Grogan, J. A. | Search bioRxiv

bioRxiv2019

Abnormal morphology biases haematocrit distribution in tumour vasculature and contributes to heterogeneity in tissue oxygenation

Oxygen heterogeneity in solid tumours is recognised as a limiting factor for therapeutic efficacy. This heterogeneity arises from the abnormal vascular structure of the tumour, but the precise mechanisms linking abnormal structure and compromised oxygen transport are only partially understood. In this paper, we investigate the role that RBC transport plays in establishing oxygen heterogeneity in tumour tissue. We focus on heterogeneity driven by network effects, which are challenging to observe experimentally due to the reduced fields of view typically considered. Motivated by our findings of abnormal vascular patterns linked to deviations from current RBC transport theory, we calculate average vessel lengths [Formula] and diameters [Formula] from tumour allografts of three cancer cell lines and observe a substantial reduction in the ratio [Formula] compared to physiological conditions. Mathematical modelling reveals that small values of the ratio{lambda} (i.e. {lambda} < 6) can bias haematocrit distribution in tumour vascular networks and drive heterogeneous oxygenation of tumour tissue. Finally, we show an increase in the value of{lambda} in tumour vascular networks following treatment with the anti-angiogenic cancer agent DC101. Based on our findings, we propose{lambda} as an effective way of monitoring the efficacy of antiangiogenic agents and as a proxy measure of perfusion and oxygenation in tumour tissue undergoing anti-angiogenic treatment. Significance statementOxygen heterogeneity in solid tumours is recognised as a limiting factor for therapeutic efficacy. This heterogeneity arises from the abnormal tumour vascular structure. We investigate the role that anomalies in RBC transport play in establishing oxygen heterogeneity in tumour tissue. We introduce a metric to characterise tumour vasculature (mean vessel length-to-diameter ratio,{lambda} ) and demonstrate how it predicts tissue oxygen heterogeneity. We also report an increase in{lambda} following treatment with the antiangiogenic agent DC101. Together, we propose{lambda} as an effective way of monitoring the action of anti-angiogenic agents and a proxy measure of oxygen heterogeneity in tumour tissue. Unravelling the causal relationship between tumour vascular structure and tissue oxygenation will pave the way for new personalised therapeutic approaches.

cancer biology↗

bioRxiv2017

The importance of geometry in the corneal micropocket assay

The corneal micropocket angiogenesis assay is an experimental protocol for studying vessel network formation, or neovascularization, in vivo. The assay is attractive due to the ease with which the developing vessel network can be observed in the same animal over time. Measurements from the assay have been used in combination with mathematical modeling to gain insights into the mechanisms of angiogenesis. While previous modeling studies have adopted planar domains to represent the assay, the hemispherical shape of the cornea and asymmetric positioning of the angiogenic source can be seen to affect vascular patterning in experimental images. As such, we aim to better understand: i) how the geometry of the assay influences vessel network formation and ii) how to relate observations from planar domains to those in the hemispherical cornea. To do so, we develop a three-dimensional, off-lattice mathematical model of neovascularization in the cornea, using a spatially resolved representation of the assay for the first time. Relative to the detailed model, we predict that the adoption of planar geometries has a noticeable impact on vascular patterning, leading to increased vessel merging, or anastomosis, in particular when circular geometries are adopted. Significant differences in the dynamics of diffusible aniogenesis simulators are also predicted between different domains. In terms of comparing predictions across domains, the distance of the vascular front to the limbus metric is found to have low sensitivity to domain choice, while metrics such as densities of tip cells and vessels and vascularized fraction are sensitive to domain choice. Given the widespread adoption and attractive simplicity of planar tissue domains, both in silico and in vitro, the differences identified in the present study should prove useful in relating the results of previous and future theoretical studies of neovascularization to in vivo observations in the cornea.\n\nAuthor summaryNeovascularization, or the formation of new blood vessels, is an important process in development, wound healing and cancer. The corneal micropocket assay is used to better understand the process and, in the case of cancer, how it can be controlled with drug therapies for improved patient outcomes. In the assay, the hemispherical shape of the cornea can influence the way the vessel network forms. This makes it difficult to directly compare results from experiments with the predictions of mathematical models or cell culture experiments, which are typically performed on flat substrates or planar matrices. In this study, we use mathematical modeling to investigate how the hemispherical shape of the cornea affects vessel formation and to identify how sensitive different measurements of neovascularization are to geometry.

physiology↗