title: Glioma-derived plasminogen activator inhibitor-1 (PAI-1) regulates the recruitment of LRP1 positive mast cells.
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.
authors.affiliation: Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Ananya
authors.initials: A
authors.lastname: Roy
authors.affiliation: Department of Engineering, Nanoscience Centre, Cambridge University, Cambridge, UK.
authors.forename: Antoine
authors.initials: A
authors.lastname: Coum
authors.affiliation: Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.|Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Voichita D
authors.initials: VD
authors.lastname: Marinescu
authors.affiliation: Cancer Research Technology, LBIC, London, UK.
authors.forename: Jelena
authors.initials: J
authors.lastname: Põlajeva
authors.affiliation: Department of Neuroscience, Neurology, Uppsala University, Uppsala, Sweden.|Present address: Danish Epilepsy Center, Dianalund, Denmark.
authors.forename: Anja
authors.initials: A
authors.lastname: Smits
authors.affiliation: Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.|Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Sven
authors.initials: S
authors.lastname: Nelander
authors.affiliation: Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Lene
authors.initials: L
authors.lastname: Uhrbom
authors.affiliation: Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Bengt
authors.initials: B
authors.lastname: Westermark
authors.affiliation: Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.|Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Karin
authors.initials: K
authors.lastname: Forsberg-Nilsson
authors.affiliation: Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.|Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Fredrik
authors.initials: F
authors.lastname: Pontén
authors.affiliation: Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Elena
authors.initials: E
authors.lastname: Tchougounova
mesh_terms: D001932:Brain Neoplasms / Q000401:mortality / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation; D005909:Glioblastoma / Q000401:mortality / Q000473:pathology*; D006801:Humans; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008407:Mast Cells / Q000378:metabolism*; D009361:Neoplasm Invasiveness / Q000473:pathology*; D010766:Phosphorylation / Q000235:genetics; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D059016:Tumor Microenvironment / Q000502:physiology
chemical_list: C475476:LRP1 protein, human; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D017395:Plasminogen Activator Inhibitor 1; C051321:SERPINE1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human
keywords: LRP1; PAI-1; SERPINE1; glioma; mast cell