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Glioma-derived plasminogen activator inhibitor-1 (PAI-1) regulates the recruitment of LRP1 positive mast cells
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
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2015 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 6, no 27, 23647-23661 p.Article in journal (Refereed) Published
Abstract [en]

Glioblastoma (GBM) is a high-grade glioma with a complex microenvironment, including various inflammatory cells and mast cells (MCs) as one of them. Previously we had identified glioma grade-dependent MC recruitment. In the present study we investigated the role of plasminogen activator inhibitor 1 (PAI-1) in MC recruitment.PAI-1, a primary regulator in the fibrinolytic cascade is capable of forming a complex with fibrinolytic system proteins together with low-density lipoprotein receptor-related protein 1 (LRP1). We found that neutralizing PAI-1 attenuated infiltration of MCs. To address the potential implication of LRP1 in this process, we used a LRP1 antagonist, receptor-associated protein (RAP), and demonstrated the attenuation of MC migration. Moreover, a positive correlation between the number of MCs and the level of PAI-1 in a large cohort of human glioma samples was observed. Our study demonstrated the expression of LRP1 in human MC line LAD2 and in MCs in human high-grade glioma. The activation of potential PAI-1/LRP1 axis with purified PAI-1 promoted increased phosphorylation of STAT3 and subsequently exocytosis in MCs.These findings indicate the influence of the PAI-1/LRP1 axis on the recruitment of MCs in glioma. The connection between high-grade glioma and MC infiltration could contribute to patient tailored therapy and improve patient stratification in future therapeutic trials.

Place, publisher, year, edition, pages
2015. Vol. 6, no 27, 23647-23661 p.
Keyword [en]
mast cell; glioma; PAI-1; SERPINE1; LRP1
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-258724DOI: 10.18632/oncotarget.4640ISI: 000363157700045PubMedID: 26164207OAI: oai:DiVA.org:uu-258724DiVA: diva2:842327
Swedish Research CouncilSwedish Cancer SocietyÅke Wiberg FoundationKnut and Alice Wallenberg Foundation

De två första författarna delar förstaförfattarskapet.

Available from: 2015-07-19 Created: 2015-07-19 Last updated: 2015-11-24Bibliographically approved

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Roy, AnanyaMarinescu, Voichita DSmits, AnjaNelander, SvenUhrbom, LeneWestermark, BengtForsberg-Nilsson, KarinPontén, Fredrik
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Neuro-OncologyDepartment of Medical Biochemistry and MicrobiologyScience for Life Laboratory, SciLifeLabNeurologyDepartment of Immunology, Genetics and Pathology
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