Spatial metrics of tumour vascular organisation predict radiation efficacy in a computational model

Intratumoural heterogeneity is known to contribute to poor therapeutic response. Variations in oxygen tension in particular have been correlated with changes in radiation response in vitro and at the clinical scale with overall survival. Heterogeneity at the microscopic scale in tumour blood vessel architecture has been described, and is one source of the underlying variations in oxygen tension. We endeavour to determine whether histologic scale measures of the erratic distribution of blood vessels within a tumour can be used to predict differing radiation response. Using a two-dimensional hybrid cellular automaton model of tumour growth, we evaluate the effect of vessel distribution on cell survival outcomes of simulated radiation therapy. Using the standard equations for the oxygen enhancement ratio for cell survival probability under differing oxygen tensions, we calculate average radiation effect over a range of different vessel densities and organisations. We go on to quantify the vessel distribution heterogeneity and measure spatial organization using Ripleys L function, a measure designed to detect deviations from spatial homogeneity. We find that under differing regimes of vessel density the correlation coefficient between the measure of spatial organization and radiation effect changes sign. This provides not only a useful way to understand the differences seen in radiation effect for tissues based on vessel architecture, but also an alternate explanation for the vessel normalization hypothesis.\n\nAuthor SummaryIn this paper we use a mathematical model, called a hybrid cellular automaton, to study the effect of different vessel distributions on radiation therapy outcomes at the cellular level. We show that the correlation between radiation outcome and spatial organization of vessels changes signs between relatively low and high vessel density. Specifically, that for relatively low vessel density, radiation efficacy is decreased when vessels are more homogeneously distributed, and the opposite is true, that radiation efficacy is improved, when vessel organisation is normalised in high densities. This result suggests an alteration to the vessel normalization hypothesis which states that normalisation of vascular beds should improve radio- and chemo-therapeutic response, but has failed to be validated in clinical studies. In this alteration, we provide a metric that differentiates between vascular architectures in different density regimes in which the hypothesis holds and does not and that could be used for quantitative histologic analysis of tumours, and for radiation dose personalisation.\n\nAuthor ContributionsConceived and designed the experiments: JGS, AGF, ARAA, PKM\n\nPerformed the experiments: JGS\n\nAnalyzed the data: JGS, AGF, ARAA, PKM\n\nWrote the paper: JGS, AGF, ARAA, PKM