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Oncotarget. 2015 Sep 15;6(27):23647-61.

Glioma-derived plasminogen activator inhibitor-1 (PAI-1) regulates the recruitment of LRP1 positive mast cells.

Author information

1
Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
2
Department of Engineering, Nanoscience Centre, Cambridge University, Cambridge, UK.
3
Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
4
Cancer Research Technology, LBIC, London, UK.
5
Department of Neuroscience, Neurology, Uppsala University, Uppsala, Sweden.
6
Present address: Danish Epilepsy Center, Dianalund, Denmark.

Abstract

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.

KEYWORDS:

LRP1; PAI-1; SERPINE1; glioma; mast cell

PMID:
26164207
PMCID:
PMC4695142
DOI:
10.18632/oncotarget.4640
[Indexed for MEDLINE]
Free PMC Article

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