Small but Fierce: Tracking the Role of Extracellular Vesicles in Glioblastoma Progression and Therapeutic Resistance

Abstract

(30%), mouse double minute 2 (MDM2) amplifications (<10%) and/ or overexpression (50%), p16INK4a deletions (30-40%), and loss of heterozygosity on chromosome 10 in 50-80% of all cases. [3] Around 5-10% of all GBMs harbor isocitrate dehydrogenase (IDH) mutations with a better prognosis compared to tumors carrying the wildtype form known to exhibit a much more aggressive clinical behavior, particularly in adults. [4,5] It is now appreciated that IDH-wildtype and IDH-mutant gliomas represent distinct clinical and genetic entities, and efforts have been made to restrict the term "glioblastoma" to tumors without IDH mutations. [6,7] The standard-of-care treatment consists of maximal surgical resection of the tumor in combination with radiation and temozolomide (TMZ) chemotherapy. However, GBM is insidious and treatments have not been effective in preventing eventual disease progression as recurrence remains inevitable. [8-11] Transcriptomic, genomic, and epigenomic characterization have unveiled the highly heterogeneous nature of GBM with complex interactions among different cells within as well as cells surrounding the tumor. [3,12-17] Comprehensive longitudinal analyses of the tumor transcriptome have uncovered intricate intertumoral heterogeneity and classified GBM into three distinct subtypes: classical (CL), proneural (PN), and mesenchymal (MES). [18] In addition to this intertumoral heterogeneity, single-cell RNA sequencing demonstrated the presence of numerous transcriptome subtypes within the same tumor. [14] Further, single-cell lineage tracking and expression analysis of specimens from The Cancer Genome Atlas (TCGA) revealed that malignant cells in GBM exist in four main cellular states: neural-progenitor-like, oligodendrocyte-progenitor-like, astrocyte-like, and mesenchymal-like. [19] The number and frequency of cells in each defined state varies between patients and is influenced by mutations in the neurofibromin 1 (NF1) locus and copy number amplifications of EGFR, cyclin dependent kinase 4 (CDK4), and platelet-derived growth factor receptor alpha (PDGFRA) loci. The intricate combination of inter-as well as intratumoral heterogeneity plays a key role in rendering conventional and experimental targeted therapy approaches ultimately ineffective. [20-22] The majority of glioma cells lack the capacity to recapitulate a phenocopy of the original tumor and only a small subpopulation of neural stem-like cells within the tumor, called glioma stem cells (GSCs) or tumor initiating cells, have that ability upon xenotransplantation in immunocompromised mice. [23-25] Evidence suggests that these GSCs act as a driving Glioblastoma is the most common and aggressive brain tumor in adults. Most patients die within a year and long-term survival remains rare, owing to a combination of rapid progression/degeneration, lack of successful treatments, and high recurrence rates. Extracellular vesicles are cell-derived membranous structures involved in numerous physiological and pathological processes. In the context of cancer, th...

Emerging Concepts on the Role of Extracellular Vesicles and Its Cargo Contents in Glioblastoma-Microglial Crosstalk

“…MiR-301a, from hypoxic GDEVs, inhibits transcription elongation factor A-like 7 (TCEAL7) and thereby leads to the activation of Wnt/β-catenin pathway making normoxic GBM cells resistant to radiation. Few lncRNAs such as AHIF and H19 are actively found to be released from hypoxic GDEVs conferring radioresistance, invasion, and stemness to cancer cells [104,105]. LncRNA ROR1-AS1/ miR-4686 axis contributes to tumor progression [106].…”

Nanotechnology-Inspired Extracellular Vesicles Theranostics for Diagnosis and Therapy of Central Nervous System Diseases

“…Several imaging techniques have been used to study the physiological and pathological mechanism of EVs. With the use of different imaging probes or reporters, EVs were shown to interact with brain endothelial cells, cross the BBB, and accumulate in microglia, neurons, and astrocytes in the lesion area. − Different reporters have been used to label EVs for imaging applications including lipophilic dyes (such as PKH67, PKH26, DiI, DiD, DiR, and R18) by coincubation, fluorophores (such as Cy5.5, rhodamine, and CFSE) by chemical reaction, bioluminescents (such as Gaussia luciferase and split NanoLuc), and fluorescent proteins (such as GFP and mCherry) or other reporters such as a cyclization recombination enzyme (Cre) and tetracycline transactivator (tTA), through donor cell modification. − We and Verweij et al have recently reviewed advances in EV imaging and discussed the advantages and limitations of different techniques. , Among the mentioned strategies, lipophilic dyes labeling is simple, universal, and highly efficient; however, their application is complicated by an unbound dye, aggregates, and micelle formation . EV release, physical properties, and biological functions might also be affected by lipid dyes.…”

“…80−87 We and Verweij et al have recently reviewed advances in EV imaging and discussed the advantages and limitations of different techniques. 88,89 Among the mentioned strategies, lipophilic dyes labeling is simple, universal, and highly efficient; however, their application is complicated by an unbound dye, aggregates, and micelle formation. 90 EV release, physical properties, and biological functions might also be affected by lipid dyes.…”

Plant extracellular vesicles: A novel bioactive nanoparticle for tumor therapy

“…Although various types of extracellular vesicles have been identified at the first International Society for Extracellular Vesicles (ISEV) meeting, since most of the examples in this review cannot distinguish their types, this paper uses extracellular vesicles (or exosomes) to refer to them ( Witwer and Thery, 2019 ). In mammalian cells, both normal cells and cancer cells can secrete extracellular vesicles as a tool for cell-to-cell communication ( Muralidharan-Chari et al, 2010 ; Kuriyama et al, 2020 ; Mittal et al, 2020 ; Schweiger and Tannous, 2020 ; Wu et al, 2021 ), Information transfer through binding of vesicle membrane proteins to receptor membrane proteins and through internalization of vesicle contents by receptor cells ( Menard et al, 2018 ; Ko and Naora, 2020 ; Vu et al, 2020 ; Tang et al, 2022 ). Similarly, plant multi-vesicular bodies secrete exosome-like nanoparticles ( An et al, 2007 ), which, in addition to being involved in the formation of the plant’s own cell wall ( Chukhchin et al, 2019 ) are also involved in plant-microbe interactions ( Rutter and Innes, 2018 ), including plant defense and silencing fungi gene et al ( Regente et al, 2017 ; Cai et al, 2018 ; Bleackley et al, 2019 ; Cai et al, 2019 ).…”