Darko Markovic

Publications (2)17.31 Total impact

• Source

  Available from: Konrad Gabrusiewicz

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

  Marcin Sliwa, Darko Markovic, Konrad Gabrusiewicz, Michael Synowitz, Rainer Glass, Malgorzata Zawadzka, Aleksandra Wesolowska, Helmut Kettenmann, Bozena Kaminska
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  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 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.
  Brain 02/2007; 130(Pt 2):476-89. · 9.46 Impact Factor
• Article: A1 adenosine receptors in microglia control glioblastoma-host interaction.

  Michael Synowitz, Rainer Glass, Katrin Färber, Darko Markovic, Golo Kronenberg, Ken Herrmann, Juergen Schnermann, Christiane Nolte, Nico van Rooijen, Juergen Kiwit, Helmut Kettenmann
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  ABSTRACT: We report that experimental glioblastoma grow more vigorously in A(1) adenosine receptor (A(1)AR)-deficient mice associated with a strong accumulation of microglial cells at and around the tumors. A(1)ARs were prominently expressed in microglia associated with tumor cells as revealed with immunocytochemistry but low in microglia in the unaffected brain tissue. The A(1)AR could also be detected on microglia from human glioblastoma resections. To study functional interactions between tumor and host cells, we studied glioblastoma growth in organotypical brain slice cultures. A(1)AR agonists suppressed tumor growth. When, however, microglial cells were depleted from the slices, the agonists even stimulated tumor growth. Thus, adenosine attenuates glioblastoma growth acting via A(1)AR in microglia.
  Cancer Research 10/2006; 66(17):8550-7. · 7.86 Impact Factor