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60th Annual Meeting of the German Society of Neurosurgery (DGNC)
Joint Meeting with the Benelux countries and Bulgaria

German Society of Neurosurgery (DGNC)

24 - 27 May 2009, Münster

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Inhibition of Tissue Factor signalling suppresses proliferation, migration and invasion of low- and high-grade glioma cells

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  • F. Geßler - Experimentelle Neurochirurgie, Johann-Wolfgang-Goethe-Universität, Frankfurt am Main
  • V. Voss - Experimentelle Neurochirurgie, Johann-Wolfgang-Goethe-Universität, Frankfurt am Main
  • S. Dützmann - Klinik und Poliklinik für Neurochirurgie, Johann-Wolfgang-Goethe-Universität, Frankfurt am Main
  • V. Seifert - Klinik und Poliklinik für Neurochirurgie, Johann-Wolfgang-Goethe-Universität, Frankfurt am Main
  • R. Gerlach - Klinik und Poliklinik für Neurochirurgie, Johann-Wolfgang-Goethe-Universität, Frankfurt am Main
  • D. Kögel - Experimentelle Neurochirurgie, Johann-Wolfgang-Goethe-Universität, Frankfurt am Main

Deutsche Gesellschaft für Neurochirurgie. 60. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC), Joint Meeting mit den Benelux-Ländern und Bulgarien. Münster, 24.-27.05.2009. Düsseldorf: German Medical Science GMS Publishing House; 2009. DocMI.06-06

doi: 10.3205/09dgnc207, urn:nbn:de:0183-09dgnc2075

Published: May 20, 2009

© 2009 Geßler 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: Almost all patients with low grade gliomas suffer from recurrent tumors and malignisation over the years. Cell signalling and mechanisms leading to transformation from low to high grade gliomas are not yet understood. Tissue Factor (TF) is activated by hypoxia and its expression positively correlates with histological grading. TF is known to act as a trigger for several intracellular signalling pathways. To evaluate whether TF plays a role in the transformation process from low- to high-grade gliomas, we compared the effects of TF inhibition on the migratory and invasive potential, as well as on cell growth in low-grade versus high-grade glioma cell lines.

Methods: TF expression under normoxic and hypoxic conditions was analyzed by RT-PCR and Western Blotting. Inhibition of TF-dependent signalling was achieved via 1) lentiviral-mediated knockdown of TF and 2) a neutralizing monoclonal antibody (mAB TF9-10H10) specific for the signalling domain of TF. Cell proliferation, migration and invasion were measured by MTT-assays, scratch-migration-assays and modified Boyden-chamber-assays, respectively.

Results: TF expression was elevated in several glioma cell lines investigated, and was further enhanced in all cell lines under hypoxic conditions. The neutralizing TF antibody potently reduced proliferation under normoxic and hypoxic conditions in high-grade (MZ-18 and MZ-304) as well as in low-grade (HS 683) cell lines abundantly expressing TF (p<0.05). Scratch-assays revealed significantly reduced cell migration after inhibition of TF-signalling (p<0.05) in all cell lines analyzed, both under normoxic and hypoxic conditions. The number of invading cells was also significantly reduced by blocking TF signalling in high-grade (p<0.05) and low-grade (p<0.01) glioma cell lines. Interestingly, the potentiating effects of hypoxia on cell invasion in untreated cultures (p<0.01) were completely blocked by inhibition of TF in all analyzed cell lines.

Conclusions: Proliferation, migration and invasion of glioma cells are significantly reduced by inhibition of TF signalling. Our results underscore the importance of TF in glioma progression and malignisation and suggest that TF may be a suitable target for the development of novel therapies against low-grade and high-grade glioma.