Pawan Kumar

• 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.