The Multifaceted Role of Extracellular Vesicles in Glioblastoma: microRNA Nanocarriers for Disease Progression and Gene Therapy

Abstract

Glioblastoma (GB) is the most aggressive form of brain cancer in adults, characterized by poor survival rates and lack of effective therapies. MicroRNAs (miRNAs) are small, non-coding RNAs that regulate gene expression post-transcriptionally through specific pairing with target messenger RNAs (mRNAs). Extracellular vesicles (EVs), a heterogeneous group of cell-derived vesicles, transport miRNAs, mRNAs and intracellular proteins, and have been shown to promote horizontal malignancy into adjacent tissue, as well as resistance to conventional therapies. Furthermore, GB-derived EVs have distinct miRNA contents and are able to penetrate the blood–brain barrier. Numerous studies have attempted to identify EV-associated miRNA biomarkers in serum/plasma and cerebrospinal fluid, but their collective findings fail to identify reliable biomarkers that can be applied in clinical settings. However, EVs carrying specific miRNAs or miRNA inhibitors have great potential as therapeutic nanotools in GB, and several studies have investigated this possibility on in vitro and in vivo models. In this review, we discuss the role of EVs and their miRNA content in GB progression and resistance to therapy, with emphasis on their potential as diagnostic, prognostic and disease monitoring biomarkers and as nanocarriers for gene therapy.

MicroRNA Interrelated Epithelial Mesenchymal Transition (EMT) in Glioblastoma

“…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 ].…”

Therapeutic Potential of Stem Cell-Derived Extracellular Vesicles on Atherosclerosis-Induced Vascular Dysfunction and Its Key Molecular Players

“…Many studies have shown that when endothelial cells are activated, they secrete a number of nanovesicles that would help initiate and aggravate the atherogenic process. The term nanovesicles, also known as extracellular vesicles (EVs), bring together two separate classes of small particles of the order of nm called exosomes (40–100 nm) and microparticles (MPs) or microvesicles (MVs) (100–1,500 nm) that are released by cells physiologically, and in pathological conditions this release is amplified ( Alexandru et al, 2021 ; Simionescu, Zonda, Petrovici, & Georgescu, 2021 ). These vesicles are rich in lipids, proteins, and microRNAs (miRNAs) and have the ability to regulate posttranscriptional gene expression in target cells ( Constantin, Filippi, Alexandru, Nemecz, & Georgescu, 2020 ).…”

Microvesicles and Microvesicle-Associated microRNAs Reflect Glioblastoma Regression: Microvesicle-Associated miR-625-5p Has Biomarker Potential

“…EVs exhibited diagnostic potential in different pathologies [ 24 , 25 ], as well as biomarker potential in the context of treatment response and disease recurrence [ 26 , 27 , 28 , 29 , 30 , 31 ]. Additionally, EVs contain distinctive miRNA signatures [ 14 ], which change under pathological conditions [ 24 , 32 , 33 ] and could be applied in clinical settings as biomarkers for prognosis and therapeutic response monitoring. A particular type of EV is represented by microvesicles (MVs), which are phosphatidylserine (PS)-positive EVs (100–1000 nm) with variable shapes generated by blebbing of the plasma membrane of activated cells [ 11 , 33 ].…”

“…Additionally, EVs contain distinctive miRNA signatures [ 14 ], which change under pathological conditions [ 24 , 32 , 33 ] and could be applied in clinical settings as biomarkers for prognosis and therapeutic response monitoring. A particular type of EV is represented by microvesicles (MVs), which are phosphatidylserine (PS)-positive EVs (100–1000 nm) with variable shapes generated by blebbing of the plasma membrane of activated cells [ 11 , 33 ]. MVs transport miRNAs, exhibit markers from their cells of origin, such as EGFR, its mutant variant (EGFRvIII) or epithelial cell adhesion molecule (EpCAM) [ 12 , 34 ], and have been shown to have diagnostic and therapeutic potential in various pathologies, including GB [ 24 , 33 , 35 ].…”