The invasion promoting effect of microglia on glioblastoma cells is inhibited by cyclosporin A.
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 mum, 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.
Sliwa
Marcin
M
Laboratory of Transcription Regulation, Department of Cell Biology, Nencki Institute of Experimental Biology, Warsaw, Poland.
Markovic
Darko
D
Gabrusiewicz
Konrad
K
Synowitz
Michael
M
Glass
Rainer
R
Zawadzka
Malgorzata
M
Wesolowska
Aleksandra
A
Kettenmann
Helmut
H
Kaminska
Bozena
B
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001932:Brain Neoplasms / Q000473:pathology* / Q000517:prevention & control; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D016572:Cyclosporine / Q000494:pharmacology* / Q000627:therapeutic use; D005909:Glioblastoma / Q000473:pathology* / Q000517:prevention & control; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D017628:Microglia / Q000187:drug effects* / Q000502:physiology; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects; D046509:Tissue Culture Techniques; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D016572:Cyclosporine