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Global extracellular vesicle proteomic signature defines U87-MG glioma cell hypoxic status with potential implications for non-invasive diagnostics
Lund Univ, Div Oncol & Pathol, Dept Clin Sci, Lund, Sweden.
Lund Univ, Div Oncol & Pathol, Dept Clin Sci, Lund, Sweden.
Lund Univ, Div Oncol & Pathol, Dept Clin Sci, Lund, Sweden.
Lund Univ, Div Oncol & Pathol, Dept Clin Sci, Lund, Sweden.
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2019 (English)In: Journal of Neuro-Oncology, ISSN 0167-594X, E-ISSN 1573-7373, Vol. 144, no 3, p. 477-488Article in journal (Refereed) Published
Abstract [en]

Purpose Glioblastoma multiforme (GBM) is the most common and lethal of primary malignant brain tumors. Hypoxia constitutes a major determining factor for the poor prognosis of high-grade glioma patients, and is known to contribute to the development of treatment resistance. Therefore, new strategies to comprehensively profile and monitor the hypoxic status of gliomas are of high clinical relevance. Here, we have explored how the proteome of secreted extracellular vesicles (EVs) at the global level may reflect hypoxic glioma cells. Methods We have employed shotgun proteomics and label free quantification to profile EVs isolated from human high-grade glioma U87-MG cells cultured at normoxia or hypoxia. Parallel reaction monitoring was used to quantify the identified, hypoxia-associated EV proteins. To determine the potential biological significance of hypoxia-associated proteins, the cumulative Z score of identified EV proteins was compared with GBM subtypes from HGCC and TCGA databases. Results In total, 2928 proteins were identified in EVs, out of which 1654 proteins overlapped with the ExoCarta EV-specific database. We found 1034 proteins in EVs that were unique to the hypoxic status of U87-MG cells. We subsequently identified an EV protein signature, "HYPSIGNATURE", encompassing nine proteins that strongly represented the hypoxic situation and exhibited close proximity to the mesenchymal GBM subtype. Conclusions We propose, for the first time, an EV protein signature that could comprehensively reflect the hypoxic status of high-grade glioma cells. The presented data provide proof-of-concept for targeted proteomic profiling of glioma derived EVs, which should motivate future studies exploring its utility in non-invasive diagnosis and monitoring of brain tumor patients.

Place, publisher, year, edition, pages
SPRINGER , 2019. Vol. 144, no 3, p. 477-488
Keywords [en]
Glioblastoma, Hypoxia, Extracellular vesicles, Mass spectrometry, Label free quantification
National Category
Cancer and Oncology
Identifiers
URN: urn:nbn:se:uu:diva-395696DOI: 10.1007/s11060-019-03262-4ISI: 000487899900006PubMedID: 31414377OAI: oai:DiVA.org:uu-395696DiVA, id: diva2:1365113
Funder
Swedish Research CouncilSwedish Cancer SocietySwedish Childhood Cancer FoundationGunnar Nilsson Cancer FoundationAvailable from: 2019-10-23 Created: 2019-10-23 Last updated: 2019-10-23Bibliographically approved

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