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61st Annual Meeting of the German Society of Neurosurgery (DGNC) as part of the Neurowoche 2010
Joint Meeting with the Brazilian Society of Neurosurgery on the 20 September 2010

German Society of Neurosurgery (DGNC)

21 - 25 September 2010, Mannheim

Bone specific growth factors induce resistance against adjuvant treatment in meningioma cells

Meeting Abstract

  • Martin Proescholdt - Klinik für Neurochirurgie, Universitätsklinikum Regensburg, Germany
  • Heinz-Georg Bloß - Klinik für Neurochirurgie, Universitätsklinikum Regensburg, Germany
  • Eva-Maria Störr - Klinik für Neurochirurgie, Universitätsklinikum Regensburg, Germany
  • Annette Lohmeier - Klinik für Neurochirurgie, Universitätsklinikum Regensburg, Germany
  • Alexander Brawanski - Klinik für Neurochirurgie, Universitätsklinikum Regensburg, Germany

Deutsche Gesellschaft für Neurochirurgie. 61. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC) im Rahmen der Neurowoche 2010. Mannheim, 21.-25.09.2010. Düsseldorf: German Medical Science GMS Publishing House; 2010. DocP1738

DOI: 10.3205/10dgnc209, URN: urn:nbn:de:0183-10dgnc2092

Published: September 16, 2010

© 2010 Proescholdt et al.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by-nc-nd/3.0/deed.en). You are free: to Share – to copy, distribute and transmit the work, provided the original author and source are credited.


Outline

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Objective: Meningiomas are considered to be benign tumors with slow growth rates and in the majority of cases, complete surgical resection will be curative. However, a certain subset of meningiomas are biologically complex, show a high recurrence rate and a low susceptibility to adjuvant treatment. Invasion of the bone has been shown to be a risk factor for recurrence. We hypothesized that the molecular environment of the bone may induce a more aggressive biology in meningiomas leading to resistance towards adjuvant treatment. We have therefore treated meningioma cells in vitro with hydroxyurea (HU), a chemotherapeutic agent known to induce apoptotic cell death in meningiomas, in the presence or absence of bone specific growth factors (BSGF) such as insulin like growth factor (IGF) I&II, transforming growth factor (TGF) beta 1&2. We subsequently analyzed the toxicity, rate of apoptotic cell deaths and the molecular pathways causing the observed effects.

Methods: Meningioma cell culture was established from 21 tumors resected from 7 male (33.4%) and 14 female (66.6) patients, with a mean age of 62.7 years (range: 43–82 years). The purity of the cultures was defined by immunofluorescent staining for meningioma – specific markers and ultrastructural analysis using transmission electron microsopy. The cells were treated with HU at a concentration of 100 µmol/l, IGF I&II was added at a concentration of 100 ng/ml, TGF beta 1&2 at 10 ng/ml. Treatment with the phosphoinositide 3-kinase (PI3K) inhibitor Wortmannin was performed at 20 µmol/l. Cell toxicity and apoptotic cell death was analyzed by an aquous colorimetric assay and TUNEL labeling respectively. Akt phosphorylation was investigated by Western blotting utilizing pAkt specific antibodies

Results: HU treatment induced significant toxicity and a high rate of apoptotic cell death (p<0.001 vs. ctrl) in all meningioma cultures. However, the presence of BSGF's completely abolished this treatment effect. pAkt Western revealed a strong Akt phophorylation induced by BSGF's, indicating activation of Akt as the major antiapoptotic mechanism. Antagonizing the PI3K/pAkt pathway with Wortmannin completely restored the susceptibility of meningioma cells towards HU.

Conclusions: Our data indicate that the molecular bone microenvironment provides a protective niche to meningioma cells by activation of the PI3K/pAkt pathway leading to a resistance against adjuvant treatment