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Gliomas are primary brain tumors with a high invasive potential and infiltrative spread. Among them, glioblastoma multiforme (GBM) exhibits microvascular hyperplasia and pronounced necrosis triggered by hypoxia. Histological samples showing garland-like hypercellular structures (so-called pseudopalisades) centered around one or several sites of vaso-occlusion are typical for GBM and hint on poor prognosis of patient survival.
This thesis focuses on studying the establishment and maintenance of these histological patterns specific to GBM with the aim of modeling the microlocal tumor environment under the influence of acidity, tissue anisotropy and hypoxia-induced angiogenesis. This aim is reached with two classes of models: multiscale and multiphase. Each of them features a reaction-diffusion equation (RDE) for the acidity acting as a chemorepellent and inhibitor of growth, coupled in a nonlinear way to a reaction-diffusion-taxis equation (RDTE) for glioma dynamics. The numerical simulations of the resulting systems are able to reproduce pseudopalisade-like patterns. The effect of tumor vascularization on these patterns is studied through a flux-limited model belonging to the multiscale class. Thereby, PDEs of reaction-diffusion-taxis type are deduced for glioma and endothelial cell (EC) densities with flux-limited pH-taxis for the tumor and chemotaxis towards vascular endothelial growth factor (VEGF) for ECs. These, in turn, are coupled to RDEs for acidity and VEGF produced by tumor. The numerical simulations of the obtained system show pattern disruption and transient behavior due to hypoxia-induced angiogenesis. Moreover, comparing two upscaling techniques through numerical simulations, we observe that the macroscopic PDEs obtained via parabolic scaling (directed tissue) are able to reproduce glioma patterns, while no such patterns are observed for the PDEs arising by a hyperbolic limit (directed tissue). This suggests that brain tissue might be undirected - at least as far as glioma migration is concerned. We also investigate two different ways of including cell level descriptions of response to hypoxia and the way they are related.
We propose a model for glioma patterns in a microlocal tumor environment under
the influence of acidity, angiogenesis, and tissue anisotropy. The bottom-up model deduction
eventually leads to a system of reaction–diffusion–taxis equations for glioma and endothelial cell
population densities, of which the former infers flux limitation both in the self-diffusion and taxis
terms. The model extends a recently introduced (Kumar, Li and Surulescu, 2020) description of
glioma pseudopalisade formation with the aim of studying the effect of hypoxia-induced tumor
vascularization on the establishment and maintenance of these histological patterns which are typical
for high-grade brain cancer. Numerical simulations of the population level dynamics are performed
to investigate several model scenarios containing this and further effects.
Gliomas are primary brain tumors with a high invasive potential and infiltrative spread. Among them, glioblastoma multiforme (GBM) exhibits microvascular hyperplasia and pronounced necrosis triggered by hypoxia. Histological samples showing garland-like hypercellular structures (so-called pseudopalisades) centered around the occlusion site of a capillary are typical for GBM and hint on poor prognosis of patient survival. We propose a multiscale modeling approach in the kinetic theory of active particles framework and deduce by an upscaling process a reaction-diffusion model with repellent pH-taxis. We prove existence of a unique global bounded classical solution for a version of the obtained macroscopic system and investigate the asymptotic behavior of the solution. Moreover, we study two different types of scaling and compare the behavior of the obtained macroscopic PDEs by way of simulations. These show that patterns (not necessarily of Turing type), including pseudopalisades, can be formed for some parameter ranges, in accordance with the tumor grade. This is true when the PDEs are obtained via parabolic scaling (undirected tissue), while no such patterns are observed for the PDEs arising by a hyperbolic limit (directed tissue). This suggests that brain tissue might be undirected - at least as far as glioma migration is concerned. We also investigate two different ways of including cell level descriptions of response to hypoxia and the way they are related .