Extracellular vesicles: The key for precision medicine in glioblastoma

Abstract

Glioblastoma (GBM) represents the most aggressive and lethal disease of the central nervous system. Diagnosis is delayed following the occurrence of symptoms, and treatment is based on standardized approaches that are unable to cope with its heterogeneity, mutability, and invasiveness. The follow-up of patients relies on burdensome schedules for magnetic resonance imaging (MRI). However, to personalize treatment, biomarkers and liquid biopsy still represent unmet clinical needs. Extracellular vesicles (EVs) may be the key to revolutionize the entire process of care for patients with GBM. EVs can be collected noninvasively (eg, blood) and impressively possess multilayered information, which is constituted by their concentration and molecular cargo. EV-based liquid biopsy may facilitate GBM diagnosis and enable the implementation of personalized treatment, resulting in customized care for each patient and for each analyzed time point of the disease, thereby tackling the distinctive heterogeneity and mutability of GBM that confounds effective treatment. Herein, we discuss the limitations of current GBM treatment options and the rationale behind the need for personalized care. We also review the evidence supporting GBM-associated EVs as a promising tool capable of fulfilling the still unmet clinical need for effective and timely personalized care of patients with GBM.

Keywords: biomarker; extracellular vesicles; glioblastoma; liquid biopsy.

Fig. 1

GBM-derived EVs: (A) Transmission electron micrograph of GBM tissue (green) releasing vesicles in the extracellular space. EXOs are shown by white arrows, whereas MVs and LOs are shown by black arrows (magnification × 25 000). (B) Transmission electron micrograph of GBM tissue containing MVBs (black arrows) with several EXOs inside (magnification × 14 500). (C) Transmission electron micrograph of EVs isolated from the plasma of a patient with GBM after immunogold labeling. The different EV subpopulations, EXOs (gray arrows) and MVs and LOs (black arrows) are classified by morphological features, similarly to that identified in GBM tissue and are stained with a mouse anti-CD9 primary antibody (1:10, BD Pharmingen), followed by a rabbit antimouse IgG bridge antibody (1:250, Dako) and protein A gold 10 nm (PAG10, 1:50).

Fig. 2

EVs: the key for precision medicine in GBM. (A) GBM-associated EVs (EXOs in purple, MVs in blue, and LOs in yellow) can be isolated from peripheral blood and used as a platform for liquid biopsy. EVs possess multilayered information constituted by their concentration and molecular cargo, spanning DNA and RNA to proteins and lipids. (B) The concentration and cargo of EVs indicate GBM presence allowing diagnosis, monitoring of tumor response to therapy, and identifying relapse. (C) An EV-based liquid biopsy approach may enable the characterization of the whole-GBM molecular set-up. Tumor characterization at baseline would allow treatment personalization (left panel), and serially, during treatment, it would allow treatment tailoring, thus maximizing its efficacy and tackling GBM molecular dynamicity (right panel).