Tumor-derived extracellular vesicles disrupt the blood–brain barrier endothelium following high-frequency irreversible electroporation
Abstract High-frequency irreversible electroporation (H-FIRE), a nonthermal brain tumor ablation therapeutic, generates a central tumor ablation zone while transiently disrupting the peritumoral blood–brain barrier (BBB). We hypothesized that bystander effects of H-FIRE tumor cell ablation, mediated...
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Nature Portfolio
2024-11-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-024-79019-5 |
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| author | Kelsey R. Murphy Kenneth N. Aycock Spencer Marsh Alayna N. Hay Ilektra Athanasiadi Shay Bracha Christine Chang Robert Gourdie Rafael V. Davalos John H. Rossmeisl Nikolaos G. Dervisis |
| author_facet | Kelsey R. Murphy Kenneth N. Aycock Spencer Marsh Alayna N. Hay Ilektra Athanasiadi Shay Bracha Christine Chang Robert Gourdie Rafael V. Davalos John H. Rossmeisl Nikolaos G. Dervisis |
| author_sort | Kelsey R. Murphy |
| collection | DOAJ |
| description | Abstract High-frequency irreversible electroporation (H-FIRE), a nonthermal brain tumor ablation therapeutic, generates a central tumor ablation zone while transiently disrupting the peritumoral blood–brain barrier (BBB). We hypothesized that bystander effects of H-FIRE tumor cell ablation, mediated by small tumor-derived extracellular vesicles (sTDEV), disrupt the BBB endothelium. Monolayers of bEnd.3 cerebral endothelial cells were exposed to supernatants of H-FIRE or radiation (RT)-treated LL/2 and F98 cancer cells. Endothelial cell response was evaluated microscopically and via flow cytometry for apoptosis. sTDEV were isolated following H-FIRE and RT, characterized via nanoparticle tracking analysis (NTA) and transmission electron microscopy, and applied to a Transwell BBB endothelium model to quantify permeability changes. Supernatants of H-FIRE-treated tumor cells, but not supernatants of sham- or RT-treated cells, disrupted endothelial cell monolayer integrity while maintaining viability. sTDEV released by glioma cells treated with 3000 V/cm H-FIRE increased permeability of the BBB endothelium model compared to sTDEV released after lower H-FIRE doses and RT. NTA revealed significantly decreased sTDEV release after the 3000 V/cm H-FIRE dose. Our results demonstrate that sTDEV increase permeability of the BBB endothelium after H-FIRE ablation in vitro. sTDEV-mediated mechanisms of BBB disruption may be exploited for drug delivery to infiltrative margins following H-FIRE ablation. |
| format | Article |
| id | doaj-art-1c33b80635644a4d85d9b9bb588d4bf2 |
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| language | English |
| publishDate | 2024-11-01 |
| publisher | Nature Portfolio |
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| series | Scientific Reports |
| spelling | doaj-art-1c33b80635644a4d85d9b9bb588d4bf22025-08-20T02:22:30ZengNature PortfolioScientific Reports2045-23222024-11-0114111210.1038/s41598-024-79019-5Tumor-derived extracellular vesicles disrupt the blood–brain barrier endothelium following high-frequency irreversible electroporationKelsey R. Murphy0Kenneth N. Aycock1Spencer Marsh2Alayna N. Hay3Ilektra Athanasiadi4Shay Bracha5Christine Chang6Robert Gourdie7Rafael V. Davalos8John H. Rossmeisl9Nikolaos G. Dervisis10Department of Biomedical and Veterinary Sciences, Virginia-Maryland College of Veterinary MedicineDepartment of Biomedical Engineering and Mechanics, Virginia TechFralin Biomedical Research Institute at Virginia Tech Carilion School of Medicine, Virginia TechDepartment of Small Animal Clinical Sciences, Virginia-Maryland College of Veterinary MedicineDepartment of Small Animal Clinical Sciences, Virginia-Maryland College of Veterinary MedicineDepartment of Veterinary Clinical Sciences, College of Veterinary Medicine, The Ohio State UniversityDepartment of Veterinary Small Animal Clinical Sciences, College of Veterinary Medicine, Texas A&M UniversityDepartment of Biomedical Engineering and Mechanics, Virginia TechDepartment of Biomedical Engineering and Mechanics, Virginia TechDepartment of Small Animal Clinical Sciences, Virginia-Maryland College of Veterinary MedicineDepartment of Small Animal Clinical Sciences, Virginia-Maryland College of Veterinary MedicineAbstract High-frequency irreversible electroporation (H-FIRE), a nonthermal brain tumor ablation therapeutic, generates a central tumor ablation zone while transiently disrupting the peritumoral blood–brain barrier (BBB). We hypothesized that bystander effects of H-FIRE tumor cell ablation, mediated by small tumor-derived extracellular vesicles (sTDEV), disrupt the BBB endothelium. Monolayers of bEnd.3 cerebral endothelial cells were exposed to supernatants of H-FIRE or radiation (RT)-treated LL/2 and F98 cancer cells. Endothelial cell response was evaluated microscopically and via flow cytometry for apoptosis. sTDEV were isolated following H-FIRE and RT, characterized via nanoparticle tracking analysis (NTA) and transmission electron microscopy, and applied to a Transwell BBB endothelium model to quantify permeability changes. Supernatants of H-FIRE-treated tumor cells, but not supernatants of sham- or RT-treated cells, disrupted endothelial cell monolayer integrity while maintaining viability. sTDEV released by glioma cells treated with 3000 V/cm H-FIRE increased permeability of the BBB endothelium model compared to sTDEV released after lower H-FIRE doses and RT. NTA revealed significantly decreased sTDEV release after the 3000 V/cm H-FIRE dose. Our results demonstrate that sTDEV increase permeability of the BBB endothelium after H-FIRE ablation in vitro. sTDEV-mediated mechanisms of BBB disruption may be exploited for drug delivery to infiltrative margins following H-FIRE ablation.https://doi.org/10.1038/s41598-024-79019-5 |
| spellingShingle | Kelsey R. Murphy Kenneth N. Aycock Spencer Marsh Alayna N. Hay Ilektra Athanasiadi Shay Bracha Christine Chang Robert Gourdie Rafael V. Davalos John H. Rossmeisl Nikolaos G. Dervisis Tumor-derived extracellular vesicles disrupt the blood–brain barrier endothelium following high-frequency irreversible electroporation Scientific Reports |
| title | Tumor-derived extracellular vesicles disrupt the blood–brain barrier endothelium following high-frequency irreversible electroporation |
| title_full | Tumor-derived extracellular vesicles disrupt the blood–brain barrier endothelium following high-frequency irreversible electroporation |
| title_fullStr | Tumor-derived extracellular vesicles disrupt the blood–brain barrier endothelium following high-frequency irreversible electroporation |
| title_full_unstemmed | Tumor-derived extracellular vesicles disrupt the blood–brain barrier endothelium following high-frequency irreversible electroporation |
| title_short | Tumor-derived extracellular vesicles disrupt the blood–brain barrier endothelium following high-frequency irreversible electroporation |
| title_sort | tumor derived extracellular vesicles disrupt the blood brain barrier endothelium following high frequency irreversible electroporation |
| url | https://doi.org/10.1038/s41598-024-79019-5 |
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