Role of oxygen in cancer: looking beyond hypoxia

Although cancer is considered to be a disease caused by DNA alterations, the high genetic variability of tumor cells makes it difficult to exploit these alterations for the treatment of cancer. The influence of non-genetic factors on cancer is increasingly being acknowledged and a growing line of research suggests that hypoxia (a decrease in normal oxygen levels) may play a fundamental role in the development of this disease. This line of research is supported by the fact that tumors often have hypoxic areas, that hypoxia activates the hypoxia-inducible factor 1 (HIF-1) and that HIF-1 activation plays a key role in cancer development. Evidence suggests, however, that the idea of hypoxia playing a central role in cancer development has some drawbacks. For instance, hypoxia has not been found in many tumors, HIF-1 activation has been observed in non-hypoxic tumor areas, and hypoxic tumor cells commonly have a reduced nutrient supply that restricts cell proliferation and tumor growth. This article reviews the literature that does not support the idea of hypoxia playing a central role in cancer development and discusses a broader view in which the role of oxygen in cancer is not limited to a reduction in its normal levels. According to this novel view, a deviation of the oxygen metabolism from the pathway that generates energy to the pathway that produces reactive oxygen species is crucial for cancer development. Interestingly, this switch in oxygen metabolism occurs under both hypoxic and normoxic conditions and may be exploited therapeutically.