The complex interactions between the cellular and non-cellular components of the brain tumor microenvironmental landscape and their therapeutic implications

Abstract

Glioblastoma (GBM), an aggressive high-grade glial tumor, is resistant to therapy and has a poor prognosis due to its universal recurrence rate. GBM cells interact with the non-cellular components in the tumor microenvironment (TME), facilitating their rapid growth, evolution, and invasion into the normal brain. Herein we discuss the complexity of the interactions between the cellular and non-cellular components of the TME and advances in the field as a whole. While the stroma of non-central nervous system (CNS) tissues is abundant in fibrillary collagens, laminins, and fibronectin, the normal brain extracellular matrix (ECM) predominantly includes proteoglycans, glycoproteins, and glycosaminoglycans, with fibrillary components typically found only in association with the vasculature. However, recent studies have found that in GBMs, the microenvironment evolves into a more complex array of components, with upregulated collagen gene expression and aligned fibrillary ECM networks. The interactions of glioma cells with the ECM and the degradation of matrix barriers are crucial for both single-cell and collective invasion into neighboring brain tissue. ECM-regulated mechanisms also contribute to immune exclusion, resulting in a major challenge to immunotherapy delivery and efficacy. Glioma cells chemically and physically control the function of their environment, co-opting complex signaling networks for their own benefit, resulting in radio- and chemo-resistance, tumor recurrence, and cancer progression. Targeting these interactions is an attractive strategy for overcoming therapy resistance, and we will discuss recent advances in preclinical studies, current clinical trials, and potential future clinical applications. In this review, we also provide a comprehensive discussion of the complexities of the interconnected cellular and non-cellular components of the microenvironmental landscape of brain tumors to guide the development of safe and effective therapeutic strategies against brain cancer.

A tale of two tumors: differential, but detrimental, effects of glioblastoma extracellular vesicles (EVs) on normal human brain cells

“…The GBM tumor microenvironment is a source of therapeutic resistance (Goenka et al ., 2021; Zhang et al ., 2019b) and the GBM TME remains a focus of intense study (Bikfalvi et al ., 2023; Faisal et al ., 2022), including the roles of GBM EVs in various TME niches (Graner, 2019; Russo et al ., 2022). As astrocytes are among the most prominent of cell types in the GBM TME, we focused on astrocyte molecular changes in response to incubation with GBM EVs.…”

Spatiotemporal Insights into Glioma Oncostream Dynamics: Unraveling Formation, Stability, and Disassembly Pathways

“…[ 43 ] The invasive phenotype of glioma cells is governed by a complex interplay of factors, signaling cascades, and interactions between cellular and ECM components. [ 44 , 45 , 46 , 47 , 48 , 49 ] This complexity presents challenges in targeting glioma invasion. [ 44 , 50 ] Our data sheds light on this intricate regulation through oncostream‐focused in vitro modeling and pharmacological testing, demonstrating the multifaceted nature of glioma cell migration and the influence of cellular components and ECM on it.…”

“…[ 44 , 45 , 46 , 47 , 48 , 49 ] This complexity presents challenges in targeting glioma invasion. [ 44 , 50 ] Our data sheds light on this intricate regulation through oncostream‐focused in vitro modeling and pharmacological testing, demonstrating the multifaceted nature of glioma cell migration and the influence of cellular components and ECM on it.…”

Glioblastoma Mesenchymal Transition and Invasion are Dependent on a NF-κB/BRD2 Chromatin Complex

“…GBM is a highly aggressive brain tumor characterized by its infiltrative nature and resistance to conventional therapies. The TME plays a crucial role in GBM pathogenesis, with the interaction between cellular and non-cellular components being a major determinant of treatment outcomes (40). ECM, a non-cellular component constitutes a complex structural network that provides support and facilitates cellular growth, survival, maturation, differentiation, and migration.…”