Glioblastoma Vasculature: From its Critical Role in Tumor Survival to Relevant in Vitro Modelling

Fátima Baltazar,Bruno Sarmento,Cláudia Martins,Catarina Pacheco,Joaquim Monteiro,Bruno M Costa

doi:10.3389/fddev.2022.823412

Abstract

Biochemical and biophysical cues governing glioblastoma (GBM) progression are complex and dynamic. Tumor blood vessels, often recognized only by their transport functions, are more deeply involved in this process. Vessels are involved in tumor immune evasion, matrix alterations and stem cell stimulation, contributing for tumor treatment resistance and patients’ poor survival. Given blood vessel complex and dynamic nature, they are hardly represented in conventional GBM monolayered in vitro models. However, other in vitro approaches, such as three-dimensional (3D) models, incorporating extracellular matrix (ECM), malignant and stromal cells, and promoting their communication, can resemble neovascularization, growing blood vessels in a tumor-like microenvironment. These models mimic GBM physiological architecture and key biochemical and biophysical environments, allowing the investigation of the impact of vascularization in tumor progression. For researchers in neuro-oncology field, 3D vascularized GBM models are of great interest. They are promising tools to evaluate individual driven neovascularization and identify mediators involved in those processes. Moreover, they may be used to test potential anti-GBM therapies targeting blood vessels or influenced by them. This review will discuss the significance of blood vessels in GBM and review novel 3D pre-clinical vascular models.

Highlights

Glioblastoma (GBM) is the most frequent, aggressive and lethal primary brain tumor in adults
GBM activates astrocytes into reactive astrocytes, which, in turn, express and release high levels of cytokines, as interleukin 6 (IL-6) and connective tissue growth factor (CTGF), known to trigger the activation of oncogenic factors and to ease tumor invasion (Edwards et al, 2011)
endothelial cells (ECs) play a critical role in the survival and self-renewal of Glioblastoma stem cells (GSCs) via jagged canonical Notch ligand 1 (JAG1), delta like canonical Notch ligand 4 (DLL4), nitric oxide (NO), interleukin 8 (IL-8), sonic hedgehog protein (Shh) and fibroblast growth factor pathway (FGF), among others

Summary

INTRODUCTION

Glioblastoma (GBM) is the most frequent, aggressive and lethal primary brain tumor in adults. Given that GBM hypervascularity has been associated with disease invasion, progression and therapy resistance, the incorporation of vasculature into 3D GBM in vitro models brings these systems closer to the native biology of the tumor, representing the complex crosstalk between tumor cells, tumorassociated blood vessels, and other non-neoplastic TME components in a more realistic manner. This opens avenues to study the behavior of the GBM perivascular niche in detail, understanding how vascular networks contribute to the aggressiveness and invasive profile of the tumor. We will elucidate the significance of this modelling of the tumor’s perivascular tissue in cancer biology studies and in therapy screening

GLIOBLASTOMA VASCULAR COMPARTMENT

GLIOBLASTOMA VASCULATURE AND TUMOR MICROENVIRONMENT

Glioblastoma Vasculature Shelters and Regulates Glioblastoma Stem Cells

Glioblastoma Vasculature Promotes Tumor Immunosuppressive Environment

Spherical Models—“Free” or Matrix-Supported Spheroids

Scaffold-Based Models

Microfluidic-Based Models

DISCUSSION