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McKeown 2014 Br J Radiol

From Bioblast
Publications in the MiPMap
McKeown SR (2014) Defining normoxia, physoxia and hypoxia in tumours-implications for treatment response. https://doi.org/10.1259/bjr.20130676

» Br J Radiol 87:20130676. PMID:24588669 Open Access

McKeown SR (2014) Br J Radiol

Abstract: Tumour hypoxia is increasingly recognized as a major deleterious factor in cancer therapies, as it compromises treatment and drives malignant progression. This review seeks to clarify the oxygen levels that are pertinent to this issue. It is argued that normoxia (20% oxygen) is an extremely poor comparator for "physoxia", i.e. the much lower levels of oxygen universally found in normal tissues, which averages about 5% oxygen, and ranges from about 3% to 7.4%. Importantly, it should be recognized that the median oxygenation in untreated tumours is significantly much lower, falling between approximately 0.3% and 4.2% oxygen, with most tumours exhibiting median oxygen levels <2%. This is partially dependent on the tissue of origin, and it is notable that many prostate and pancreatic tumours are profoundly hypoxic. In addition, therapy can induce even further, often unrecognized, changes in tumour oxygenation that may vary longitudinally, increasing or decreasing during treatment in ways that are not always predictable. Studies that fail to take cognizance of the actual physiological levels of oxygen in tissues (approximately 5%) and tumours (approximately 1%) may fail to identify the real circumstances driving tumour response to treatment and/or malignant progression. This can be of particular importance in genetic studies in vitro when comparison to human tumours is required.

Selected quotes

  • Despite the many studies on tumour hypoxia, there is considerable confusion in the use of the terms “normoxia” and “hypoxia”. Oxygenation measurements in normal tissues show that they exhibit distinct normal ranges, which vary between tissues (Table 1). However, “normoxia” is almost universally used to describe the “normal” oxygen levels in tissue culture flasks, i.e. about 20–21 % oxygen (160 mmHg). Although this is not exact, as it is dependent on altitude and added CO2, for most situations, 20 % is a good approximation. Despite the widespread usage of “normoxia”, this is far from an accurate comparator for peripheral tissue oxygenation. Even in lung alveoli, the oxygen level is reduced to about 14.5 % oxygen (110 mmHg) by the presence of water vapour and expired CO2.13 It drops further in arterial blood and, by the time it reaches peripheral tissues, the median oxygen levels range from 3.4 % to 6.8 % with an average of about 6.1 % (Table 2).13
  • “Physiological hypoxia” can then be defined as the oxygen level at which tissues respond to maintain their preferred oxygen level. This can be by physiological means, e.g. vasodilation, increasing blood flow, and/or upregulation of hypoxia response genes.12 Since physoxia varies for individual tissues, they are likely to have different hypoxic trigger points below which this occurs. In normal tissues, this will presumably be transitory but sufficient to return the tissue to its preferred oxygen level. However, since normal tissues are ordinarily maintained at 3–7 % oxygen, physiological hypoxia is likely to be in the range 2–6 % oxygen. This suggests that hypoxia response elements may well upregulate at different oxygen levels in different tissues. Currently, it is difficult to envisage how “physiological hypoxia” can be measured since homeostasis should work to reverse it almost immediately, so any manifestation would be transitory.
  • Having identified the approximate range of “physiological hypoxia”, this helps to delineate the oxygen levels which are found in pathology. Indeed it begs the question, why in pathological tissues do the homeostatic mechanisms not respond effectively to reverse the falling oxygen levels? In ischaemic disease, which can be either chronic (e.g. in diabetes, reduced lung function etc.) or acute (e.g. stroke, coronary artery occlusion etc.), re-establishment of homeostasis may not be possible owing to the loss/occlusion/reduced flow of vessels feeding the tissue in question.
  • In experimental studies, it is crucial that investigators control for oxygenation to mimic, as far as is possible, the significant low oxygen levels found in most human tumour cells; that is at or <1 %, and often <0.1 % oxygen (7.5 to <0.75 mmHg).


Cited by

  • Komlódi T, Schmitt S, Zdrazilova L, Donnelly C, Zischka H, Gnaiger E. Oxygen dependence of hydrogen peroxide production in isolated mitochondria and permeabilized cells. MitoFit Preprints (in prep).
  • Komlódi T, Gnaiger E (2022) Discrepancy on oxygen dependence of mitochondrial ROS production - review. MitoFit Preprints 2022 (in prep).


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