Understanding Neovascularization in Glioblastoma: Insights from the Current Literature

Abstract

Glioblastomas (GBMs), among the most aggressive and resilient brain tumors, characteristically exhibit high angiogenic potential, leading to the formation of a dense yet aberrant vasculature, both morphologically and functionally. With these premises, numerous expectations were initially placed on anti-angiogenic therapies, soon dashed by their limited efficacy in concretely improving patient outcomes. Neovascularization in GBM soon emerged as a complex, dynamic, and heterogeneous process, hard to manage with the classical standard of care. Growing evidence has revealed the existence of numerous non-canonical strategies of angiogenesis, variously exploited by GBM to meet its ever-increasing metabolic demand and differently involved in tumor progression, recurrence, and escape from treatments. In this review, we provide an accurate description of each neovascularization mode encountered in GBM tumors to date, highlighting the molecular players and signaling cascades primarily involved. We also detail the key architectural and functional aspects characteristic of the GBM vascular compartment because of an intricate crosstalk between the different angiogenic networks. Additionally, we explore the repertoire of emerging therapies against GBM that are currently under study, concluding with a question: faced with such a challenging scenario, could combined therapies, tailored to the patient's genetic signatures, represent an effective game changer?

Keywords: aberrant angiogenesis; emerging therapies; glioblastoma (GBM); pro-angiogenic factors; strategies of neovascularization.

Figure 1

Some important morphological aspects of angiogenesis in GBM (E&E staining). (A) The image shows glomeruloid vessels (vessels with multiple lumina) and endothelial multilayering because of endothelial hyperplasia (200× magnification). (B) Atypical, branched vessel network (100× magnification). (C) An island of viable tumor cells encircling the blood vessels in a radial pattern (200× magnification). (D) Ectatic hyalinized vessels and intervening spindle-shaped stromal cells (200× magnification).

Figure 2

Schematic representation of the “angiogenic switch” in GBM. During tumor progression, the needle of the scale shifts in favor of pro-angiogenic factors, released by GBM cancer cells and TME, under hypoxic conditions, resulting in aberrant growth of GBM vasculature. Abbreviations: GBM, glioblastoma; TME, tumor microenvironment; VEGF, vascular endothelial growth factor; FGF, fibroblast growth factor; TGF-beta, transforming growth factor-beta; PDGF, platelet-derived growth factor; ANG, angiopoietin; MMP, matrix metalloproteinase; PDGFR, platelet-derived growth factor receptor; VEGFR, vascular endothelial growth factor receptor. This figure was created with Servier Medical Art (https://smart.servier.com).