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Oxygenation and radiosensitization consequences of solid tumour perfusion

University of British Columbia

Solid tumours often develop regions that are poorly oxygenated (hypoxic). Hypoxic tumour cells are resistant to radiation and are associated with poor patient outcome. “Chronic hypoxia” develops where vascular density is insufficient, causing tumour cells beyond ~70-100 μm from blood vessels to receive little oxygen. “Transient hypoxia” occurs in solid tumours where fluctuating microregional perfusion exposes tumour cells to cycles of hypoxia and reoxygenation. The fundamental understanding of transient hypoxia in vivo is lacking, and there are no available strategies to eliminate transient hypoxia. This thesis hypothesizes that transiently hypoxic tumour cells are long-lived radiation resistant cells and that eliminating the development of transient hypoxia will improve tumour radiation response. This thesis first investigated the rate of hypoxic cell turnover in vivo. Exogenous hypoxia reporters were used to label hypoxic tumour cells, while loss of labelled cells over time indicated loss of hypoxic cells. The perfusion-modifying drug pentoxifylline was used to control which hypoxic populations were labelled and therefore which populations were lost over time. We find that transiently hypoxic tumour cells survive longer than neighbouring chronically hypoxic cells, further justifying transient hypoxia as an important therapeutic target. To better study tumour perfusion-modifying interventions, this thesis next validated 2-18F-fluoroethanol as a novel reporter of solid tumour perfusion compatible with positron emission tomography. We found 2-18F-fluoroethanol to effectively respond to established tumour perfusion-modifying interventions and applied 2-18F-fluoroethanol to characterize novel interventions aiming to modify tumour perfusion and transient hypoxia. This thesis then focused on the angiotensin II type 1 receptor blocker telmisartan. Telmisartan treatment reduced tumour collagen 1 content, increased and stabilized tumour perfusion, reduced the development of transient hypoxia, and improved tumour radiation response. This presents the target of telmisartan, cancer associated fibroblast activity and tumour collagen 1 content, as a potential microenvironmental cause of transient hypoxia. Overall, this thesis provides insight into the basic biology of transient hypoxia in vivo, validates a novel non-invasive reporter of solid tumour perfusion, and identifies telmisartan as a clinically relevant treatment to stably reduce the development of transient hypoxia in solid tumours and improve radiation response.

Text

2020-08-05

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/75372

Pathology and Laboratory Medicine

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/