gms | German Medical Science

62nd Annual Meeting of the German Society of Neurosurgery (DGNC)
Joint Meeting with the Polish Society of Neurosurgeons (PNCH)

German Society of Neurosurgery (DGNC)

7 - 11 May 2011, Hamburg

Radiosensitization of stem-like glioma cells as an effective therapeutic strategy to inhibit glioma invasion

Meeting Abstract

  • A. Giese - The Translational Neurooncology Research Group, Department of Neurosurgery University Medical Centre Göttingen (UMG)
  • J. Pruefer - The Translational Neurooncology Research Group, Department of Neurosurgery University Medical Centre Göttingen (UMG)
  • C. Richter - The Translational Neurooncology Research Group, Department of Neurosurgery University Medical Centre Göttingen (UMG)
  • M. Rave-Fraenk - Department of Radiotherapy and Radiation Oncology, University Medical Centre Göttingen (UMG)
  • W. Schulz-Schaeffer - Department of Neuropathology, University Medical Centre Göttingen (UMG)
  • E. Kim - The Translational Neurooncology Research Group, Department of Neurosurgery University Medical Centre Göttingen (UMG)

Deutsche Gesellschaft für Neurochirurgie. Polnische Gesellschaft für Neurochirurgen. 62. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC), Joint Meeting mit der Polnischen Gesellschaft für Neurochirurgen (PNCH). Hamburg, 07.-11.05.2011. Düsseldorf: German Medical Science GMS Publishing House; 2011. DocMO.07.11

DOI: 10.3205/11dgnc048, URN: urn:nbn:de:0183-11dgnc0485

Published: April 28, 2011

© 2011 Giese et al.
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Outline

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Objective: Combined treatment including post-operative radio- and chemotherapy is the standard of care for high-grade malignant gliomas. The poor effectiveness of conventional treatment modalities is explained by defects in the core signaling pathways involved in the regulation of cell survival and death in glioma cells. A further level of complexity is added by the existence of distinct stem cell-like entities generally termed Brain Tumor Initiating Cells (BTICs), which are capable of escaping the cytotoxic effects of radiation and standard chemotherapy and re-populating malignant glioma after therapy. We have previously shown that the immunomodulatory agent chloroquine (ClQ) suppresses growth and activates apoptotic response in glioma cells lacking BTIC properties. This study was carried out to explore the effects of ClQ on the self-renewing ability and tumorigenic potential of glioma-derived BTICs.

Methods: Thirteen BTIC lines were established from glioma cell lines or GBM biopsies. Radioresistant cell populations were selected by exposing BTICs cultures to repetitive rounds of clinically relevant doses of ionizing radiation (IR). The self-renewal potential was evaluated in vitro using neurosphere assays. The tumorigenic potential and survival analysis were determined using an orthotopic glioma mouse model. Glioma infiltration into the brain was monitored using a brain slice model. Gene expression analysis was performed using the GeneChip Human Gene 1.0 ST arrays (Affymetrix).

Results: ClQ potently inhibits BTICs self-renewal in vitro and sensitizes BTIC-derived experimental gliomas to radiation therapy. The combined treatment with ClQ and IR rendered a significant (P < 0.05) survival advantage to mice bearing BTIC-derived tumors (147 ± 25,76 days) compared to the untreated control group (114 ± 18,34 days) of the groups treated with ClQ (96 ± 20,24 days) or IR (119 ± 26,87 days) alone. Remarkably, ClQ treatment strongly inhibits the invasive potential of BTICs as revealed in the glioma brain slice model. Molecular analyses indicate that radiosensitizing effects of ClQ involve the inhibition of the BTICs proliferative and DNA repair capacity and interference with the expression of pro-survival genes.

Conclusions: ClQ treatment augments radiotoxicity in stem-like glioma cells and inhibits glioma invasion.