a meta-analysis. Clin Cancer Res. 2005;11(4):1434–40.CrossRefPubMedPubMedCentralGoogle Scholar
  115. 115.
    Zhang LP, Chen HL. Increased vascular endothelial growth factor expression predicts a worse prognosis for laryngeal cancer patients: a meta-analysis. J Laryngol Otol. 2016;131(1):44–50.CrossRefPubMedPubMedCentralGoogle Scholar
  116. 116.
    Bellahcene A, Castronovo V, Ogbureke KU, Fisher LW, Fedarko NS. Small integrin-binding ligand N-linked glycoproteins (SIBLINGs): multifunctional proteins in cancer. Nat Rev Cancer. 2008;8(3):212–26.CrossRefPubMedPubMedCentralGoogle Scholar
  117. 117.
    Zhu Y, Denhardt DT, Cao H, Sutphin PD, Koong AC, Giaccia AJ, et al. Hypoxia upregulates osteopontin expression in NIH-3T3 cells via a Ras-activated enhancer. Oncogene. 2005;24(43):6555–63.CrossRefPubMedPubMedCentralGoogle Scholar
  118. 118.
    Fisher LW, Jain A, Tayback M, Fedarko NS. Small integrin binding ligand N-linked glycoprotein gene family expression in different cancers. Clin Cancer Res. 2004;10(24):8501–11.CrossRefPubMedPubMedCentralGoogle Scholar
  119. 119.
    Wai PY, Kuo PC. Osteopontin: regulation in tumor metastasis. Cancer Metastasis Rev. 2008;27(1):103–18.CrossRefPubMedPubMedCentralGoogle Scholar
  120. 120.
    Wang KX, Denhardt DT. Osteopontin: role in immune regulation and stress responses. Cytokine Growth Factor Rev. 2008;19(5-6):333–45.CrossRefPubMedGoogle Scholar
  121. 121.
    Weber GF, Lett GS, Haubein NC. Osteopontin is a marker for cancer aggressiveness and patient survival. Br J Cancer. 2010;103(6):861–9.CrossRefPubMedPubMedCentralGoogle Scholar
  122. 122.
    Le QT, Kong C, Lavori PW, O'Byrne K, Erler JT, Huang X, 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. 2007;69(1):167–75.CrossRefPubMedGoogle Scholar
  123. 123.
    Bache M, Reddemann R, Said HM, Holzhausen HJ, Taubert H, Becker A, et al. Immunohistochemical detection of osteopontin in advanced head-and-neck cancer: prognostic role and correlation with oxygen electrode measurements, hypoxia-inducible-factor-1alpha-related markers, and hemoglobin levels. Int J Radiat Oncol Biol Phys. 2006;66(5):1481–7.CrossRefPubMedGoogle Scholar
  124. 124.
    Overgaard J, Eriksen JG, Nordsmark M, Alsner J, Horsman MR. Plasma osteopontin, hypoxia, and response to the hypoxia sensitiser nimorazole in radiotherapy of head and neck cancer: results from the DAHANCA 5 randomised double-blind placebo-controlled trial. Lancet Oncol. 2005;6(10):757–64.CrossRefPubMedGoogle Scholar
  125. 125.
    Lim AM, Rischin D, Fisher R, Cao H, Kwok K, Truong D, et al. Prognostic significance of plasma osteopontin in patients with locoregionally advanced head and neck squamous cell carcinoma treated on TROG 02.02 phase III trial. Clin Cancer Res. 2012;18(1):301–7.CrossRefPubMedGoogle Scholar
  126. 126.
    Toustrup K, Sorensen BS, Nordsmark M, Busk M, Wiuf C, Alsner J, et al. Development of a hypoxia gene expression classifier with predictive impact for hypoxic modification of radiotherapy in head and neck cancer. Cancer Res. 2011;71(17):5923–31.CrossRefPubMedGoogle Scholar
  127. 127.
    Toustrup K, Sorensen BS, Alsner J, Overgaard J. Hypoxia gene expression signatures as prognostic and predictive markers in head and neck radiotherapy. Semin Radiat Oncol. 2012;22(2):119–27.CrossRefPubMedGoogle Scholar
  128. 128.
    Linge A, Lohaus F, Lock S, Nowak A, Gudziol V, Valentini C, et al. HPV status, cancer stem cell marker expression, hypoxia gene signatures and tumour volume identify good prognosis subgroups in patients with HNSCC after primary radiochemotherapy: a multicentre retrospective study of the German Cancer Consortium Radiation Oncology Group (DKTK-ROG). Radiother Oncol. 2016;121(3):364–73.CrossRefPubMedGoogle Scholar
  129. 129.
    Arteel GE, Thurman RG, Yates JM, Raleigh JA. Evidence that hypoxia markers detect oxygen gradients in liver: pimonidazole and retrograde perfusion of rat liver. Br J Cancer. 1995;72(4):889–95.CrossRefPubMedPubMedCentralGoogle Scholar
  130. 130.
    Bourgeois M, Rajerison H, Guerard F, Mougin-Degraef M, Barbet J, Michel N, et al. Contribution of [64Cu]-ATSM PET in molecular imaging of tumour hypoxia compared to classical [18F]-MISO--a selected review. Nucl Med Rev Cent East Eur. 2011;14(2):90–5.CrossRefPubMedGoogle Scholar
  131. 131.
    Chen L, Zhang Z, Kolb HC, Walsh JC, Zhang J, Guan Y. (1)(8)F-HX4 hypoxia imaging with PET/CT in head and neck cancer: a comparison with (1)(8)F-FMISO. Nucl Med Commun. 2012;33(10):1096–102.CrossRefPubMedPubMedCentralGoogle Scholar
  132. 132.
    Dubois LJ, Lieuwes NG, Janssen MH, Peeters WJ, Windhorst AD, Walsh JC, et al. Preclinical evaluation and validation of [18F]HX4, a promising hypoxia marker for PET imaging. Proc Natl Acad Sci U S A. 2011;108(35):14620–5.CrossRefPubMedPubMedCentralGoogle Scholar
  133. 133.
    Suh YE, Lawler K, Henley-Smith R, Pike L, Leek R, Barrington S, et al. Association between hypoxic volume and underlying hypoxia-induced gene expression in oropharyngeal squamous cell carcinoma. Br J Cancer. 2017;116:1057–64.Google Scholar
  134. 134.
    Rasey JS, Grunbaum Z, Magee S, Nelson NJ, Olive PL, Durand RE, et al. Characterization of radiolabeled fluoromisonidazole as a probe for hypoxic cells. Radiat Res. 1987;111(2):292–304.CrossRefPubMedPubMedCentralGoogle Scholar
  135. 135.
    Maeda K, Osato T, Umezawa H. A new antibiotic, azomycin. J Antibiot. 1953;6(4):182.PubMedPubMedCentralGoogle Scholar
  136. 136.
    Hodolic M, Fettich J, Kairemo K. Hypoxia PET tracers in EBRT dose planning in head and neck cancer. Curr Radiopharm. 2015;8(1):32–7.CrossRefPubMedPubMedCentralGoogle Scholar
  137. 137.
    Tamaki N, Hirata K. Tumor hypoxia: a new PET imaging biomarker in clinical oncology. Int J Clin Oncol. 2016;21(4):619–25.CrossRefPubMedPubMedCentralGoogle Scholar
  138. 138.
    Troost EG, Laverman P, Philippens ME, Lok J, van der Kogel AJ, Oyen WJ, et al. Correlation of [18F]FMISO autoradiography and pimonidazole [corrected] immunohistochemistry in human head and neck carcinoma xenografts. Eur J Nucl Med Mol Imaging. 2008;35(10):1803–11.CrossRefPubMedPubMedCentralGoogle Scholar
  139. 139.
    Troost EG, Laverman P, Kaanders JH, Philippens M, Lok J, Oyen WJ, et al. Imaging hypoxia after oxygenation-modification: comparing [18F]FMISO autoradiography with pimonidazole immunohistochemistry in human xenograft tumors. Radiother Oncol. 2006;80(2):157–64.CrossRefPubMedPubMedCentralGoogle Scholar
  140. 140.
    Dubois L, Landuyt W, Haustermans K, Dupont P, Bormans G, Vermaelen P, et al. Evaluation of hypoxia in an experimental rat tumour model by [(18)F]fluoromisonidazole PET and immunohistochemistry. Br J Cancer. 2004;91(11):1947–54.CrossRefPubMedPubMedCentralGoogle Scholar
  141. 141.
    Rajendran JG, Schwartz DL, O'Sullivan J, Peterson LM, Ng P, Scharnhorst J, et al. Tumor hypoxia imaging with [F-18] fluoromisonidazole positron emission tomography in head and neck cancer. Clin Cancer Res. 2006;12(18):5435–41.CrossRefPubMedPubMedCentralGoogle Scholar
  142. 142.
    Eschmann SM, Paulsen F, Reimold M, Dittmann H, Welz S, Reischl G, et al. Prognostic impact of hypoxia imaging with 18F-misonidazole PET in non-small cell lung cancer and head and neck cancer before radiotherapy. J Nucl Med. 2005;46(2):253–60.PubMedPubMedCentralGoogle Scholar
  143. 143.
    Dirix P, Vandecaveye V, De Keyzer F, Stroobants S, Hermans R, Nuyts S. Dose painting in radiotherapy for head and neck squamous cell carcinoma: value of repeated functional imaging with (18)F-FDG PET, (18)F-fluoromisonidazole PET, diffusion-weighted MRI, and dynamic contrast-enhanced MRI. J Nucl Med. 2009;50(7):1020–7.CrossRefPubMedPubMedCentralGoogle Scholar
  144. 144.
    Rischin D, Hicks RJ, Fisher R, Binns D, Corry J, Porceddu S, et al. Prognostic significance of [18F]-misonidazole positron emission tomography-detected tumor hypoxia in patients with advanced head and neck cancer randomly assigned to chemoradiation with or without tirapazamine: a substudy of Trans-Tasman Radiation Oncology Group Study 98.02. J Clin Oncol: official journal of the American Society of Clinical Oncology. 2006;24(13):2098–104.CrossRefGoogle Scholar
  145. 145.
    Wiedenmann NE, Bucher S, Hentschel M, Mix M, Vach W, Bittner M-I, et al. Serial [18F]-fluoromisonidazole PET during radiochemotherapy for locally advanced head and neck cancer and its correlation with outcome. Radiother Oncol. 2015;117(1):113–7.CrossRefPubMedPubMedCentralGoogle Scholar
  146. 146.
    Lee NY, Mechalakos JG, Nehmeh S, Lin Z, Squire OD, Cai S, et al. Fluorine-18-labeled fluoromisonidazole positron emission and computed tomography-guided intensity-modulated radiotherapy for head and neck cancer: a feasibility study. Int J Radiat Oncol Biol Phys. 2008;70(1):2–13.CrossRefPubMedPubMedCentralGoogle Scholar
  147. 147.
    Henriques de Figueiredo B, Merlin T, de Clermont-Gallerande H, Hatt M, Vimont D, Fernandez P, et al. Potential of [18F]-Fluoromisonidazole positron-emission tomography for radiotherapy planning in head and neck squamous cell carcinomas. Strahlenther Onkol. 2013;189(12):1015–9.CrossRefPubMedPubMedCentralGoogle Scholar
  148. 148.
    Piert M, Machulla HJ, Picchio M, Reischl G, Ziegler S, Kumar P, et al. Hypoxia-specific tumor imaging with 18F-fluoroazomycin arabinoside. J Nucl Med. 2005;46(1):106–13.PubMedPubMedCentralGoogle Scholar
  149. 149.
    Postema EJ, McEwan AJ, Riauka TA, Kumar P, Richmond DA, Abrams DN, et al. Initial results of hypoxia imaging using 1-alpha-D: -(5-deoxy-5-[18F]-fluoroarabinofuranosyl)-2-nitroimidazole ( 18F-FAZA). Eur J Nucl Med Mol Imaging. 2009;36(10):1565–73.CrossRefPubMedPubMedCentralGoogle Scholar
  150. 150.
    Kumar P, Stypinski D, Xia H, McEwan AJB, Machulla HJ, Wiebe LI. Fluoroazomycin arabinoside (FAZA): synthesis, 2H and 3H-labelling and preliminary biological evaluation of a novel 2-nitroimidazole marker of tissue hypoxia. J Label Compd Radiopharm. 1999;42(1):3–16.CrossRefGoogle Scholar
  151. 151.
    Saga T, Inubushi M, Koizumi M, Yoshikawa K, Zhang M-R, Obata T, et al. Prognostic value of PET/CT with 18F-fluoroazomycin arabinoside for patients with head and neck squamous cell carcinomas receiving chemoradiotherapy. Ann Nucl Med. 2016;30(3):217–24.CrossRefPubMedPubMedCentralGoogle Scholar
  152. 152.
    Rischin D, Fisher R, Peters L, Corry J, Hicks R. Hypoxia in head and neck cancer: studies with hypoxic positron emission tomography imaging and hypoxic cytotoxins. Int J Radiat Oncol Biol Phys. 2007;69(2 Suppl):S61–3.CrossRefPubMedPubMedCentralGoogle Scholar
  153. 153.
    Graves EE, Hicks RJ, Binns D, Bressel M, Le Q-T, Peters L, et al. Quantitative and qualitative analysis of [18F]FDG and [18F]FAZA positron emission tomography of head and neck cancers and associations with HPV status and treatment outcome. Eur J Nucl Med Mol Imaging. 2016;43(4):617–25.CrossRefPubMedGoogle Scholar
  154. 154.
    Graves EE, Vilalta M, Cecic IK, Erler JT, Tran PT, Felsher D, et al. Hypoxia in models of lung cancer: implications for targeted therapeutics. Clin Cancer Res. 2010;16(19):4843–52.CrossRefPubMedPubMedCentralGoogle Scholar
  155. 155.
    Young RJ, Moller A. Immunohistochemical detection of tumour hypoxia. Methods Mol Biol. 2010;611:151–9.CrossRefPubMedPubMedCentralGoogle Scholar
  156. 156.
    Rijken PF, Bernsen HJ, Peters JP, Hodgkiss RJ, Raleigh JA, van der Kogel AJ. Spatial relationship between hypoxia and the (perfused) vascular network in a human glioma xenograft: a quantitative multi-parameter analysis. Int J Radiat Oncol Biol Phys. 2000;48(2):571–82.CrossRefPubMedGoogle Scholar
  157. 157.
    Busk M, Jakobsen S, Horsman MR, Mortensen LS, Iversen AB, Overgaard J, et al. PET imaging of tumor hypoxia using 18F-labeled pimonidazole. Acta Oncol. 2013;52(7):1300–7.CrossRefPubMedPubMedCentralGoogle Scholar
  158. 158.
    Evans SM, Joiner B, Jenkins WT, Laughlin KM, Lord EM, Koch CJ. Identification of hypoxia in cells and tissues of epigastric 9L rat glioma using EF5 [2-(2-nitro-1H-imidazol-1-yl)-N-(2,2,3,3,3- pentafluoropropyl) acetamide]. Br J Cancer. 1995;72(4):875–82.CrossRefPubMedPubMedCentralGoogle Scholar
  159. 159.
    Chitneni SK, Bida GT, Dewhirst MW, Zalutsky MR. A simplified synthesis of the hypoxia imaging agent 2-(2-Nitro-1H-imidazol-1-yl)-N-(2,2,3,3,3-[(18)F]pentafluoropropyl)-acetamide ([(18)F]EF5). Nucl Med Biol. 2012;39(7):1012–8.CrossRefPubMedPubMedCentralGoogle Scholar
  160. 160.
    Evans SM, Hahn S, Pook DR, Jenkins WT, Chalian AA, Zhang P, et al. Detection of hypoxia in human squamous cell carcinoma by EF5 binding. Cancer Res. 2000;60(7):2018–24.PubMedPubMedCentralGoogle Scholar
  161. 161.
    Panek R, Welsh L, Baker LC, Schmidt MA, Wong KH, Riddell A, et al. Non-invasive imaging of cycling hypoxia in head and neck cancer using intrinsic susceptibility MRI. Clin Cancer Res. 2017;23(15):4233–41.CrossRefPubMedPubMedCentralGoogle Scholar
  162. 162.
    Bennett M, Feldmeier J, Smee R, Milross C. Hyperbaric oxygenation for tumour sensitisation to radiotherapy: a systematic review of randomised controlled trials. Cancer Treat Rev. 2008;34(7):577–91.CrossRefPubMedPubMedCentralGoogle Scholar
  163. 163.
    Haffty BG, Hurley R, Peters LJ. Radiation therapy with hyperbaric oxygen at 4 atmospheres pressure in the management of squamous cell carcinoma of the head and neck: results of a randomized clinical trial. Cancer J Sci Am. 1999;5(6):341–7.PubMedPubMedCentralGoogle Scholar
  164. 164.
    Kaanders JH, Bussink J, van der Kogel AJ. ARCON: a novel biology-based approach in radiotherapy. Lancet Oncol. 2002;3(12):728–37.CrossRefPubMedPubMedCentralGoogle Scholar
  165. 165.
    Kaanders JH, Pop LA, Marres HA, Bruaset I, van den Hoogen FJ, Merkx MA, et al. ARCON: experience in 215 patients with advanced head-and-neck cancer. Int J Radiat Oncol Biol Phys. 2002;52(3):769–78.CrossRefPubMedPubMedCentralGoogle Scholar
  166. 166.
    Kaanders JH, Pop LA, Marres HA, Liefers J, van den Hoogen FJ, van Daal WA, et al. Accelerated radiotherapy with carbogen and nicotinamide (ARCON) for laryngeal cancer. Radiother Oncol. 1998;48(2):115–22.CrossRefPubMedPubMedCentralGoogle Scholar
  167. 167.
    Welsh L, Panek R, Riddell A, Wong K, Leach MO, Tavassoli M, et al. Blood transfusion during radical chemo-radiotherapy does not reduce tumour hypoxia in squamous cell cancer of the head and neck. Br J Cancer. 2017;116(1):28–35.CrossRefPubMedPubMedCentralGoogle Scholar
  168. 168.
    Hoff CM, Lassen P, Eriksen JG, Hansen HS, Specht L, Overgaard M, et al. Does transfusion improve the outcome for HNSCC patients treated with radiotherapy? – Results from the randomized DAHANCA 5 and 7 trials. Acta Oncol. 2011;50(7):1006–14.CrossRefPubMedPubMedCentralGoogle Scholar
  169. 169.
    Bhide SA, Ahmed M, Rengarajan V, Powell C, Miah A, Newbold K, et al. Anemia during sequential induction chemotherapy and chemoradiation for head and neck cancer: the impact of blood transfusion on treatment outcome. Int J Radiat Oncol Biol Phys. 2009;73(2):391–8.CrossRefPubMedPubMedCentralGoogle Scholar
  170. 170.
    Sealy R, Cridland S, Barry L, Norris R. Irradiation with misonidazole and hyperbaric oxygen: final report on a randomized trial in advanced head and neck cancer. Int J Radiat Oncol Biol Phys. 1986;12(8):1343–6.CrossRefPubMedPubMedCentralGoogle Scholar
  171. 171.
    Tobin DA, Vermund H. A randomized study of hyperbaric oxygen as an adjunct to regularly fractionated radiation therapy for clinical treatment of advanced neoplastic disease. Am J Roentgenol Radium Ther Nucl Med. 1971;111(3):613–21.CrossRefPubMedGoogle Scholar
  172. 172.
    Bennett MH, Feldmeier J, Smee R, Milross C. Hyperbaric oxygenation for tumour sensitisation to radiotherapy. Cochrane Database Syst Rev. 2005;(4)Google Scholar
  173. 173.
    Giebfried JW, Lawson W, Biller HF. Complications of hyperbaric oxygen in the treatment of head and neck disease. Otolaryngol Head Neck Surg: official journal of American Academy of Otolaryngology-Head and Neck Surgery. 1986;94(4):508–12.Google Scholar
  174. 174.
    Bennett MH, Feldmeier J, Smee R, Milross C. Hyperbaric oxygenation for tumour sensitisation to radiotherapy. Cochrane Database Syst Rev. 2012;4:CD005007.Google Scholar
  175. 175.
    Janssens GO, Rademakers SE, Terhaard CH, Doornaert PA, Bijl HP, van den Ende P, et al. Accelerated radiotherapy with carbogen and nicotinamide for laryngeal cancer: results of a phase III randomized trial. J Clin Oncol: official journal of the American Society of Clinical Oncology. 2012;30(15):1777–83.CrossRefGoogle Scholar
  176. 176.
    Nijkamp MM, Span PN, Terhaard CH, Doornaert PA, Langendijk JA, van den Ende PL, et al. Epidermal growth factor receptor expression in laryngeal cancer predicts the effect of hypoxia modification as an additive to accelerated radiotherapy in a randomised controlled trial. Eur J Cancer. 2013;49(15):3202–9.CrossRefPubMedGoogle Scholar
  177. 177.
    Janssens GO, Rademakers SE, Terhaard CH, Doornaert PA, Bijl HP, van den Ende P, et al. Improved recurrence-free survival with ARCON for anemic patients with laryngeal cancer. Clin Cancer Res. 2014;20(5):1345–54.CrossRefPubMedGoogle Scholar
  178. 178.
    Lee WR, Berkey B, Marcial V, Fu KK, Cooper JS, Vikram B, et al. Anemia is associated with decreased survival and increased locoregional failure in patients with locally advanced head and neck carcinoma: a secondary analysis of RTOG 85-27. Int J Radiat Oncol Biol Phys. 1998;42(5):1069–75.CrossRefPubMedGoogle Scholar
  179. 179.
    Lambin P, Ramaekers BLT, van Mastrigt GAPG, Van den Ende P, de Jong J, De Ruysscher DKM, et al. Erythropoietin as an adjuvant treatment with (chemo) radiation therapy for head and neck cancer. Cochrane Database Syst Rev. 2009;3(3):CD006158.  https://doi.org/10.1002/14651858.CD006158.pub2.CrossRefGoogle Scholar
  180. 180.
    Tonia T, Mettler A, Robert N, Schwarzer G, Seidenfeld J, Weingart O, et al. Erythropoietin or darbepoetin for patients with cancer. Cochrane Database Syst Rev. 2012;12(12):CD003407.  https://doi.org/10.1002/14651858.CD003407.pub5.CrossRefPubMedPubMedCentralGoogle Scholar
  181. 181.
    Bennett CL, Lai SY, Sartor O, et al. Consensus on the existence of functional erythropoietin receptors on cancer cells. JAMA Oncol. 2016;2(1):134–6.CrossRefPubMedGoogle Scholar
  182. 182.
    Bennett CL, Lai SY, Henke M, Barnato SE, Armitage JO, Sartor O. Association between pharmaceutical support and basic science research on erythropoiesis-stimulating agents. Arch Intern Med. 2010;170(16):1490–8.Google Scholar
  183. 183.
    Winter SC, Shah KA, Campo L, Turley H, Leek R, Corbridge RJ, et al. Relation of erythropoietin and erythropoietin receptor expression to hypoxia and anemia in head and neck squamous cell carcinoma. Clin Cancer Res. 2005;11(21):7614–20.CrossRefPubMedGoogle Scholar
  184. 184.
    Arcasoy MO, Amin K, Chou S-C, Haroon ZA, Varia M, Raleigh JA. Erythropoietin and erythropoietin receptor expression in head and neck cancer: relationship to tumor hypoxia. Clin Cancer Res. 2005;11(1):20–7.PubMedPubMedCentralGoogle Scholar
  185. 185.
    Bohlius J, Schmidlin K, Brillant C, Schwarzer G, Trelle S, Seidenfeld J, et al. Erythropoietin or Darbepoetin for patients with cancer - meta-analysis based on individual patient data. Cochrane Database Syst Rev. 2009;8(3):CD007303.  https://doi.org/10.1002/14651858.CD007303.pub2.CrossRefGoogle Scholar
  186. 186.
    Bohlius J, Wilson J, Seidenfeld J, Piper M, Schwarzer G, Sandercock J, et al. Erythropoietin or Darbepoetin for patients with cancer. Cochrane Database Syst Rev. 2006;(3):CD003407.Google Scholar
  187. 187.
    Datta NR, Bose AK, Kapoor HK, Gupta S. Head and neck cancers: results of thermoradiotherapy versus radiotherapy. Int J Hyperthermia. 1990;6(3):479–86.CrossRefPubMedGoogle Scholar
  188. 188.
    Datta NR, Rogers S, Ordóñez SG, Puric E, Bodis S. Hyperthermia and radiotherapy in the management of head and neck cancers: a systematic review and meta-analysis. Int J Hyperthermia. 2016;32(1):31–40.CrossRefPubMedGoogle Scholar
  189. 189.
    Walton MI, Wolf CR, Workman P. Molecular enzymology of the reductive bioactivation of hypoxic cell cytotoxins. Int J Radiat Oncol Biol Phys. 1989;16:983–6.CrossRefPubMedGoogle Scholar
  190. 190.
    Van den Bogaert W, van der Schueren E, Horiot JC, De Vilhena M, Schraub S, Svoboda V, et al. The EORTC randomized trial on three fractions per day and misonidazole (trial no. 22811) in advanced head and neck cancer: long-term results and side effects. Radiother Oncol. 1995;35(2):91–9.CrossRefPubMedGoogle Scholar
  191. 191.
    Lee DJ, Cosmatos D, Marcial VA, Fu KK, Rotman M, Cooper JS, et al. Results of an RTOG phase III trial (RTOG 85-27) comparing radiotherapy plus etanidazole with radiotherapy alone for locally advanced head and neck carcinomas. Int J Radiat Oncol Biol Phys. 1995;32(3):567–76.CrossRefPubMedGoogle Scholar
  192. 192.
    Eschwege F, Sancho-Garnier H, Chassagne D, Brisgand D, Guerra M, Malaise EP, et al. Results of a European randomized trial of Etanidazole combined with radiotherapy in head and neck carcinomas [see comments]. Int J Radiat Oncol Biol Phys. 1997;39(2):275–81.CrossRefPubMedGoogle Scholar
  193. 193.
    Zeman EM, Brown JM, Lemmon MJ, Hirst VK, Lee WW. SR 4233: a new bioreductive agent with high selective toxicity for hypoxic mammalian cells. Int J Radiat Oncol Biol Phys. 1986;12:1239–42.CrossRefPubMedGoogle Scholar
  194. 194.
    Dorie MJ, Brown JM. Modification of the antitumor activity of chemotherapeutic drugs by the hypoxic cytotoxic agent tirapazamine. Cancer Chemother Pharmacol. 1997;39(4):361–6.CrossRefPubMedGoogle Scholar
  195. 195.
    Beck R, Roper B, Carlsen JM, Huisman MC, Lebschi JA, Andratschke N, et al. Pretreatment 18F-FAZA PET predicts success of hypoxia-directed radiochemotherapy using tirapazamine. J Nucl Med. 2007;48(6):973–80.CrossRefPubMedGoogle Scholar
  196. 196.
    Rischin D, Peters L, Hicks R, Hughes P, Fisher R, Hart R, et al. Phase I trial of concurrent tirapazamine, cisplatin, and radiotherapy in patients with advanced head and neck cancer. J Clin Oncol: official journal of the American Society of Clinical Oncology. 2001;19(2):535–42.CrossRefGoogle Scholar
  197. 197.
    Rischin D, Peters L, Fisher R, Macann A, Denham J, Poulsen M, et al. Tirapazamine, Cisplatin, and Radiation versus Fluorouracil, Cisplatin, and Radiation in patients with locally advanced head and neck cancer: a randomized phase II trial of the Trans-Tasman Radiation Oncology Group (TROG 98.02). J Clin Oncol: official journal of the American Society of Clinical Oncology. 2005;23(1):79–87.CrossRefGoogle Scholar
  198. 198.
    Rischin D, Peters L, O'Sullivan B, Giralt J, Yuen K, Trotti A, et al. Phase III study of tirapazamine, cisplatin and radiation versus cisplatin and radiation for advanced squamous cell carcinoma of the head and neck. J Clin Oncol: official journal of the American Society of Clinical Oncology. 2008;26(May 20 suppl):abstr LBA6008.CrossRefGoogle Scholar
  199. 199.
    Peters LJ, O'Sullivan B, Giralt J, Fitzgerald TJ, Trotti A, Bernier J, et al. Critical impact of radiotherapy protocol compliance and quality in the treatment of advanced head and neck cancer: results from TROG 02.02. J Clin Oncol: official journal of the American Society of Clinical Oncology. 2010;28(18):2996–3001.CrossRefGoogle Scholar
  200. 200.
    Hicks KO, Pruijn FB, Secomb TW, Hay MP, Hsu R, Brown JM, et al. Use of three-dimensional tissue cultures to model extravascular transport and predict in vivo activity of hypoxia-targeted anticancer drugs. JNCI: Journal of the National Cancer Institute. 2006;98(16):1118–28.CrossRefPubMedGoogle Scholar
  201. 201.
    Li Q, Lin Q, Yun Z. Hypoxia-activated cytotoxicity of benznidazole against clonogenic tumor cells. Cancer Biol Ther. 2016;17(12):1266–73.CrossRefPubMedPubMedCentralGoogle Scholar
  202. 202.
    Sun JD, Liu Q, Ahluwalia D, Ferraro DJ, Wang Y, Jung D, et al. Comparison of hypoxia-activated prodrug evofosfamide (TH-302) and ifosfamide in preclinical non-small cell lung cancer models. Cancer Biol Ther. 2016;17(4):371–80.CrossRefPubMedPubMedCentralGoogle Scholar
  203. 203.
    Liu Y, Liu Y, Bu W, Xiao Q, Sun Y, Zhao K, et al. Radiation-/hypoxia-induced solid tumor metastasis and regrowth inhibited by hypoxia-specific upconversion nanoradiosensitizer. Biomaterials. 2015;49:1–8.CrossRefPubMedGoogle Scholar
  204. 204.
    Oku N, Matoba S, Yamazaki YM, Shimasaki R, Miyanaga S, Igarashi Y. Complete stereochemistry and preliminary structure–activity relationship of rakicidin A, a hypoxia-selective cytotoxin from micromonospora sp. J Nat Prod. 2014;77(11):2561–5.CrossRefPubMedGoogle Scholar
  205. 205.
    Jiang BH, Jiang G, Zheng JZ, Lu Z, Hunter T, Vogt PK. Phosphatidylinositol 3-kinase signaling controls levels of hypoxia-inducible factor 1. Cell Growth Differ: the molecular biology journal of the American Association for Cancer Research. 2001;12(7):363–9.Google Scholar
  206. 206.
    Hudson CC, Liu M, Chiang GG, Otterness DM, Loomis DC, Kaper F, et al. Regulation of hypoxia-inducible factor 1alpha expression and function by the mammalian target of rapamycin. Mol Cell Biol. 2002;22(20):7004–14.CrossRefPubMedPubMedCentralGoogle Scholar
  207. 207.
    Geiger JL, Bauman JE, Gibson MK, Gooding WE, Varadarajan P, Kotsakis A, et al. Phase II trial of everolimus in patients with previously treated recurrent or metastatic head and neck squamous cell carcinoma. Head Neck. 2016;38(12):1759–64.CrossRefPubMedPubMedCentralGoogle Scholar
  208. 208.
    Massarelli E, Lin H, Ginsberg LE, Tran HT, Lee JJ, Canales JR, et al. Phase II trial of everolimus and erlotinib in patients with platinum-resistant recurrent and/or metastatic head and neck squamous cell carcinoma. Ann Oncol. 2015;26(7):1476–80.CrossRefPubMedPubMedCentralGoogle Scholar
  209. 209.
    Soulières D, Faivre S, Mesía R, Remenár É, Li S-H, Karpenko A, et al. Buparlisib and paclitaxel in patients with platinum-pretreated recurrent or metastatic squamous cell carcinoma of the head and neck (BERIL-1): a randomised, double-blind, placebo-controlled phase 2 trial. Lancet Oncol. 2017;18(3):323–35.CrossRefPubMedGoogle Scholar
  210. 210.
    Lee NY, Le QT. New developments in radiation therapy for head and neck cancer: intensity-modulated radiation therapy and hypoxia targeting. Semin Oncol. 2008;35(3):236–50.CrossRefPubMedPubMedCentralGoogle Scholar
  211. 211.
    Hu Y, Liu J, Huang H. Recent agents targeting HIF-1alpha for cancer therapy. J Cell Biochem. 2012;114:498–509.Google Scholar
  212. 212.
    Lu H, Liang K, Lu Y, Fan Z. The anti-EGFR antibody cetuximab sensitizes human head and neck squamous cell carcinoma cells to radiation in part through inhibiting radiation-induced upregulation of HIF-1α. Cancer Lett. 2012;322(1):78–85.CrossRefPubMedPubMedCentralGoogle Scholar
  213. 213.
    Li X, Fan Z. The epidermal growth factor receptor antibody cetuximab induces autophagy in cancer cells by downregulating HIF-1alpha and Bcl-2 and activating the beclin 1/hVps34 complex. Cancer Res. 2010;70(14):5942–52.CrossRefPubMedPubMedCentralGoogle Scholar
  214. 214.
    Boeckx C, Baay M, Wouters A, Specenier P, Vermorken JB, Peeters M. Anti-epidermal growth factor receptor therapy in head and neck squamous cell carcinoma: focus on potential molecular mechanisms of drug resistance. Oncologist. 2013;18(7):850–64.CrossRefPubMedPubMedCentralGoogle Scholar
  215. 215.
    Boeckx C, Van den Bossche J, De Pauw I, Peeters M, Lardon F, Baay M, et al. The hypoxic tumor microenvironment and drug resistance against EGFR inhibitors: preclinical study in cetuximab-sensitive head and neck squamous cell carcinoma cell lines. BMC Res Notes. 2015;8(1):203.CrossRefPubMedPubMedCentralGoogle Scholar
  216. 216.
    Hsu HW, Wall NR, Hsueh CT, Kim S, Ferris RL, Chen CS, et al. Combination antiangiogenic therapy and radiation in head and neck cancers. Oral Oncol. 2014;50(1):19–26.CrossRefPubMedGoogle Scholar
  217. 217.
    Argiris A, Bauman JE, Ohr J, Gooding WE, Heron DE, Duvvuri U, et al. Phase II randomized trial of radiation therapy, cetuximab, and pemetrexed with or without bevacizumab in patients with locally advanced head and neck cancer. Ann Oncol. 2016;27(8):1594–600.CrossRefPubMedGoogle Scholar
  218. 218.
    Ahn PH, Machtay M, Anne PR, Cognetti D, Keane WM, Wuthrick E, et al. Phase I trial using induction cisplatin, docetaxel, 5-FU and erlotinib followed by cisplatin, bevacizumab and erlotinib with concurrent radiotherapy for advanced head and neck cancer. Am J Clin Oncol. 2016. [Epub ahead of print].Google Scholar
  219. 219.
    Fury MG, Xiao H, Sherman EJ, Baxi S, Smith-Marrone S, Schupak K, et al. Phase II trial of bevacizumab + cetuximab + cisplatin with concurrent intensity-modulated radiation therapy for patients with stage III/IVB head and neck squamous cell carcinoma. Head Neck. 2016;38(S1):E566–E70.CrossRefPubMedGoogle Scholar
  220. 220.
    Jeong W, Rapisarda A, Park SR, Kinders RJ, Chen A, Melillo G, et al. Pilot trial of EZN-2968, an antisense oligonucleotide inhibitor of hypoxia-inducible factor-1 alpha (HIF-1α), in patients with refractory solid tumors. Cancer Chemother Pharmacol. 2014;73(2):343–8.CrossRefPubMedGoogle Scholar
  221. 221.
    Giaccia A, Siim BG, Johnson RS. HIF-1 as a target for drug development. Nat Rev Drug Discov. 2003;2(10):803–11.CrossRefPubMedGoogle Scholar
  222. 222.
    Caponigro F, Di Gennaro E, Ionna F, Longo F, Aversa C, Pavone E, et al. Phase II clinical study of valproic acid plus cisplatin and cetuximab in recurrent and/or metastatic squamous cell carcinoma of Head and Neck-V-CHANCE trial. BMC Cancer. 2016;16(1):918.CrossRefPubMedPubMedCentralGoogle Scholar
  223. 223.
    Galloway TJ, Wirth LJ, Colevas AD, Gilbert J, Bauman JE, Saba NF, et al. A phase I study of CUDC-101, a multitarget inhibitor of HDACs, EGFR, and HER2, in combination with chemoradiation in patients with head and neck squamous cell carcinoma. Clin Cancer Res. 2015;21(7):1566–73.CrossRefPubMedGoogle Scholar
  224. 224.
    Welsh S, Williams R, Kirkpatrick L, Paine-Murrieta G, Powis G. Antitumor activity and pharmacodynamic properties of PX-478, an inhibitor of hypoxia-inducible factor-1alpha. Mol Cancer Ther. 2004;3(3):233–44.PubMedGoogle Scholar
  225. 225.
    Falchook GS, Wheler JJ, Naing A, Jackson EF, Janku F, Hong D, et al. Targeting hypoxia-inducible factor-1alpha (HIF-1alpha) in combination with antiangiogenic therapy: a phase I trial of bortezomib plus bevacizumab. Oncotarget. 2014;5(21):10280–92.CrossRefPubMedPubMedCentralGoogle Scholar
  226. 226.
    Hicks R, Rischin D, Fisher R, Binns D, Scott A, Peters L. Utility of FMISO PET in advanced head and neck cancer treated with chemoradiation incorporating a hypoxia-targeting chemotherapy agent. Eur J Nucl Med Mol Imaging. 2005;32(12):1384–91.CrossRefPubMedGoogle Scholar
  227. 227.
    Trinkaus ME, Hicks RJ, Young RJ, Peters LJ, Solomon B, Bressel M, et al. Correlation of p16 status, hypoxic imaging using [18F]-misonidazole positron emission tomography and outcome in patients with loco-regionally advanced head and neck cancer. J Med Imaging Radiat Oncol. 2014;58(1):89–97.CrossRefPubMedGoogle Scholar
  228. 228.
    Zschaeck S, Haase R, Abolmaali N, Perrin R, Stützer K, Appold S, et al. Spatial distribution of FMISO in head and neck squamous cell carcinomas during radio-chemotherapy and its correlation to pattern of failure. Acta Oncol. 2015;54(9):1355–63.CrossRefPubMedGoogle Scholar
  229. 229.
    Lassen P, Eriksen JG, Hamilton-Dutoit S, Tramm T, Alsner J, Overgaard J. HPV-associated p16-expression and response to hypoxic modification of radiotherapy in head and neck cancer. Radiother Oncol. 2010;94(1):30–5.CrossRefPubMedGoogle Scholar
  230. 230.
    Lassen P, Eriksen JG, Krogdahl A, Therkildsen MH, Ulhoi BP, Overgaard M, et al. The influence of HPV-associated p16-expression on accelerated fractionated radiotherapy in head and neck cancer: evaluation of the randomised DAHANCA 6&7 trial. Radiother Oncol. 2011;100(1):49–55.CrossRefPubMedPubMedCentralGoogle Scholar
  231. 231.
    Kong CS, Narasimhan B, Cao H, Kwok S, Erickson JP, Koong A, et al. The relationship between human papillomavirus status and other molecular prognostic markers in head and neck squamous cell carcinomas. Int J Radiat Oncol Biol Phys. 2009;74(2):553–61.CrossRefPubMedPubMedCentralGoogle Scholar
  232. 232.
    Fakhry C, Westra WH, Li S, Cmelak A, Ridge JA, Pinto H, et al. Improved survival of patients with human papillomavirus-positive head and neck squamous cell carcinoma in a prospective clinical trial. J Natl Cancer Inst. 2008;100(4):261–9.CrossRefPubMedPubMedCentralGoogle Scholar
  233. 233.
    Weinberger PM, Yu Z, Haffty BG, Kowalski D, Harigopal M, Brandsma J, et al. Molecular classification identifies a subset of human papillomavirus--associated oropharyngeal cancers with favorable prognosis. J Clin Oncol: official journal of the American Society of Clinical Oncology. 2006;24(5):736–47.CrossRefGoogle Scholar
  234. 234.
    Jemal A, Simard EP, Dorell C, Noone A-M, Markowitz LE, Kohler B, et al. Annual report to the nation on the status of cancer, 1975–2009, featuring the burden and trends in human papillomavirus (HPV)–Associated cancers and HPV vaccination coverage levels. J Natl Cancer Inst. 2013;105(3):175–201.CrossRefPubMedPubMedCentralGoogle Scholar
  235. 235.
    Snow AN, Laudadio J. Human papillomavirus detection in head and neck squamous cell carcinomas. Adv Anat Pathol. 2010;17(6):394–403.CrossRefPubMedPubMedCentralGoogle Scholar
  236. 236.
    Fakhry C, Gillison ML. Clinical implications of human papillomavirus in head and neck cancers. J Clin Oncol: official journal of the American Society of Clinical Oncology. 2006;24(17):2606–11.CrossRefGoogle Scholar
  237. 237.
    Chakravarthy A, Henderson S, Thirdborough SM, Ottensmeier CH, Su X, Lechner M, et al. Human papillomavirus drives tumor development throughout the head and neck: improved prognosis is associated with an immune response largely restricted to the oropharynx. J Clin Oncol. 2016;34(34):4132–41.CrossRefPubMedPubMedCentralGoogle Scholar
  238. 238.
    Mandal R, Şenbabaoğlu Y, Desrichard A, Havel JJ, Dalin MG, Riaz N, et al. The head and neck cancer immune landscape and its immunotherapeutic implications. JCI Insight. 2016;1(17):e89829.CrossRefPubMedPubMedCentralGoogle Scholar
  239. 239.
    Keck MK, Zuo Z, Khattri A, Stricker TP, Brown CD, Imanguli M, et al. Integrative analysis of head and neck cancer identifies two biologically distinct HPV and three non-HPV subtypes. Clin Cancer Res. 2015;21(4):870–81.CrossRefPubMedPubMedCentralGoogle Scholar
  240. 240.
    Cancer Genome Atlas Network. Comprehensive genomic characterization of head and neck squamous cell carcinomas. Nature. 2015;517(7536):576–82.CrossRefGoogle Scholar
  241. 241.
    Hong A, Zhang M, Veillard AS, Jahanbani J, Lee CS, Jones D, et al. The prognostic significance of hypoxia inducing factor 1-alpha in oropharyngeal cancer in relation to human papillomavirus status. Oral Oncol. 2013;49(4):354–9.CrossRefPubMedGoogle Scholar
  242. 242.
    Lee N, Schoder H, Beattie B, Lanning R, Riaz N, McBride S, et al. Strategy of using intratreatment hypoxia imaging to selectively and safely guide radiation dose de-escalation concurrent with chemotherapy for locoregionally advanced human papillomavirus-related oropharyngeal carcinoma. Int J Radiat Oncol Biol Phys. 2016;96(1):9–17.CrossRefPubMedPubMedCentralGoogle Scholar
  243. 243.
    Hodi FS, Chesney J, Pavlick AC, Robert C, Grossmann KF, McDermott DF, et al. Combined nivolumab and ipilimumab versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled, phase 2 trial. Lancet Oncol. 17(11):1558–68.Google Scholar
  244. 244.
    Topalian SL, Hodi FS, Brahmer JR. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366:2443–54Google Scholar
  245. 245.
    Hamid O, Sosman JA, Lawrence DP, Sullivan RJ, Ibrahim N, Kluger HM, et al. Clinical activity, safety, and biomarkers of MPDL3280A, an engineered PD-L1 antibody in patients with locally advanced or metastatic melanoma (mM). ASCO Meeting Abstracts. 2013;31(15_suppl):9010.Google Scholar
  246. 246.
    Seiwart T, Burtness B, Weiss J, Gluck I, Eder J, Pai S, et al. A phase Ib study of MK-3475 in patients with human papillomavirus (HPV)-associated and non-HPV–associated head and neck (H/N) cancer. J Clin Oncol. 2014;32(suppl; abstr 6011):5s.Google Scholar
  247. 247.
    Labiano S, Palazon A, Melero I. Immune response regulation in the tumor microenvironment by hypoxia. Semin Oncol. 2015;42(3):378–86.CrossRefPubMedGoogle Scholar
  248. 248.
    Huber V, Camisaschi C, Berzi A, Ferro S, Lugini L, Triulzi T, et al. Cancer acidity: an ultimate frontier of tumor immune escape and a novel target of immunomodulation. Semin Cancer Biol. 2017;43:74–89.CrossRefPubMedGoogle Scholar
  249. 249.
    Kareva I, Hahnfeldt P. The emerging “hallmarks” of metabolic reprogramming and immune evasion: distinct or linked? Cancer Res. 2013;73(9):2737–42.CrossRefPubMedGoogle Scholar
  250. 250.
    Chouaib S, Noman MZ, Kosmatopoulos K, Curran MA. Hypoxic stress: obstacles and opportunities for innovative immunotherapy of cancer. Oncogene. 2017;36(4):439–45.CrossRefPubMedGoogle Scholar
  251. 251.
    Caldwell CC, Kojima H, Lukashev D, Armstrong J, Farber M, Apasov SG, et al. Differential effects of physiologically relevant hypoxic conditions on T lymphocyte development and effector functions. J Immunol. 2001;167(11):6140–9.CrossRefPubMedGoogle Scholar
  252. 252.
    Nakagawa Y, Negishi Y, Shimizu M, Takahashi M, Ichikawa M, Takahashi H. Effects of extracellular pH and hypoxia on the function and development of antigen-specific cytotoxic T lymphocytes. Immunol Lett. 2015;167(2):72–86.CrossRefPubMedPubMedCentralGoogle Scholar
  253. 253.
    Lugini L, Matarrese P, Tinari A, Lozupone F, Federici C, Iessi E, et al. Cannibalism of live lymphocytes by human metastatic but not primary melanoma cells. Cancer Res. 2006;66(7):3629–38.CrossRefPubMedPubMedCentralGoogle Scholar
  254. 254.
    Tittarelli A, Janji B, Van Moer K, Noman MZ, Chouaib S. The selective degradation of synaptic connexin 43 ;protein by hypoxia-induced autophagy impairs natural killer cell-mediated tumor cell killing. J Biol Chem. 2015;290(39):23670–9.CrossRefPubMedPubMedCentralGoogle Scholar
  255. 255.
    Mancino A, Schioppa T, Larghi P, Pasqualini F, Nebuloni M, Chen IH, et al. Divergent effects of hypoxia on dendritic cell functions. Blood. 2008;112(9):3723–34.CrossRefPubMedPubMedCentralGoogle Scholar
  256. 256.
    Ward RC, Kaufman HL. Targeting costimulatory pathways for tumor immunotherapy. Int Rev Immunol. 2007;26(3–4):161–96.CrossRefPubMedPubMedCentralGoogle Scholar
  257. 257.
    Yang M, Ma C, Liu S, Sun J, Shao Q, Gao W, et al. Hypoxia skews dendritic cells to a T helper type 2-stimulating phenotype and promotes tumour cell migration by dendritic cell-derived osteopontin. Immunology. 2009;128(1pt2):e237–e49.CrossRefPubMedPubMedCentralGoogle Scholar
  258. 258.
    Noy R, Pollard Jeffrey W. Tumor-associated macrophages: from mechanisms to therapy. Immunity. 2014;41(1):49–61.CrossRefPubMedPubMedCentralGoogle Scholar
  259. 259.
    Doedens AL, Stockmann C, Rubinstein MP, Liao D, Zhang N, DeNardo DG, et al. Macrophage expression of hypoxia-inducible factor-1 alpha suppresses T-cell function and promotes tumor progression. Cancer Res. 2010;70(19):7465–75.CrossRefPubMedPubMedCentralGoogle Scholar
  260. 260.
    Corzo CA, Condamine T, Lu L, Cotter MJ, Youn JI, Cheng P, et al. HIF-1alpha regulates function and differentiation of myeloid-derived suppressor cells in the tumor microenvironment. J Exp Med. 2010;207(11):2439–53.CrossRefPubMedPubMedCentralGoogle Scholar
  261. 261.
    Noman MZ, Desantis G, Janji B, Hasmim M, Karray S, Dessen P, et al. PD-L1 is a novel direct target of HIF-1alpha, and its blockade under hypoxia enhanced MDSC-mediated T cell activation. J Exp Med. 2014;211(5):781–90.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Sir Charles Gairdner Hospital and University of Western AustraliaPerthAustralia
  2. 2.Stanford University Medical CenterStanfordUSA
  3. 3.Peter MacCallum Cancer CentreMelbourneAustralia

Personalised recommendations