Glioblastoma multiforme restructures the topological connectivity of cerebrovascular networks

Artur Hahn,Björn Tews,Martin Bendszus,Sabine Heiland,Gergely Solecki,Julia Bode,Thomas Krüwel,Frank Winkler,Michael O Breckwoldt,Felix T Kurz

doi:10.1038/s41598-019-47567-w

Abstract

Glioblastoma multiforme alters healthy tissue vasculature by inducing angiogenesis and vascular remodeling. To fully comprehend the structural and functional properties of the resulting vascular network, it needs to be studied collectively by considering both geometric and topological properties. Utilizing Single Plane Illumination Microscopy (SPIM), the detailed capillary structure in entire healthy and tumor-bearing mouse brains could be resolved in three dimensions. At the scale of the smallest capillaries, the entire vascular systems of bulk U87- and GL261-glioblastoma xenografts, their respective cores, and healthy brain hemispheres were modeled as complex networks and quantified with fundamental topological measures. All individual vessel segments were further quantified geometrically and modular clusters were uncovered and characterized as meta-networks, facilitating an analysis of large-scale connectivity. An inclusive comparison of large tissue sections revealed that geometric properties of individual vessels were altered in glioblastoma in a relatively subtle way, with high intra- and inter-tumor heterogeneity, compared to the impact on the vessel connectivity. A network topology analysis revealed a clear decomposition of large modular structures and hierarchical network organization, while preserving most fundamental topological classifications, in both tumor models with distinct growth patterns. These results augment our understanding of cerebrovascular networks and offer a topological assessment of glioma-induced vascular remodeling. The findings may help understand the emergence of hypoxia and necrosis, and prove valuable for therapeutic interventions such as radiation or antiangiogenic therapy.

Highlights

Vascular networks are transport networks that provide vital substances such as oxygen and nutrients to living tissue and remove biological waste products
Most studies of this nature have focused on local vessel properties, such as microvascular density (MVD), vessel segment geometry and space-filling properties
We found a mean fractional vessel volume of 〈fVVh〉 = 9.8 ± 3.3%, which is in reasonable agreement with documented values of an intracranial mean 〈fVVic〉 = 5.8 ± 0.4% and maximum 〈fVVmax〉 ≈ 7.9% in the medulla and cerebral cortex, determined from micro-CT measurements at 20 μm isotropic resolution[60]

Summary

Introduction

Vascular networks are transport networks that provide vital substances such as oxygen and nutrients to living tissue and remove biological waste products. Their characteristic morphology allows regulation of the surrounding biological environment, including thermoregulation and physiological ion balance to maintain tissue homeostasis[1]. Extensive research has been conducted to investigate the structure of tumor vasculature and how it sets itself apart from healthy vessel constructs. Most studies of this nature have focused on local vessel properties, such as microvascular density (MVD), vessel segment geometry and space-filling properties (see, e.g.18–21 and references therein). A detailed structural and functional quantification of such entire vascular networks may unveil previously unknown consequences of vascular remodeling and aid the development of targeted antiangiogenic therapies

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