The Vascular Microenvironment in Glioblastoma: A Comprehensive Review

Abstract

Glioblastoma multiforme, the deadliest primary brain tumor, is characterized by an excessive and aberrant neovascularization. The initial expectations raised by anti-angiogenic drugs were soon tempered due to their limited efficacy in improving the overall survival. Intrinsic resistance and escape mechanisms against anti-VEGF therapies evidenced that tumor angiogenesis is an intricate multifaceted phenomenon and that vessels not only support the tumor but exert indispensable interactions for resistance and spreading. This holistic review covers the essentials of the vascular microenvironment of glioblastoma, including the perivascular niche components, the vascular generation patterns and the implicated signaling pathways, the endothelial–tumor interrelation, and the interconnection between vessel aberrancies and immune disarrangement. The revised concepts provide novel insights into the preclinical models and the potential explanations for the failure of conventional anti-angiogenic therapies, leading to an era of new and combined anti-angiogenic-based approaches.

Glioblastoma-Specific Strategies of Vascularization: Implications in Anti-Angiogenic Therapy Resistance

“…Vessel co-option has been reported in both high-grade and low-grade gliomas [ 32 , 38 ]; it appears to occur mainly at the tumor–brain interface and in the peritumor regions, contributing to tumor infiltration [ 21 ]. It might be assumed that vessel co-option and angiogenesis occur where the perivascular niche is set around a vessel with microvascular sprouting or vascular cluster conformation, as in the moderately aggressive GBM types or regions [ 39 ]. Vessel co-option and angiogenesis can occur simultaneously in different areas of the same tumor, or a switch between the two mechanisms can occur over time [ 18 ].…”

“…The tumor microenvironment plays a remarkable role in the transdifferentiation process. The interaction between tumor cells and the endothelium is bidirectional, and their roles seem to be interchangeable, depending on the microenvironment demands [ 39 , 111 ]. A study on human GBM tissues reported the existence of a perivascular niche in which GSCs are close to CD34 + endothelial cells [ 112 ].…”

Distribution, Function, and Expression of the Apelinergic System in the Healthy and Diseased Mammalian Brain

“…Current therapies relying on anti-VEGF mAb usually target tumor angiogenesis. Unfortunately, such therapies have not increased patient survival [ 94 ]. These treatments have been shown to decrease the apelin expression inside the tumor, thus, increasing its invasiveness [ 95 ].…”

Implications of Cellular Immaturity in Necrosis and Microvascularization in Glioblastomas IDH-Wild-Type

“…Over time, four microvascular architectures have been identified: microvascular sprouting, vascular cluster, vascular garland, and glomeruloid vascular proliferation [ 9 ]. The first pattern resembles physiological angiogenesis, and its presence denotes a higher survival rate.…”

“…The vascular cluster is defined by at least two vessels without interposed stroma. The vascular garland is arranged perinecrotically and consists of neoformation vessels with a circular arrangement [ 9 , 10 ]. The glomeruloid proliferation consists of at least two vessels embedded in the stroma, mimicking the appearance of the glomerulus [ 9 , 11 ].…”