Biological, diagnostic and therapeutic implications of exosomes in glioma

Abstract

Despite therapeutic advances, overall survival in glioblastoma is dismal. To optimize progress, a more detailed understanding of glioma's molecular, cellular, and intercellular pathophysiology is needed. Recent investigation has revealed a vital role for exosomes in inter-cellular signaling, tumor cell support, and regulation of the tumor microenvironment. Exosomes carry miRNAs, lncRNAs, mRNAs, proteins, immune regulatory molecules, nucleic acids, and lipids; however, the composition of exosome cargo is variable depending on the cell of origin. Specific exosomal miRNA contents such as miR-21, miR-301a, miR-151a, miR-148a, and miR-5096 are altered in high-grade glioma. Unique proteomic, genomic, and miRNA signatures of tumor exosomes have been associated with disease pathobiology, temozolomide resistance, immunosuppression, and tumor proliferation. Exosomes hold promise for tissue diagnostic glioma diagnosis and monitoring response to therapy. This review summarizes the current understanding of exosomes, their crucial role in glioma pathology, and future directions for their use in diagnosis and treatment. METHODS: The MEDLINE/PubMed database was reviewed for papers written in English and publication dates of 1981-2023, using the search string "Exosome", "Extracellular vesicles", "Glioma", "Exosomes in glioma".

Figure 1:

a).Schematic representation of exosome biogenesis and their general composition. The scheme depicts exosome synthesis beginning with invagination of the plasma membrane, which forms new small vesicles called early endosomes. They are then transferred to late endosomal compartments, termed multivesicular bodies (MVB) once intraluminal vesicles (ILVs) are formed. MVBs fuse with the plasma membrane and release the intraluminal vesicles, now called exosomes. b). An example of exosome structure is shown with common membrane proteins CD9, CD63, CD81, CD81, Integrins, GTPase, and Annexin. Common cargo includes mRNA, miRNA, lncRNA, proteins, DNA, lipids, HSP70, HSP90, ALIX, and TSG101. mRNA, messenger RNA; miRNA, microRNA; lncRNA, long noncoding RNA; HSP70, Heat Shock Protein 70 (HSP70); HSP90 Heat Shock Protein 90; ALIX, Apoptosis Linked Gene 2-Interacting Protein; TSG101, Tumor Susceptibility Gene 101.

Figure 2:

Exosome-mediated cellular crosstalk between tumor cells, astrocytes, and immune cells in the glioma tumor microenvironment drives immunosuppression. Glioma-derived exosomes contain miR-29a and miR-92a, which promote the differentiation of MDSCs and enrich TME in immunosuppressive factors. Astrocytes release multiple signaling factors, which promote an anti-inflammatory environment and inhibit T-cell activity. TME, tumor microenvironment; MDSCs, myeloid-derive suppressor cells.

Figure 3:

Exosomes serve as a biomarker and drug carrier. a) Utility of glioma-derived exosomes in serum-based liquid biopsy for detecting tumor recurrence, decreased KPS, and elevated tumor grade. b) Example of exosome utility as drug delivery vehicles for glioma therapy in a murine model. Delivery of exosomal curcumin and JS1124 (a signal transducer and activator of stat3 inhibitor) to the rodent brain via intranasal injection. KPS, Karnofsky Performance Score.