Clinical Significance of Extracellular Vesicles in Plasma from Glioblastoma Patients

Purpose: Glioblastoma (GBM) is the most common primary brain tumor. The identification of blood biomarkers reflecting the tumor status represents a major unmet need for optimal clinical management of GBM patients. Their high number in body fluids, their stability and the presence of many tumor-associated proteins and RNAs make extracellular vesicles (EVs) potentially optimal biomarkers. Here, we investigated the potential role of plasma EVs from GBM patients for diagnosis and follow-up after treatment and as a prognostic tool. Experimental Design: Plasma from healthy controls (n=33), GBM patients (n=43) and patients with different central nervous system malignancies (n=25) were collected. EVs were isolated by ultracentrifugation and characterized in terms of morphology by transmission electron microscopy, concentration and size by Nanoparticle Tracking Analysis, and protein composition by mass spectrometry. An orthotopic mouse model of human GBM confirmed human plasma EV quantifications. Associations between plasma EV concentration and clinicopathologic features of GBM patients were analyzed. All statistical tests were two-sided. Results: GBM releases heterogeneous EVs detectable in plasma. Plasma EV concentration was higher in GBM compared to healthy controls (P<.001), brain metastases (P<.001) and extra-axial brain tumors (P<.001). After surgery, a significant drop in plasma EV concentration was measured (P<.001). Plasma EV concentration was also increased in GBM-bearing mice (P<.001). Proteomic profiling revealed a GBM distinctive signature. Conclusions:Higher EV plasma levels may assist in GBM clinical diagnosis: their reduction after GBM resection, their rise at recurrence and their protein cargo might provide indications about tumor, therapy response, and monitoring.

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