Transient hypoxia

Hypoxia (low tissue oxygenation) is a common characteristic of tumours, and it is becoming increasingly evident that hypoxia in tumours is inherently dynamic and can fluctuate over a range of time scales. Several studies have described the use of both blood oxygen level dependent (BOLD) MRI and electron paramagnetic resonance (EPR) in mouse tumour xenograft models, and report cyclic fluctuations with frequencies of minutes to hours, or even days. There is evidence that the basis of such fluctuations is due to poor blood vessel structuring in tumours or the presence of high fluid pressure.

Blood oxygen level dependent (BOLD) MRI can be used to measure fluctuations in blood oxygenation in the brain following a particular task, allowing the region of the brain associated with the task to be identified. Miguel Gonçalves has been using BOLD MRI to investigate fluctuations in oxygenation and comparing these with responses to inhaled gases (such as oxygen and carbon dioxide). He is also evaluating techniques for identifying regions of the tumour that are functionally connected, using techniques such as independent component analysis (ICA). This will enable theoretical models of tumour blood vessel architecture to be evaluated and developed, and remodelling associated with successful blood vessel-targeting therapies to be monitored. Such models are likely to provide novel insights into drug delivery in tumours and resistance to interventions such as radiotherapy, the efficacy of which fundamentally relies on adequate tissue oxygenation.

BOLD MRI imaging of transient hypoxia in a tumour xenograft model.

Figure 1: (a) Map of a tumour cross-section showing transient changes in blood oxygen level dependent (BOLD) MRI signal during an hour-long ‘resting state’ scan. Observed fluctuations are interpreted to be due to oscillations in red blood cell flux inducing regional, transient hypoxia (28). (b) Changes in BOLD signal in the same tumour during three gas challenges: 1) air to carbogen (95% O2, 5% CO2); 2) air to 100% O2; 3) air to air+5% CO2. These gas challenges provide information about regional blood vessel functionality (hyperoxia response) and maturity (hypercapnia response). (c) A map showing the magnitude of variations in BOLD signal during resting state measurements shown in (a), which shows a strong correspondence with the change in BOLD signal following oxygen administration (hyperoxia) in (d), but not with changes following the air+CO2 challenge (hypercapnia) in (e). This suggests that the fluctuations are caused by functionally perfused vessels, but are independent of their maturity in this tumour type.

Associated publications:

Burrell JS, Walker-Samuel S, Baker LC, Boult JK, Ryan AJ, Waterton JC, Halliday J, Robinson SP. Investigating temporal fluctuations in tumor vasculature with combined carbogen and ultrasmall superparamagnetic iron oxide particle (CUSPIO) imaging. Magn Reson Med 2011;66(1):227-234. [link]

Goncalves MR, Johnson SP, Pedley RB, Lythgoe MF, Walker-Samuel S, Investigating patterns of cyclic hypoxia in pre-clinical models of colorectal cancer, Proceedings of the British Chapter of the International Society for Magnetic Resonance in Medicine, 2011 (Manchester).

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