Endothelial-Tumor Cell Interaction in Brain and CNS Malignancies

Abstract

Glioblastoma and other brain or CNS malignancies (like neuroblastoma and medulloblastoma) are difficult to treat and are characterized by excessive vascularization that favors further tumor growth. Since the mean overall survival of these types of diseases is low, the finding of new therapeutic approaches is imperative. In this review, we discuss the importance of the interaction between the endothelium and the tumor cells in brain and CNS malignancies. The different mechanisms of formation of new vessels that supply the tumor with nutrients are discussed. We also describe how the tumor cells (TC) alter the endothelial cell (EC) physiology in a way that favors tumorigenesis. In particular, mechanisms of EC–TC interaction are described such as (a) communication using secreted growth factors (i.e., VEGF, TGF-β), (b) intercellular communication through gap junctions (i.e., Cx43), and (c) indirect interaction via intermediate cell types (pericytes, astrocytes, neurons, and immune cells). At the signaling level, we outline the role of important mediators, like the gasotransmitter nitric oxide and different types of reactive oxygen species and the systems producing them. Finally, we briefly discuss the current antiangiogenic therapies used against brain and CNS tumors and the potential of new pharmacological interventions that target the EC–TC interaction.

Tumor Vessels Fuel the Fire in Glioblastoma

“…In vitro and in vivo studies report that pericyte-derived TNTs actively explore and sense their surrounding microenvironment, and connect to targeted vessels through pericyte-to-pericyte and/or pericyte-to-EC bounds. TNTs may have a primary role in the early phases of angiogenesis in the tumors from the central nervous system [ 91 , 92 , 93 ].…”

The 3.0 Cell Communication: New Insights in the Usefulness of Tunneling Nanotubes for Glioblastoma Treatment

“…In addition, GSCs transdifferentiate into pericytes and contribute to the vascular structure [44,45]. Another phenomenon, called "vasculogenic mimicry", takes place in GBM, where GSCs differentiate into endothelial-like cells, forming vessel-like structures.…”

“…GBMs are among the most vascularized solid tumors found in humans, and blood vessels play a key role in supporting tumor progression [50], especially the endothelial cells (ECs) that are closely associated with GSCs [45]. Therefore, hindering communication between the endothelium and GSCs might represent a strategy to hamper GSCs survival.…”

Cell-of-Origin and Genetic, Epigenetic, and Microenvironmental Factors Contribute to the Intra-Tumoral Heterogeneity of Pediatric Intracranial Ependymoma

“…The molecular response to hypoxia is mainly mediated by the hypoxia-inducible factor (HIF) family of TFs, especially HIF1α, that is also involved in the maintenance of stemness features and induction of angiogenesis [ 160 ]. In low oxygen concentrations, CSCs secrete a number of angiogenetic factors, such as VEGF and PDGF [ 161 ] that in turn recruit endothelial cells to shape new blood vessels, followed by CSC epigenetic adaptation to the newly formed, normoxic niche.…”