An Inflammatory Landscape for Preoperative Neurologic Deficits in Glioblastoma

Abstract

Introduction: Patients with glioblastoma (GBM), one of the most aggressive forms of primary brain tumors, exhibit a wide range of neurologic signs, ranging from headaches to neurologic deficits and cognitive impairment, at first clinical presentation. While such variability is attributed to inter-individual differences in increased intracranial pressure, tumor infiltration, and vascular compromise, a direct association with disease stage, tumor size and location, edema, and necrotic cell death has yet to be established. The lack of specificity of neurologic symptoms often confounds the diagnosis of GBM. It also limits clinicians’ ability to elect treatment regimens that not only prolong survival but also promote symptom management and high quality of life. Methods: To decipher the heterogeneous presentation of neurologic symptoms in GBM, we investigated differences in the molecular makeup of tumors from patients with and without preoperative neurologic deficits. We used the Ivy GAP (Ivy Glioblastoma Atlas Project) database to integrate RNA sequencing data from histologically defined GBM tumor compartments and neurologic examination records for 41 patients. We investigated the association of neurologic deficits with various tumor and patient attributes. We then performed differential gene expression and co-expression network analysis to identify a transcriptional signature specific to neurologic deficits in GBM. Using functional enrichment analysis, we finally provided a comprehensive and detailed characterization of involved pathways and gene interactions. Results: An exploratory investigation of the association of tumor and patient variables with the early development of neurologic deficits in GBM revealed a lack of robust and consistent clinicopathologic prognostic factors. We detected significant differences in the expression of 728 genes (FDR-adjusted p -value ≤ 0.05 and relative fold-change ≥ 1.5), unique to the cellular tumor (CT) anatomical compartment, between neurologic deficit groups. Upregulated differentially expressed genes in CT were enriched for mesenchymal subtype-predictive genes. Applying a systems approach, we then identified co-expressed gene sets that correlated with neurological deficit manifestation (FDR-adjusted p -value < 0.1). Collectively, these findings uncovered significantly enriched immune activation, oxidative stress response, and cytokine-mediated proinflammatory processes. Conclusion: Our study posits that inflammatory processes, as well as a mesenchymal tumor subtype, are implicated in the pathophysiology of preoperative neurologic deficits in GBM.

Potential Neurotoxic Effects of Glioblastoma-Derived Exosomes in Primary Cultures of Cerebellar Neurons via Oxidant Stress and Glutathione Depletion

“…Among these, glioblastoma cells could release factors responsible for neurotoxic effects as well as immunomodulatory factors with paracrine effects towards the surrounding neurological structures directly or through cancer-derived exosomes [ 38 , 39 ]. Katrib and colleagues (2019) have established a strict relationship among inflammation, GBM oxidative stress, and neurological deficit by identifying a panel of genes involved in these processes [ 40 ]. Similarly, Lange and colleagues (2021) have recently highlighted a link between glioblastoma and tumor-associated epilepsy describing the processes leading to the dysregulation of the glutamatergic signaling, including imbalance of the redox system [ 41 ].…”

ELAVL1 Role in Cell Fusion and Tunneling Membrane Nanotube Formations with Implication to Treat Glioma Heterogeneity

“…Hypoxia, mechanical stress, chronic inflammation, cytotoxic stress, and oncometabolites associated with free radical formations are reported to potentiate intercellular membrane fusion events, and these conditions are often associated with the glioma microenvironment [ 14 , 20 , 21 , 22 , 23 , 27 , 35 , 44 , 45 , 46 , 47 ]. The mRNA-binding protein of ELAV-family HuR is a valuable biomarker of brain tumor progression [ 48 , 49 , 50 , 51 ] and is involved in the regulation of the key cell-signaling pathways responsible for the inflammatory glioma microenvironment, the hypoxia-related stress response, the transitions of classic and proneural glioma subtypes to the mesenchymal subtype, the metabolic stress, and the reactive oxygen species (ROS) generation associated with D-2HG oncometabolite production in low-grade gliomas harboring single alleles with IDH1-R132H/C/S mutations [ 52 , 53 , 54 , 55 ].…”

Future development of chimeric antigen receptor T cell therapies for patients suffering from malignant glioma

“…Tumour progression is likely to occur during the course of autologous CAR-T cell manufacturing, especially aggressive tumours, such as glioblastoma [46,47]. Progression may induce new neurological symptoms and deficits [48], which would require management with corticosteroids [49]. Secondly, newly diagnosed, treatment-naive glioma patients display a reduced number of circulating CD4 + T cells.…”