PMID- 17107968
OWN - NLM
STAT- MEDLINE
DCOM- 20070220
LR  - 20131121
IS  - 1460-2156 (Electronic)
IS  - 0006-8950 (Linking)
VI  - 130
IP  - Pt 2
DP  - 2007 Feb
TI  - The invasion promoting effect of microglia on glioblastoma cells is inhibited by 
      cyclosporin A.
PG  - 476-89
AB  - 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.
FAU - Sliwa, Marcin
AU  - Sliwa M
AD  - Laboratory of Transcription Regulation, Department of Cell Biology, Nencki 
      Institute of Experimental Biology, Warsaw, Poland.
FAU - Markovic, Darko
AU  - Markovic D
FAU - Gabrusiewicz, Konrad
AU  - Gabrusiewicz K
FAU - Synowitz, Michael
AU  - Synowitz M
FAU - Glass, Rainer
AU  - Glass R
FAU - Zawadzka, Malgorzata
AU  - Zawadzka M
FAU - Wesolowska, Aleksandra
AU  - Wesolowska A
FAU - Kettenmann, Helmut
AU  - Kettenmann H
FAU - Kaminska, Bozena
AU  - Kaminska B
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20061114
PL  - England
TA  - Brain
JT  - Brain : a journal of neurology
JID - 0372537
RN  - 0 (Antineoplastic Agents)
RN  - 83HN0GTJ6D (Cyclosporine)
SB  - IM
MH  - Animals
MH  - Antineoplastic Agents/*pharmacology/therapeutic use
MH  - Brain Neoplasms/*pathology/prevention & control
MH  - Cell Division/drug effects
MH  - Cell Movement/drug effects
MH  - Cyclosporine/*pharmacology/therapeutic use
MH  - Glioblastoma/*pathology/prevention & control
MH  - Humans
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Inbred DBA
MH  - Microglia/*drug effects/physiology
MH  - Neoplasm Invasiveness
MH  - Neoplasm Transplantation
MH  - Rats
MH  - Rats, Wistar
MH  - Signal Transduction/drug effects
MH  - Tissue Culture Techniques
MH  - Tumor Cells, Cultured
EDAT- 2006/11/17 09:00
MHDA- 2007/02/21 09:00
CRDT- 2006/11/17 09:00
PHST- 2006/11/17 09:00 [pubmed]
PHST- 2007/02/21 09:00 [medline]
PHST- 2006/11/17 09:00 [entrez]
AID - awl263 [pii]
AID - 10.1093/brain/awl263 [doi]
PST - ppublish
SO  - Brain. 2007 Feb;130(Pt 2):476-89. doi: 10.1093/brain/awl263. Epub 2006 Nov 14.