Abstract
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 seek 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 Ripley’s L function, a measure designed to detect deviations from complete spatial randomness. 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.
Highlights
It is increasingly recognised that an important aspect of cancers is their heterogeneity [1]
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
We show that the correlation between radiation outcome and spatial organization of vessels changes signs between relatively low and high vessel density
Summary
It is increasingly recognised that an important aspect of cancers is their heterogeneity [1]. Microenvironmental heterogeneity is becoming widely accepted as a key factor in tumour progression and response to therapy [1]. Growth factors, extracellular matrix and other cell types are all part of the normal tissue that surrounds and pervades a solid tumour and has been shown to vary widely across different tumour stages and types. This is, in part, due to the dynamic and heterogeneous interplay between the tumour and its microenvironment. For many years, understood the importance of cell biological and microenvironmental factors on radiation response. With the advent of modern quantitative histologic [4] and biological imaging methods [5], this paradigm is poised to change
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