The invasion promoting effect of microglia on glioblastoma cells is inhibited by cyclosporin A

Item Type:	Article
Title:	The invasion promoting effect of microglia on glioblastoma cells is inhibited by cyclosporin A
Creators Name:	Sliwa, M. and Markovic, D. and Gabrusiewicz, K. and Synowitz, M. and Glass, R. and Zawadzka, M. and Wesolowska, A. and Kettenmann, H. and Kaminska, B.
Abstract:	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 microm, 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.
Keywords:	Cyclosporin A, Glioma Microenvironment, Invasiveness, Microglia, Signal Transduction, Animals, Mice, Rats
Source:	Brain
ISSN:	0006-8950
Publisher:	Oxford University Press
Volume:	130
Number:	Pt. 2
Page Range:	476-489
Date:	1 February 2007
Official Publication:	https://doi.org/10.1093/brain/awl263
PubMed:	View item in PubMed

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