Defining normoxia, physoxia and hypoxia in tumours—implications for treatment response

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.

Efficacy and safety of the hypoxia-activated prodrug TH-302 in combination with gemcitabine and nab-paclitaxel in human tumor xenograft models of pancreatic cancer

“…Numerous studies have demonstrated an association between the magnitude of intratumoral hypoxia and the outcome of cancer treatment. [3][4][5][6][7][8] This association has also been shown for PDAC, where a more hypoxic phenotype is associated with a worse prognosis. 38,39 We hypothesize that the clinical outcome for patients treated with the triplet treatment may be more favorable than doublet nab-paclitaxel and gemcitabine, given the multiple therapeutic modalities employed including hypoxia-selective targeting.…”

“…[1][2][3][4] Published studies show that the magnitude and extent of tumor hypoxia correlate directly with poor clinical prognosis. 5 The basis for the correlation between tumor hypoxia and prognosis has been ascribed to both therapeutic treatment failure and hypoxia-induced pro-metastatic potential.…”

The cellular stress proteins CHCHD10 and MNRR1 (CHCHD2): Partners in mitochondrial and nuclear function and dysfunction

“…Thus, the relative effect of each on transcription of ORE-containing genes may change continuously as oxygen levels decline. Experimental oxygen tension is 20% although this is high compared to physiological levels in vivo, which range from ~3% to 8% in most tissues and ~13% in lung (19,34). One of the most critical periods of oxygen sensing is during placental development where oxygen levels switch from 2-3% prior to 12 weeks of gestation to 8% afterwards (35).…”

Influence of oxygen concentration on T cell proliferation and susceptibility to apoptosis in healthy men and women

“…Other parameters important for maintaining the culture usually are 100% humidity and temperature of 37°C. Even though it is now commonly known that this oxygen concentration is similar to the atmospheric one and therefore is almost two to ten-fold higher than maintained in the blood [16], various authors still consider 21% of oxygen in culture gas mixture as a normal condition and regard all lowered oxygen contents as hypoxic ones [17]. We fully support the view of Atkuri et al [18] that only conditions of in vitro experiments closely mimicking the physiological ones, also with respect to the oxygen concentration, would allow to explore the actual in vivo processes and that such conditions should be used wherever possible.…”