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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, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
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2015 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 6, no 27, p. 23647-23661Article 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, p. 23647-23661
Keyword [en]
mast cell, glioma, PAI-1, SERPINE1, LRP1
National Category
Cancer and Oncology
Identifiers
URN: urn:nbn:se:uu:diva-258724DOI: 10.18632/oncotarget.4640ISI: 000363157700045PubMedID: 26164207OAI: oai:DiVA.org:uu-258724DiVA: diva2:842327
Funder
Swedish Research CouncilSwedish Cancer SocietyÅke Wiberg FoundationKnut and Alice Wallenberg Foundation
Note

De två första författarna delar förstaförfattarskapet.

Available from: 2015-07-19 Created: 2015-07-19 Last updated: 2017-12-04Bibliographically approved

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Roy, AnanyaMarinescu, Voichita DSmits, AnjaNelander, SvenUhrbom, LeneWestermark, BengtForsberg-Nilsson, KarinPontén, FredrikTchougounova, Elena
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