Abstract
Radiologic images provide a way to monitor tumor development and its response to therapies in a longitudinal and minimally invasive fashion. However, they operate on a macroscopic scale (average value per voxel) and are not able to capture microscopic scale (cell-level) phenomena. Nevertheless, to examine the causes of frequent fast fluctuations in tissue oxygenation, models simulating individual cells' behavior are needed. Here, we provide a link between the average data values recorded for radiologic images and the cellular and vascular architecture of the corresponding tissues. Using hybrid agent-based modeling, we generate a set of tissue morphologies capable of reproducing oxygenation levels observed in radiologic images. We then use these in silico tissues to investigate whether oxygen fluctuations can be explained by changes in vascular oxygen supply or by modulations in cellular oxygen absorption. Our studies show that intravascular changes in oxygen supply reproduce the observed fluctuations in tissue oxygenation in all considered regions of interest. However, larger-magnitude fluctuations cannot be recreated by modifications in cellular absorption of oxygen in a biologically feasible manner. Additionally, we develop a procedure to identify plausible tissue morphologies for a given temporal series of average data from radiology images. In future applications, this approach can be used to generate a set of tissues comparable with radiology images and to simulate tumor responses to various anti-cancer treatments at the tissue-scale level.
Highlights
IntroductionTumor tissues harbor regions of different levels of oxygen, including the well-oxygenated areas (normoxia) and zones with reduced oxygen availability (hypoxia)
Tumor tissues harbor regions of different levels of oxygen, including the well-oxygenated areas and zones with reduced oxygen availability
Developed imaging techniques provide a way to measure the magnitude of frequent short-term oxygen fluctuations, but they operate on a macro-scale
Summary
Tumor tissues harbor regions of different levels of oxygen, including the well-oxygenated areas (normoxia) and zones with reduced oxygen availability (hypoxia). Hypoxic regions can be created due to irregular blood flow in the aberrant tumor vasculature or shutdown of small vessels These phenomena lead to a perfusion-limited hypoxia that is observable for shorter times, often minutes to hours, and can be reversed when the blood flow is restored[2,3]. Several studies have demonstrated the existence of 20–30 minute-long cycles in red blood cell flux that can vary by 2–5 fold and lead to periodic changes in pO2 within the tumor tissue[3,4,5] It has been observed in murine experiments that tumors experience very fast and sometimes quite large fluctuations (more than 5-fold) in oxygen levels within the tissue. Electron paramagnetic resonance (EPR) imaging has shown that intratumor fluctuations in pO2 can reach a magnitude as high as 30 mmHg over a period as short as 3 minutes[6,7]
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