Tumor Oxygenation Status: Facts and Fallacies

  • Peter VaupelEmail author
  • Arnulf Mayer
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 977)


In this chapter we allude to a series of facts and fallacies often encountered in the description of tumor hypoxia, a relevant trait of the tumor microenvironment and a paramount driver of tumor aggressiveness and treatment resistance. The critical role of diffusion distances, terminological inconsistencies considering O2 partial pressures vs. O2 concentrations and with it the use of inept units, the impact of O2 depletion on proliferation and cell viability, the switch in the Warburg dogma, the distribution of hypoxic subvolumes within a tumor, the involvement of O2 diffusion shunts in the development of chronic hypoxia, and the role of endogenous biomarkers as surrogates for the assessment of hypoxia are discussed in more detail. Special emphasis is put on the clinical relevance of these misconceptions and misinterpretations and their impact on the assessment of hypoxia as well as hypoxia-targeted treatment planning.


Tumor hypoxia Oxygen diffusion distances Hypoxia- inducible factor (HIF) Hypoxia- inducible biomarkers Warburg dogma 



The authors would like to thank Professor Gabriele Multhoff, Dept. Radiooncology and Radiotherapy, Klinikum rechts der Isar, Technical University Munich, for providing FaDu tumors for hypoxia distance metrics.


  1. 1.
    Vaupel P, Mayer A, Höckel M (2004) Tumor hypoxia and malignant progression. Methods Enzymol 381:335–354CrossRefPubMedGoogle Scholar
  2. 2.
    Vaupel P, Mayer A (2007) Hypoxia in cancer: significance and impact on clinical outcome. Cancer Metastasis Rev 26(2):225–239CrossRefPubMedGoogle Scholar
  3. 3.
    Ruan K, Song G, Ouyang G (2009) Role of hypoxia in the hallmarks of human cancer. J Cell Biochem 107(6):1053–1062CrossRefPubMedGoogle Scholar
  4. 4.
    Mayer A, Vaupel P (2013) Hypoxia, lactate accumulation, and acidosis: siblings or accomplices driving tumor progression and resistance to therapy? Adv Exp Med Biol 789:203–209CrossRefPubMedGoogle Scholar
  5. 5.
    Vaupel P, Mayer A (2016) Hypoxia-driven adenosine accumulation: a crucial microenvironmental factor promoting tumor progression. Adv Exp Med Biol 876:177–183CrossRefPubMedGoogle Scholar
  6. 6.
    Thomlinson RH, Gray LH (1955) The histological structure of some human lung cancers and the possible implications for radiotherapy. Br J Cancer 9(4):539–549CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Koh WJ, Rasey JS, Evans ML et al (1992) Imaging of hypoxia in human tumors with [F-18]fluoromisonidazole. Int J Radiat Oncol Biol Phys 22(1):199–212CrossRefPubMedGoogle Scholar
  8. 8.
    Vaupel P, Schlenger K, Knoop C et al (1991) Oxygenation of human tumors: evaluation of tissue oxygen distribution in breast cancers by computerized O2 tension measurements. Cancer Res 51(12):3316–3322PubMedGoogle Scholar
  9. 9.
    Wang GL, Semenza GL (1993) Characterization of hypoxia-inducible factor 1 and regulation of DNA binding activity by hypoxia. J Biol Chem 268(29):21513–21518PubMedGoogle Scholar
  10. 10.
    Carreau A, El Hafny-Rahbi B, Matejuk A et al (2011) Why is the partial oxygen pressure of human tissues a crucial parameter? Small molecules and hypoxia. J Cell Mol Med 15(6):1239–1253CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Muz B, de la Puente P, Azab F et al (2015) The role of hypoxia in cancer progression, angiogenesis, metastasis, and resistance to therapy. Hypoxia (Auckl) 3:83–92CrossRefGoogle Scholar
  12. 12.
    Brahimi-Horn MC, Laferrière J, Mazure N et al (2008) Hypoxia and tumour angiogenesis. In: Marmé D, Fusenig N (eds) Tumor angiogenesis: basic mechanisms and cancer therapy. Springer, Berlin\Heidelberg, pp 171–194. doi: 10.1007/978-3-540-33177-3_10 CrossRefGoogle Scholar
  13. 13.
    Spencer JA, Ferraro F, Roussakis E et al (2014) Direct measurement of local oxygen concentration in the bone marrow of live animals. Nature 508(7495):269–273CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Vaupel P (1976) Effect of percentual water content in tissues and liquids on the diffusion coefficients of O2, CO2, N2, and H2. Pflügers Arch 361(2):201–204CrossRefPubMedGoogle Scholar
  15. 15.
    Vaupel P (2004) Tumor microenvironmental physiology and its implications for radiation oncology. Semin Radiat Oncol 14(3):198–206CrossRefPubMedGoogle Scholar
  16. 16.
    Vaupel P (1990) Oxygenation of human tumors. Strahlenther Onkol 166(6):377–386PubMedGoogle Scholar
  17. 17.
    Tannock IF (1968) The relation between cell proliferation and the vascular system in a transplanted mouse mammary tumour. Br J Cancer 22(2):258–273CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Warburg O (1956) On respiratory impairment in cancer cells. Science 124(3215):269–270PubMedGoogle Scholar
  19. 19.
    Vaupel P, Mayer A (2012) Availability, not respiratory capacity governs oxygen consumption of solid tumors. Int J Biochem Cell Biol 44(9):1477–1481CrossRefPubMedGoogle Scholar
  20. 20.
    Gentric G, Mieulet V, Mechta-Grigoriou F (2016) Heterogeneity in cancer metabolism: new concepts in an old field. Antioxid Redox Signal. doi: 10.1089/ars.2016.6750 PubMedGoogle Scholar
  21. 21.
    Semenza GL (2010) HIF-1: upstream and downstream of cancer metabolism. Curr Opin Genet Dev 20(1):51–56CrossRefPubMedGoogle Scholar
  22. 22.
    Warburg OH (1962) New methods of cell physiology. Applied to cancer, photosynthesis, and mechanism of X-ray action. Interscience, New YorkGoogle Scholar
  23. 23.
    Grosu AL, Souvatzoglou M, Röper B et al (2007) Hypoxia imaging with FAZA-PET and theoretical considerations with regard to dose painting for individualization of radiotherapy in patients with head and neck cancer. Int J Radiat Oncol Biol Phys 69(2):541–551CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.Department of Radiation Oncology and Radiotherapy, Tumor Pathophysiology DivisionUniversity Medical CenterMainzGermany

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