Historical Context
With the understanding that oxygen was related to the amount of cell killing, Thomlinson and Gray performed histological evaluation of squamous cell carcinoma of the lung [1]. They found that necrosis in these tumours was related to the size of the tumour relative to its blood supply. Tumours over 200 μm always contained areas of necrosis. This suggested that viable cells adjacent to the necrosis were likely chronically hypoxic. Acute hypoxia, where there is fluctuating levels of oxygenation within tumour, was first described by Chaplin et al [2]
Hypoxia in Tumours
Hypoxia in tumours occurs through two mechanisms.
Chronic Hypoxia
Cells located distant from nutrient vessels have reduced access to oxygen and other nutrients. First hypothesised in 1955 when the central cores of bronchial tumours were noted to be necrotic, tumour hypoxia is now known to be a more dynamic process with hypoxia cells dying as new cells push them further away from nutrient vessels.
Acute Hypoxia
Transient blood flow through tumour vasculature also leads to dynamic changes in oxic status (acute hypoxia)
Significance of Hypoxia
Hypoxic tumour cells are resistant to radiation damage, and may be responsible for failure of tumour control after radiotherapy.
Evidence for Tumour Hypoxia
Experimental evidence for hypoxia exists in animal models, laboratory studies and in human tumours.
Experimental data
The presence of hypoxic cells has been shown to alter cell survival curves in sarcoma models. Mouse studies also suggested that haemoglobin concentration (and oxygen carrying capacity) was related to cell survival.
Human data
Due to ethical considerations other methods are used to measure human tumour hypoxia. Indirect methods are typically used, such as measuring tumour vascularisation, haemoglobin oxygen saturation, tumour metabolic activity, hypoxia markers or measurements of tumour oxygen partial pressure. Results from radiotherapy are better in tumours which had a high oxygen partial pressure prior to treatment commencing.
Studies in humans treated with hypoxia modification also suggests that reversing hypoxia is beneficial in tumour control. The most common method of achieving this was with hyperbaric oxygen, where increased rates of control with SCC of the head and neck were seen.
