Oncotarget

Research Papers:

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

Ananya Roy, Antoine Coum, Voichita D. Marinescu, Jelena Põlajeva, Anja Smits, Sven Nelander, Lene Uhrbom, Bengt Westermark, Karin Forsberg-Nilsson, Fredrik Pontén and Elena Tchougounova _

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Oncotarget. 2015; 6:23647-23661. https://doi.org/10.18632/oncotarget.4640

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Abstract

Ananya Roy1,*, Antoine Coum2,*, Voichita D. Marinescu3, Jelena Põlajeva4, Anja Smits5,6, Sven Nelander3, Lene Uhrbom1, Bengt Westermark1, Karin Forsberg-Nilsson3, Fredrik Pontén3 and Elena Tchougounova1

1 Uppsala University, Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala, Sweden

2 Nanoscience Centre, Department of Engineering, Cambridge University, Cambridge, UK

3 Uppsala University, Department of Immunology, Genetics and Pathology, and Science for Life Laboratory, Rudbeck Laboratory, Uppsala, Sweden

4 Cancer Research Technology, LBIC, London, UK

5 Uppsala University, Department of Neuroscience, Neurology, Uppsala, Sweden

6 Present address: Danish Epilepsy Center, Dianalund, Denmark

* These authors have contributed equally to this work

Correspondence to:

Elena Tchougounova, email:

Keywords: mast cell, glioma, PAI-1, SERPINE1, LRP1

Received: April 28, 2015 Accepted: June 12, 2015 Published: June 25, 2015

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.


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