Glioma‐derived macrophage migration inhibitory factor (MIF) promotes mast cell recruitment in a STAT5‐dependent manner

Abstract

Recently, glioma research has increased its focus on the diverse types of cells present in brain tumors. We observed previously that gliomas are associated with a profound accumulation of mast cells (MCs) and here we investigate the underlying mechanism. Gliomas express a plethora of chemoattractants. First, we demonstrated pronounced migration of human MCs toward conditioned medium from cultures of glioma cell lines. Subsequent cytokine array analyses of media from cells, cultured in either serum-containing or -free conditions, revealed a number of candidates which were secreted in high amounts in both cell lines. Among these, we then focused on macrophage migration inhibitory factor (MIF), which has been reported to be pro-inflammatory and -tumorigenic. Infiltration of MCs was attenuated by antibodies that neutralized MIF. Moreover, a positive correlation between the number of MCs and the level of MIF in a large cohort of human glioma tissue samples was observed. Further, both glioma-conditioned media and purified MIF promoted differential phosphorylation of a number of signaling molecules, including signal transducer and activator of transcription 5 (STAT5), in MCs. Inhibition of pSTAT5 signaling significantly attenuated the migration of MCs toward glioma cell-conditioned medium shown to contain MIF. In addition, analysis of tissue microarrays (TMAs) of high-grade gliomas revealed a direct correlation between the level of pSTAT5 in MCs and the level of MIF in the medium. In conclusion, these findings indicate the important influence of signaling cascades involving MIF and STAT5 on the recruitment of MCs to gliomas.

Cancer Stem Cell-Secreted Macrophage Migration Inhibitory Factor Stimulates Myeloid Derived Suppressor Cell Function and Facilitates Glioblastoma Immune Evasion

“…H). While MIF has been implicated in multiple cancers outside of the central nervous system and its activation of tumor immune suppression is well documented , its role as a mediator of a GBM CSC/tumor‐infiltrating MDSC interaction was previously unknown. Further, the finding that CXCR2, but not CXCR4, facilitated MIF‐driven MDSC function (Fig.…”

Role of Mast Cells in Shaping the Tumor Microenvironment

“…Roy et al [54] investigated the recruitment pattern of MCs to glioma tumors and reported that glioma-derived plasminogen activator inhibitor-1 (PAI-1) promotes MC recruitment and that the level of PAI-1 correlates with the rate of MC recruitment. Additionally, macrophage migration inhibitory factor (MIF) released by glioma cells contributes to the recruitment of MCs by inducing phosphorylation of STAT5 [55]. Also, glioma cells release CXCL12 that acts as MC chemotaxin by engaging CXCR4 [56] (Fig.…”

Heparanase promotes glioma progression via enhancing CD24 expression

“…Human brain cancer tissue microarray (TMA) BS170154a was purchased from US Biomax (Derwood, MD). A second set of TMAs contained high‐grade glioma (HGG, 102 cases), low‐grade glioma (LGG, 80 cases), and nonmalignant control brain tissue has been described elsewhere . TMAs were subjected to immunostaining applying antiheparanase (antibody 733) and anti‐CD24 (Novus Biologicals; Littleton, CO) antibodies, essentially as described …”