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

García-Romero, Noemí, Carrión-Navarro, Josefa, Esteban-Rubio, Susana, Lázaro-Ibáñez, Elisa, Peris-Celda, María, Alonso, Marta M., Guzmán-De-Villoria, Juan, Fernández-Carballal, Carlos, de Mendivil, Ana Ortiz, García-Duque, Sara, Escobedo-Lucea, Carmen, Prat-Acín, Ricardo, Belda-Iniesta, Cristóbal, Ayuso-Sacido, Angel·2017·Oncotarget
DOI 10.18632/oncotarget.13635PMC PMC5352065
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Figure 1 Experimental procedure flowchart A. Isolated hCSCs from 2 GBM patients were xenotransplanted in athymic mice. After 12 weeks, the animals were transcardially perfused. B. BBB permeability was evaluated using three assays: MRI, Evans Blue staining, and albumin extravasation. C. EVs (ABs, SMVs, and EXOs) were isolated from hCSCs-enriched culture supernatants and from mouse peripheral blood. D. EVs were identified using TEM, tracking analysis, and CD63 tetraspanin quantification. E. To ensure that the analyzed DNA was confined within the EVs, supernatants and plasma were treated with DNase before gDNA isolation; after the isolation, gDNA was pre-amplified before performing PCR analysis with human-specific primers. F. Sequences detected were sequenced to confirm their human origin.
Figure 1 Experimental procedure flowchart A. Isolated hCSCs from 2 GBM patients were xenotransplanted in athymic mice. After 12 weeks, the animals were transcardially perfused. B. BBB permeability was evaluated using three assays: MRI, Evans Blue staining, and albumin extravasation. C. EVs (ABs, SMVs, and EXOs) were isolated from hCSCs-enriched culture supernatants and from mouse peripheral blood. D. EVs were identified using TEM, tracking analysis, and CD63 tetraspanin quantification. E. To ensure that the analyzed DNA was confined within the EVs, supernatants and plasma were treated with DNase before gDNA isolation; after the isolation, gDNA was pre-amplified before performing PCR analysis with human-specific primers. F. Sequences detected were sequenced to confirm their human origin.CC BY · PubMed Central
Figure 2 Evaluation of BBB leakage in two GBM models: GBM27 presents an intact BBB A. Representative T2- and T1-weighted images of GBM27 and GBM38. The GBM27 tumor xenotransplant T2-weighted image depicts diffuse hyperintense infiltrative involvement. GBM38 xenograft tumor showed well-defined borders. T2-weighted images revealed a hyperintense mass compressing ventricular structures. GBM27 features an intact BBB, as revealed by the lack of any contrast enhancement. GBM38 shows a homogeneous enhancement, suggesting that the BBB integrity is compromised. B. Evans Blue extravasation. Examination of the brains of perfused animals previously stained with Evans Blue confirmed BBB disruption in the GBM38 model. C. Quantification of Evans Blue extravasation. *P <0.05. D-E. Immunofluorescence staining of human vimentin (yellow), mouse CD105 (green), and mouse albumin (red). Nuclei were stained with DAPI (blue). GBM27 presents no sign of albumin staining throughout the tissue, which indicates that the BBB is intact. GBM38 features a leaky BBB, as shown by albumin spreading (white asterisk) from the blood vessels (white arrows) through the tissue. Total slides with anti-human vimentin are shown in Fig S1. Scale bar: 50 μm.
Figure 2 Evaluation of BBB leakage in two GBM models: GBM27 presents an intact BBB A. Representative T2- and T1-weighted images of GBM27 and GBM38. The GBM27 tumor xenotransplant T2-weighted image depicts diffuse hyperintense infiltrative involvement. GBM38 xenograft tumor showed well-defined borders. T2-weighted images revealed a hyperintense mass compressing ventricular structures. GBM27 features an intact BBB, as revealed by the lack of any contrast enhancement. GBM38 shows a homogeneous enhancement, suggesting that the BBB integrity is compromised. B. Evans Blue extravasation. Examination of the brains of perfused animals previously stained with Evans Blue confirmed BBB disruption in the GBM38 model. C. Quantification of Evans Blue extravasation. *P <0.05. D-E. Immunofluorescence staining of human vimentin (yellow), mouse CD105 (green), and mouse albumin (red). Nuclei were stained with DAPI (blue). GBM27 presents no sign of albumin staining throughout the tissue, which indicates that the BBB is intact. GBM38 features a leaky BBB, as shown by albumin spreading (white asterisk) from the blood vessels (white arrows) through the tissue. Total slides with anti-human vimentin are shown in Fig S1. Scale bar: 50 μm.CC BY · PubMed Central
Figure 3 Morphological characterisation of EVs isolated from hCSCs supernatant from GBM27 and gDNA isolation A. Transmission electron microscopy images. ABs (500 nm to 1 μm), SMVs (500–150 nm) and EXOs (150–60 nm). B. Size distribution of EVs, as measured using Nanosizer tracking analysis. C. Quantification of the tetraspanin cell-surface glycoprotein CD63. D. Relative distribution of EVs. E. Most representative sequences analyzed are present in EVs isolated from GBM27 cells. F. Histogram showing the frequency of occurrence of target sequences after 6 consecutive experiments. G. Presence of ERBB2, CDK4, AKT3, and MDM2 sequences in all types of EVs. The remaining sequences were found randomly in ABs, SMVs, and EXOs. No sequences were detected in the supernatant. Scale bars: 1 μm (ABs), 0.2 μm (SMVs and EXOs).
Figure 3 Morphological characterisation of EVs isolated from hCSCs supernatant from GBM27 and gDNA isolation A. Transmission electron microscopy images. ABs (500 nm to 1 μm), SMVs (500–150 nm) and EXOs (150–60 nm). B. Size distribution of EVs, as measured using Nanosizer tracking analysis. C. Quantification of the tetraspanin cell-surface glycoprotein CD63. D. Relative distribution of EVs. E. Most representative sequences analyzed are present in EVs isolated from GBM27 cells. F. Histogram showing the frequency of occurrence of target sequences after 6 consecutive experiments. G. Presence of ERBB2, CDK4, AKT3, and MDM2 sequences in all types of EVs. The remaining sequences were found randomly in ABs, SMVs, and EXOs. No sequences were detected in the supernatant. Scale bars: 1 μm (ABs), 0.2 μm (SMVs and EXOs).CC BY · PubMed Central
Figure 4 Human gDNA sequences are confined inside EVs isolated from xenografted mice AKT3, MDM4, PIK3CA, and EGFR sequences were detected in EVs isolated from the peripheral blood of 10 xenografted mice. The multiple sequence alignment shows complete homology among gDNA sequences from GBM27 hCSCs, EVs isolated from hCSCs-enriched culture supernatants, and EVs found in mouse peripheral blood. These results confirm the human origin of the sequences. Keyword: GBM1= GBM27.
Figure 4 Human gDNA sequences are confined inside EVs isolated from xenografted mice AKT3, MDM4, PIK3CA, and EGFR sequences were detected in EVs isolated from the peripheral blood of 10 xenografted mice. The multiple sequence alignment shows complete homology among gDNA sequences from GBM27 hCSCs, EVs isolated from hCSCs-enriched culture supernatants, and EVs found in mouse peripheral blood. These results confirm the human origin of the sequences. Keyword: GBM1= GBM27.CC BY · PubMed Central

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Metadata

Authors
García-Romero, N., Carrión-Navarro, J., Esteban-Rubio, S., Lázaro-Ibáñez, E., Peris-Celda, M., Alonso, M. M., Guzmán-De-Villoria, J., Fernández-Carballal, C., de Mendivil, A. O., García-Duque, S., Escobedo-Lucea, C., Prat-Acín, R., Belda-Iniesta, C., & Ayuso-Sacido, A.
Affiliations
  • Fundación de Investigación HM Hospitales, HM Hospitales, Madrid, Spain
  • Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland
  • Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
  • Clínica Universidad de Navarra, CIMA, Pamplona, Spain
  • Servicio de Radiodiagnóstico, Hospital General Universitario Gregorio Marañón, Madrid, Spain
  • Servicio de Neurocirugía, Hospital General Universitario Gregorio Marañón, Madrid, Spain
  • Departamento de Neurocirugía, Hospital Universitario la Fe, Valencia, Spain
Venue
Oncotarget
Publisher
Impact Journals, LLC
Published
2016-11-26
Volume
8
Issue
1
Pages
1416-1428
ISSN
1949-2553
DOI
10.18632/oncotarget.13635
PMC
PMC5352065
Cited by
230
References
2
Language
en

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CoChat. (2026). Citation check: DNA sequences within glioma-derived extracellular vesicles can cross the intact blood-brain barrier and be detected in peripheral blood of patients. https://app.cochat.ai/papers/10.18632/oncotarget.13635
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García-Romero, N., Carrión-Navarro, J., Esteban-Rubio, S., Lázaro-Ibáñez, E., Peris-Celda, M., Alonso, M. M., Guzmán-De-Villoria, J., Fernández-Carballal, C., de Mendivil, A. O., García-Duque, S., Escobedo-Lucea, C., Prat-Acín, R., Belda-Iniesta, C., & Ayuso-Sacido, A. (2017). DNA sequences within glioma-derived extracellular vesicles can cross the intact blood-brain barrier and be detected in peripheral blood of patients. Oncotarget. https://doi.org/10.18632/oncotarget.13635