Enhanced perfusion following exposure to radiotherapy: a theoretical investigation

Abstract

Tumour angiogenesis leads to the formation of blood vessels that are structurally and spatially heterogeneous. Poor blood perfusion, in conjunction with increased hypoxia and oxygen heterogeneity, impairs a tumours response to radiotherapy. The optimal strategy for enhancing tumour perfusion remains unclear, preventing its regular deployment in combination therapies. In this work, we first identify vascular architectural features that correlate with enhanced perfusion following radiotherapy, using in vivo imaging data from vascular tumours. Then, we present a novel computational model to determine the relationship between these architectural features, blood perfusion, and tumour response to radiotherapy in silico. If perfusion is defined to be the proportion of vessels that support blood flow, we find that vascular networks with small mean diameters and large numbers of angiogenic sprouts show the largest increases in perfusion post-irradiation for both biological and synthetic tumours. We also identify cases where perfusion increases due to the pruning of hypoperfused vessels, rather than blood being rerouted. These results indicate the importance of considering network composition when determining the optimal irradiation strategy. In the future, we aim to use our findings to identify tumours that are good candidates for perfusion enhancement and to improve the efficacy of combination therapies. Author summaryDysregulated tumour vasculature often contains hypoperfused blood vessels which inhibit the delivery of blood-borne anticancer therapies. Radiotherapy, used to treat more than half of all cancer patients, causes DNA damage to vascular endothelial cells, preferentially impacting smaller vessels, leading to their death and vessel pruning. At the same time, experiments measuring changes in tumour perfusion post-irradiation produce varying outcomes and, therefore, the impact of irradiation-induced vessel pruning on network-scale perfusion remains unclear. In this study, we use recent (in vivo) imaging data to identify features of tumour vascular architectures that impact perfusion change post-irradiation. We then use a newly-developed computational framework, directly informed by the experimental observations, to elucidate the relationship between the vascular geometry and topology prior to radiotherapy and the irradiation-induced changes to network perfusion. We find that perfusion increases most significantly for networks of blood vessels with small mean diameters and large numbers of angiogenic sprouts. Our results also distinguish different mechanisms of perfusion increase and we identify cases where rerouting of blood flow causes previously hypoperfused vessels to become perfused. Our study sheds more light on the impact of radiotherapy on tumour blood flow; these insights could be useful for improving anti-cancer treatments.