DNA sequences within glioma-derived extracellular vesicles can cross the intact blood-brain barrier and be detected in peripheral blood of patients

Abstract

// Noemí García-Romero 1, 2, * , Josefa Carrión-Navarro 1, 3, * , Susana Esteban-Rubio 1, 3, * , Elisa Lázaro-Ibáñez 4 , María Peris-Celda 5 , Marta M. Alonso 6 , Juan Guzmán-De-Villoria 7 , Carlos Fernández-Carballal 8 , Ana Ortiz de Mendivil 1 , Sara García-Duque 1 , Carmen Escobedo-Lucea 4 , Ricardo Prat-Acín 9 , Cristóbal Belda-Iniesta 1, 3 , Angel Ayuso-Sacido 1, 2, 3 1 Fundación de Investigación HM Hospitales, HM Hospitales, Madrid, Spain 2 IMDEA Nanoscience, Madrid, Spain 3 Facultad de Medicina (IMMA), Universidad San Pablo-CEU, Madrid, Spain 4 Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland 5 Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA 6 Clínica Universidad de Navarra, CIMA, Pamplona, Spain 7 Servicio de Radiodiagnóstico, Hospital General Universitario Gregorio Marañón, Madrid, Spain 8 Servicio de Neurocirugía, Hospital General Universitario Gregorio Marañón, Madrid, Spain 9 Departamento de Neurocirugía, Hospital Universitario la Fe, Valencia, Spain * These authors have contributed equally to this work Correspondence to: Angel Ayuso-Sacido, email: ayusosacido@gmail.com Keywords: extracellular vesicles, brain tumors, blood-brain barrier, biomarkers Received: September 20, 2016     Accepted: November 07, 2016     Published: November 26, 2016 ABSTRACT Tumor-cell-secreted extracellular vesicles (EVs) can cross the disrupted blood-brain barrier (BBB) into the bloodstream. However, in certain gliomas, the BBB remains intact, which might limit EVs release. To evaluate the ability of tumor-derived EVs to cross the BBB, we used an orthotopic xenotransplant mouse model of human glioma-cancer stem cells featuring an intact BBB. We demonstrated that all types of tumor cells-derived EVs−apoptotic bodies, shedding microvesicles and exosomes−cross the intact BBB and can be detected in the peripheral blood, which provides a minimally invasive method for their detection compared to liquid biopsies obtained from cerebrospinal fluid (CSF). Furthermore, these EVs can be readily distinguished from total murine EVs, since they carry human-specific DNA sequences relevant for GBM biology. In a small cohort of glioma patients, we finally demonstrated that peripheral blood EVs cargo can be successfully used to detect the presence of IDH1 G395A , an essential biomarker in the current management of human glioma