Glioblastoma Microenvironment and Cellular Interactions

Abstract

The central nervous system (CNS) represents a complex network of different cells, such as neurons, glial cells, and blood vessels. In tumor pathology, glial cells result in the highest number of cancers, and glioblastoma (GB) is considered the most lethal tumor in this region. The development of GB leads to the infiltration of healthy tissue through the interaction between all the elements of the brain network. This results in a GB microenvironment, a complex peritumoral hallo composed of tumor cells and several non-tumor cells (e.g., nervous cells, stem cells, fibroblasts, vascular and immune cells), which might be the principal factor for the ineffective treatment due to the fact that the microenvironment modulates the biologic status of the tumor with the increase in its evasion capacity. Crosstalk between glioma cells and the brain microenvironment finally inhibits the beneficial action of molecular pathways, favoring the development and invasion of the tumor and its increasing resistance to treatment. A deeper understanding of cell–cell interactions in the tumor microenvironment (TME) and with the tumor cells could be the basis for a more efficient therapy.

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

“…Glioblastoma patients have a high prevalence of tumor recurrence, signifying poor prognosis and rapid death ( 361 ). Key interactions between motile glioma cells and the non-cellular components of the TME stimulates rapid invasion of the primary tumor to other areas of the brain, forming deadly secondary tumors ( 3 , 54 , 346 , 362 ). As GBM spreads throughout the brain, normal brain functions are further disrupted, and tumor lethality ensues.…”

Molecular Pathways and Genomic Landscape of Glioblastoma Stem Cells: Opportunities for Targeted Therapy

“…GSCs engage in reciprocal signaling with their microenvironment, remodeling their milieu while being simultaneously influenced by their surroundings. Four niches characterize the locations of GSCs within GBMs, including perivascular, hypoxic, necrotic, and invasive niches [ 40 ]. The tumor microenvironment influences differential expression of GSC phenotypes, resulting in intra-tumoral heterogeneity spatially distributed within the same patient.…”

“…Reactive astrocytes produce vascular endothelial growth factor which stimulates neovascularization to supply blood to tumor cells, while GSCs promote vascular dilation and increased leakiness [ 42 ]. GSCs, endothelial cells, astrocytes, and microglia also exchange microRNAs that promote angiogenesis in the microenvironment and increase the self-renewal and proliferative capacities of GSCs [ 40 ].…”

“…Intercellular communication between GBM and the tumor microenvironment is achieved via direct exchange through ion channels, transporters, gap junctions, and extracellular vesicles, as well as secretion of cytokines, chemokines, and neurotransmitters [ 40 ]. Extracellular vesicles can transport microRNA and proteins that remodel the microenvironment to promote tumor aggressiveness, stimulate angiogenesis, and promote resistance to therapy, including chemotherapeutics and radiation [ 46 ].…”

Neurotransmitters: Potential Targets in Glioblastoma

“…However, there are also studies suggesting that glioma could originate from astrocytes or oligodendrocyte precursor cells (OPCs) [ 88 ], indicating the need for further research. On the other hand, similar to the neurogenesis microenvironment induced by NSCs, a specific microenvironment composed of tumor cells, neurons, stem cells, fibroblasts and vascular and immune cells has been identified in GBM [ 19 , 89 ]. The expression of neurotransmitter receptors has been found on all kinds of cells in the GBM microenvironment [ 11 ].…”