Jelena Põlajeva1, Tobias Bergström1, Per-Henrik Edqvist1, Anders Lundequist2, Anna Sjösten1, Gunnar Nilsson3, Anja Smits4, Michael Bergqvist4, Fredrik Pontén1, Bengt Westermark1, Gunnar Pejler2, Karin Forsberg Nilsson1, Elena Tchougounova1
1Uppsala University, Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, SE-751 85 Uppsala, Sweden
2Swedish University of Agricultural Sciences, Department of Anatomy, Physiology and Biochemistry, BMC, Box 575, SE-751 23 Uppsala, Sweden
3Karolinska Institutet, Department of Medicine, Karolinska University Hospital Solna, SE-171 76 Stockholm, Sweden
4Uppsala University Hospital, Department of Neuroscience, Neurology, SE-751 85 Uppsala, Sweden
Tóm tắt
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.
