Roy Ananya, Coum Antoine, Marinescu Voichita D, Põlajeva Jelena, Smits Anja, Nelander Sven, Uhrbom Lene, Westermark Bengt, Forsberg-Nilsson Karin, Pontén Fredrik, Tchougounova Elena
Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
Department of Engineering, Nanoscience Centre, Cambridge University, Cambridge, UK.
Oncotarget. 2015 Sep 15;6(27):23647-61. doi: 10.18632/oncotarget.4640.
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.
胶质母细胞瘤（GBM）是一种高级别胶质瘤，其具有复杂的微环境，包括各种炎症细胞，肥大细胞（MCs）是其中之一。此前我们已确定胶质瘤分级依赖性MC募集。在本研究中，我们调查了纤溶酶原激活物抑制剂1（PAI-1）在MC募集中的作用。PAI-1是纤维蛋白溶解级联反应中的主要调节因子，能够与纤维蛋白溶解系统蛋白以及低密度脂蛋白受体相关蛋白1（LRP1）形成复合物。我们发现中和PAI-1可减弱MC的浸润。为了探究LRP1在此过程中的潜在影响，我们使用了LRP1拮抗剂受体相关蛋白（RAP），并证明了MC迁移的减弱。此外，在一大组人类胶质瘤样本中观察到MC数量与PAI-1水平之间呈正相关。我们的研究证明了LRP1在人MC系LAD2和人类高级别胶质瘤中的MC中表达。用纯化的PAI-1激活潜在的PAI-1/LRP1轴可促进MC中STAT3磷酸化增加，随后促进胞吐作用。这些发现表明PAI-1/LRP-1轴对胶质瘤中MC募集的影响。高级别胶质瘤与MC浸润之间的联系可能有助于患者定制治疗，并在未来的治疗试验中改善患者分层。
