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Characterization of plasma-derived protoporphyrin-IX-positive extracellular vesicles following 5-ALA use in patients with malignant glioma

BACKGROUND: Malignant gliomas are rapidly progressive brain tumors with high mortality. Fluorescence guided surgery (FGS) with 5-aminolevulinic acid (5-ALA) provides fluorescent delineation of malignant tissue, which helps achieve maximum safe resection. 5-ALA-based fluorescence is due to preferenti...

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Autores principales: Jones, Pamela S., Yekula, Anudeep, Lansbury, Elizabeth, Small, Julia L., Ayinon, Caroline, Mordecai, Scott, Hochberg, Fred H., Tigges, John, Delcuze, Bethany, Charest, Alain, Ghiran, Ionita, Balaj, Leonora, Carter, Bob S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6838454/
https://www.ncbi.nlm.nih.gov/pubmed/31628025
http://dx.doi.org/10.1016/j.ebiom.2019.09.025
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author Jones, Pamela S.
Yekula, Anudeep
Lansbury, Elizabeth
Small, Julia L.
Ayinon, Caroline
Mordecai, Scott
Hochberg, Fred H.
Tigges, John
Delcuze, Bethany
Charest, Alain
Ghiran, Ionita
Balaj, Leonora
Carter, Bob S.
author_facet Jones, Pamela S.
Yekula, Anudeep
Lansbury, Elizabeth
Small, Julia L.
Ayinon, Caroline
Mordecai, Scott
Hochberg, Fred H.
Tigges, John
Delcuze, Bethany
Charest, Alain
Ghiran, Ionita
Balaj, Leonora
Carter, Bob S.
author_sort Jones, Pamela S.
collection PubMed
description BACKGROUND: Malignant gliomas are rapidly progressive brain tumors with high mortality. Fluorescence guided surgery (FGS) with 5-aminolevulinic acid (5-ALA) provides fluorescent delineation of malignant tissue, which helps achieve maximum safe resection. 5-ALA-based fluorescence is due to preferential accumulation of the fluorophore protoporphyrin-IX (PpIX) in malignant glioma tissue. Additionally, gliomas cells release extracellular vesicles (EVs) which carry biomarkers of disease. Herein, we performed animal and human studies to investigate whether 5-ALA dosed glioma cells, in vitro and in vivo, release PpIX positive EVs in circulation which can be captured and analyzed. METHODS: We used imaging flow cytometry (IFC) to characterize PpIX-positive EVs released from 5-ALA-dosed glioma cells, glioma-bearing xenograft models, as well as patients with malignant glioma undergoing FGS. FINDINGS: We first show that glioma cells dosed with 5-ALA release 247-fold higher PpIX positive EVs compared to mock dosed glioma cells. Second, we demonstrate that the plasma of glioma-bearing mice (n = 2) dosed with 5-ALA contain significantly higher levels of circulating PpIX-positive EVs than their pre-dosing background (p = 0.004). Lastly, we also show that the plasma of patients with avidly fluorescent tumors (n = 4) undergoing FGS contain circulating PpIX-positive EVs at levels significantly higher than their pre-dosing background (p = 0.00009) and this rise in signal correlates with enhancing tumor volumes (r (2)  = 0.888). INTERPRETATION: Our findings highlight the potential of plasma-derived PpIX-positive EV-based diagnostics for malignant gliomas, offering a novel liquid biopsy platform for confirming and monitoring tumor status.
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spelling pubmed-68384542019-11-12 Characterization of plasma-derived protoporphyrin-IX-positive extracellular vesicles following 5-ALA use in patients with malignant glioma Jones, Pamela S. Yekula, Anudeep Lansbury, Elizabeth Small, Julia L. Ayinon, Caroline Mordecai, Scott Hochberg, Fred H. Tigges, John Delcuze, Bethany Charest, Alain Ghiran, Ionita Balaj, Leonora Carter, Bob S. EBioMedicine Research paper BACKGROUND: Malignant gliomas are rapidly progressive brain tumors with high mortality. Fluorescence guided surgery (FGS) with 5-aminolevulinic acid (5-ALA) provides fluorescent delineation of malignant tissue, which helps achieve maximum safe resection. 5-ALA-based fluorescence is due to preferential accumulation of the fluorophore protoporphyrin-IX (PpIX) in malignant glioma tissue. Additionally, gliomas cells release extracellular vesicles (EVs) which carry biomarkers of disease. Herein, we performed animal and human studies to investigate whether 5-ALA dosed glioma cells, in vitro and in vivo, release PpIX positive EVs in circulation which can be captured and analyzed. METHODS: We used imaging flow cytometry (IFC) to characterize PpIX-positive EVs released from 5-ALA-dosed glioma cells, glioma-bearing xenograft models, as well as patients with malignant glioma undergoing FGS. FINDINGS: We first show that glioma cells dosed with 5-ALA release 247-fold higher PpIX positive EVs compared to mock dosed glioma cells. Second, we demonstrate that the plasma of glioma-bearing mice (n = 2) dosed with 5-ALA contain significantly higher levels of circulating PpIX-positive EVs than their pre-dosing background (p = 0.004). Lastly, we also show that the plasma of patients with avidly fluorescent tumors (n = 4) undergoing FGS contain circulating PpIX-positive EVs at levels significantly higher than their pre-dosing background (p = 0.00009) and this rise in signal correlates with enhancing tumor volumes (r (2)  = 0.888). INTERPRETATION: Our findings highlight the potential of plasma-derived PpIX-positive EV-based diagnostics for malignant gliomas, offering a novel liquid biopsy platform for confirming and monitoring tumor status. Elsevier 2019-10-15 /pmc/articles/PMC6838454/ /pubmed/31628025 http://dx.doi.org/10.1016/j.ebiom.2019.09.025 Text en © 2019 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Research paper
Jones, Pamela S.
Yekula, Anudeep
Lansbury, Elizabeth
Small, Julia L.
Ayinon, Caroline
Mordecai, Scott
Hochberg, Fred H.
Tigges, John
Delcuze, Bethany
Charest, Alain
Ghiran, Ionita
Balaj, Leonora
Carter, Bob S.
Characterization of plasma-derived protoporphyrin-IX-positive extracellular vesicles following 5-ALA use in patients with malignant glioma
title Characterization of plasma-derived protoporphyrin-IX-positive extracellular vesicles following 5-ALA use in patients with malignant glioma
title_full Characterization of plasma-derived protoporphyrin-IX-positive extracellular vesicles following 5-ALA use in patients with malignant glioma
title_fullStr Characterization of plasma-derived protoporphyrin-IX-positive extracellular vesicles following 5-ALA use in patients with malignant glioma
title_full_unstemmed Characterization of plasma-derived protoporphyrin-IX-positive extracellular vesicles following 5-ALA use in patients with malignant glioma
title_short Characterization of plasma-derived protoporphyrin-IX-positive extracellular vesicles following 5-ALA use in patients with malignant glioma
title_sort characterization of plasma-derived protoporphyrin-ix-positive extracellular vesicles following 5-ala use in patients with malignant glioma
topic Research paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6838454/
https://www.ncbi.nlm.nih.gov/pubmed/31628025
http://dx.doi.org/10.1016/j.ebiom.2019.09.025
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