The role of extracellular vesicles in acquisition of resistance to therapy in glioblastomas

Abstract

Glioblastoma (GBM) is the most aggressive primary brain tumor with a median survival of 15 months despite standard care therapy consisting of maximal surgical debulking, followed by radiation therapy with concurrent and adjuvant temozolomide treatment. The natural history of GBM is characterized by inevitable recurrence with patients dying from increasingly resistant tumor regrowth after therapy. Several mechanisms including inter- and intratumoral heterogeneity, the evolution of therapy-resistant clonal subpopulations, reacquisition of stemness in glioblastoma stem cells, multiple drug efflux mechanisms, the tumor-promoting microenvironment, metabolic adaptations, and enhanced repair of drug-induced DNA damage have been implicated in therapy failure. Extracellular vesicles (EVs) have emerged as crucial mediators in the maintenance and establishment of GBM. Multiple seminal studies have uncovered the multi-dynamic role of EVs in the acquisition of drug resistance. Mechanisms include EV-mediated cargo transfer and EVs functioning as drug efflux channels and decoys for antibody-based therapies. In this review, we discuss the various mechanisms of therapy resistance in GBM, highlighting the emerging role of EV-orchestrated drug resistance. Understanding the landscape of GBM resistance is critical in devising novel therapeutic approaches to fight this deadly disease.

Mechanisms of temozolomide resistance in glioblastoma - a comprehensive review

“…Exosome samples taken from blood were able to show fluctuations in MGMT and APNG levels throughout treatment that may be suggestive of resistance development [ 246 ] . This increased understanding and utilization of EVs in diagnosis is representative of the many advancements in the field of TMZ resistance and a movement towards more novel and creative solutions to glioblastoma treatment [ 247 ] .…”

MicroRNA Interrelated Epithelial Mesenchymal Transition (EMT) in Glioblastoma

“…Thus, EVs originating from MES drive PN glioblastoma progression and, ultimately, drug resistance through an NF-κB signal transducer and STAT3 signaling [ 20 ]. EVs have also been found to be major players of drug resistance in glioblastomas by transporting anti-cancer agents out of the tumor microenvironment [ 21 ], highlighting the importance of targeting EVs in the endeavor of developing novel therapeutic strategies for this disease. miRNAs using EVs as their nano-vehicles in glioblastomas have been thoroughly reviewed elsewhere [ 22 ].…”

The Emerging World of Membrane Vesicles: Functional Relevance, Theranostic Avenues and Tools for Investigating Membrane Function

“…Glioblastoma (GBM) based radiation therapy has been shown to possess limited efficacy due to the enrichment of cancer stem cells (CSCs). CSCs have the capacity to cause recurrent rumors and are resistant to therapies usually used against GBMs (Yekula et al, 2020a). In this regard, a study by Ramakrishna et al, showed that mass exporting of miR-603 in MVs led to the treatment resistant phenotype.…”