Brain Advance Access originally published online on November 14, 2006
Brain 2007 130(2):476-489; doi:10.1093/brain/awl263
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The invasion promoting effect of microglia on glioblastoma cells is inhibited by cyclosporin A
1 Laboratory of Transcription Regulation, Department of Cell Biology, Nencki Institute of Experimental Biology Warsaw, Poland 2 Cellular Neuroscience Group, Max Delbrück Center for Molecular Medicine (MDC) Berlin, Germany 3 Department of Neurosurgery, Helios Hospital Berlin Berlin, Germany
Correspondence to: Bozena Kaminska, Laboratory of Transcription Regulation, Department of Cell Biology, Nencki Institute of Experimental Biology, 3 Pasteur Street, 02-093 Warsaw, Poland E-mail: bozenakk{at}nencki.gov.pl
The invasion of tumour cells into brain tissue is a pathologic hallmark of WHO grades II–IV gliomas and contributes significantly to the failure of current therapeutic treatments. Activated microglial cells are abundant in brain tumours and may support tumour invasiveness. We have previously demonstrated that cyclosporin A (CsA) can affect growth of glioma cells in vitro by inhibiting signalling pathways, which are essential for tumour proliferation and invasiveness. In this work, we demonstrate that migration of EGFP-transfected glioblastoma cells in organotypic brain slices was significantly inhibited by treatment with CsA. On average 77% of untreated cells migrated beyond 500 µm, while only 28–33% cells migrated as far in the brain slices treated with CsA (P < 0.001). This inhibitory effect on glioblastoma invasion was lost when glioblastoma cells were injected into microglia-depleted brain slices. Moreover, CsA significantly inhibits intracranial glioma growth in vivo. We demonstrate that microglia-derived factors increase glioma invasiveness in Matrigel assay in vitro and this is associated with activation of the PI-3K/Akt signalling pathway. The invasion promoting effect of microglia is abolished in the presence of CsA. Furthermore, glioma-derived soluble factors induce morphological transformation of microglia and activate MAPK signalling, although production of pro-inflammatory factors was not observed. Our findings that CsA interferes at clinically relevant concentrations with the tumour-promoting role of microglia and impairs invasive growth of glioma cells in vivo may provide a novel therapeutic strategy against gliomas.
Key Words: cyclosporin A; glioma microenvironment; invasiveness; microglia; signal transduction
Abbreviations:
CsA, cyclosporin A; DAPI, 4',6-diamidino-2-phenylindole; EGFP, enhanced green fluorescent protein; ERK, extracellular signal-regulated kinase; FCS, fetal calf serum; G-CM, glioma-conditioned medium; GBM, glioblastoma multiforme; i.p., intraperitoneally; JNK, c-Jun-N-terminal kinase; LPS, lipopolysaccharide; LSC, laser scanning cytometry; MAPK, mitogen-activated protein kinase; MAPKAPK 2, MAP kinase-activated protein kinase 2; MG-CM, microglia-conditioned medium; MHC, major histocompatibility complex; MMP, matrix metalloproteinase; NCS, newborn calf serum; PI-3K, phosphoinositide 3 kinase; TBS-T, Tris-buffered saline/Tween-20; TNF
, tumour necrosis factor
Received February 21, 2006. Revised June 29, 2006. Accepted August 14, 2006.
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