Old Stars and New Players in the Brain Tumor Microenvironment

Parmigiani, Elena; Scalera, Marta; Mori, Elisabetta; Tantillo, Elena; Vannini, Eleonora

doi:10.3389/fncel.2021.709917

Cited by 15 publications

(12 citation statements)

References 271 publications

(391 reference statements)

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“…Astrocytes’ morphological and functional heterogeneity plays an important role in their tumorigenic potential, and the identification of astrocyte’ subpopulations, based on marker combinations, could differentiate normal astrocytes from their malignant counterparts [ 100 ].…”

Section: Tumoral and Reactive Astrocytesmentioning

confidence: 99%

Glioblastoma Microenvironment and Cellular Interactions

Crivii

Boșca

Melincovici

et al. 2022

Cancers

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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.

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Section: Tumoral and Reactive Astrocytesmentioning

confidence: 99%

Glioblastoma Microenvironment and Cellular Interactions

Crivii

Boșca

Melincovici

et al. 2022

Cancers

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“…Nevertheless, mechanisms underpinning glioma invasion are still unclear, even though the need to better understand intercommunications across tumoral and neuronal cells is now emphasized to explain the spatial anisotropy of diffusion ( 54 , 55 ). Upregulation of genes involved in cell motility might facilitate the spread of both LGG and high-grade gliomas along WM tracts and might contribute to their invasive phenotype ( 56 ).…”

Section: Wm Tracts and Patterns Of Glioma Diffusion: The Role Of Myel...mentioning

confidence: 99%

White Matter Tracts and Diffuse Lower-Grade Gliomas: The Pivotal Role of Myelin Plasticity in the Tumor Pathogenesis, Infiltration Patterns, Functional Consequences and Therapeutic Management

Duffau

2022

Front. Oncol.

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For many decades, interactions between diffuse lower-grade glioma (LGG) and brain connectome were neglected. However, the neoplasm progression is intimately linked to its environment, especially the white matter (WM) tracts and their myelin status. First, while the etiopathogenesis of LGG is unclear, this tumor seems to appear during the adolescence, and it is mostly located within anterior and associative cerebral areas. Because these structures correspond to those which were myelinated later in the brain maturation process, WM myelination could play a role in the development of LGG. Second, WM fibers and the myelin characteristics also participate in LGG diffusion, since glioma cells migrate along the subcortical pathways, especially when exhibiting a demyelinated phenotype, which may result in a large invasion of the parenchyma. Third, such a migratory pattern can induce functional (neurological, cognitive and behavioral) disturbances, because myelinated WM tracts represent the main limitation of neuroplastic potential. These parameters are critical for tailoring an individualized therapeutic strategy, both (i) regarding the timing of active treatment(s) which must be proposed earlier, before a too wide glioma infiltration along the WM bundles, (ii) and regarding the anatomic extent of surgical resection and irradiation, which should take account of the subcortical connectivity. Therefore, the new science of connectomics must be integrated in LGG management, based upon an improved understanding of the interplay across glioma dissemination within WM and reactional neural networks reconfiguration, in order to optimize long-term oncological and functional outcomes. To this end, mechanisms of activity-dependent myelin plasticity should be better investigated.

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“…The therapeutic potential of macrophage reprogramming/repolarization has attracted a great deal of interest in recent years, but it also represents an area of uncertainty in its unknown relationship to epileptogenesis. The majority of TAMs are monocyte-derived macrophages (MDMs) that infiltrate the brain through the BBB and they account for up to 50% of the tumor mass (Parmigiani et al, 2021 ). M1-polarized macrophages display primarily pro-inflammatory, anti-tumor attributes making them an attractive therapeutic target.…”

Section: From Laboratory To Clinical Translationmentioning

confidence: 99%

Converging Mechanisms of Epileptogenesis and Their Insight in Glioblastoma

Hills

Kostarelos

Wykes

2022

Front. Mol. Neurosci.

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Glioblastoma (GBM) is the most common and advanced form of primary malignant tumor occurring in the adult central nervous system, and it is frequently associated with epilepsy, a debilitating comorbidity. Seizures are observed both pre- and post-surgical resection, indicating that several pathophysiological mechanisms are shared but also prompting questions about how the process of epileptogenesis evolves throughout GBM progression. Molecular mutations commonly seen in primary GBM, i.e., in PTEN and p53, and their associated downstream effects are known to influence seizure likelihood. Similarly, various intratumoral mechanisms, such as GBM-induced blood-brain barrier breakdown and glioma-immune cell interactions within the tumor microenvironment are also cited as contributing to network hyperexcitability. Substantial alterations to peri-tumoral glutamate and chloride transporter expressions, as well as widespread dysregulation of GABAergic signaling are known to confer increased epileptogenicity and excitotoxicity. The abnormal characteristics of GBM alter neuronal network function to result in metabolically vulnerable and hyperexcitable peri-tumoral tissue, properties the tumor then exploits to favor its own growth even post-resection. It is evident that there is a complex, dynamic interplay between GBM and epilepsy that promotes the progression of both pathologies. This interaction is only more complicated by the concomitant presence of spreading depolarization (SD). The spontaneous, high-frequency nature of GBM-associated epileptiform activity and SD-associated direct current (DC) shifts require technologies capable of recording brain signals over a wide bandwidth, presenting major challenges for comprehensive electrophysiological investigations. This review will initially provide a detailed examination of the underlying mechanisms that promote network hyperexcitability in GBM. We will then discuss how an investigation of these pathologies from a network level, and utilization of novel electrophysiological tools, will yield a more-effective, clinically-relevant understanding of GBM-related epileptogenesis. Further to this, we will evaluate the clinical relevance of current preclinical research and consider how future therapeutic advancements may impact the bidirectional relationship between GBM, SDs, and seizures.

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Old Stars and New Players in the Brain Tumor Microenvironment

Cited by 15 publications

References 271 publications

Glioblastoma Microenvironment and Cellular Interactions

Glioblastoma Microenvironment and Cellular Interactions

White Matter Tracts and Diffuse Lower-Grade Gliomas: The Pivotal Role of Myelin Plasticity in the Tumor Pathogenesis, Infiltration Patterns, Functional Consequences and Therapeutic Management

Converging Mechanisms of Epileptogenesis and Their Insight in Glioblastoma

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