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

Brain. 2007 Feb;130(Pt 2):476-89. doi: 10.1093/brain/awl263. Epub 2006 Nov 14.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Brain Neoplasms / pathology*
  • Brain Neoplasms / prevention & control
  • Cell Division / drug effects
  • Cell Movement / drug effects
  • Cyclosporine / pharmacology*
  • Cyclosporine / therapeutic use
  • Glioblastoma / pathology*
  • Glioblastoma / prevention & control
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred DBA
  • Microglia / drug effects*
  • Microglia / physiology
  • Neoplasm Invasiveness
  • Neoplasm Transplantation
  • Rats
  • Rats, Wistar
  • Signal Transduction / drug effects
  • Tissue Culture Techniques
  • Tumor Cells, Cultured


  • Antineoplastic Agents
  • Cyclosporine