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65th Annual Meeting of the German Society of Neurosurgery (DGNC)

German Society of Neurosurgery (DGNC)

11 - 14 May 2014, Dresden

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Reduced angiogenesis in NDRG1 overexpressing experimental glioma

Meeting Abstract

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  • Thomas Broggini - Department of Neurosurgery, Universitätsmedizin Charité, Berlin
  • Marie Wüstner - Department of Neurosurgery, Universitätsmedizin Charité, Berlin
  • Christoph Harms - Department of Experimental Neurology, Universitätsmedizin Charité, Berlin
  • Jonas Blaes - Department of Neurooncology, University Hospital Heidelberg, Heidelberg
  • Ulrike Harms - Department of Neurooncology, University Hospital Heidelberg, Heidelberg
  • Susanne Müller - Department of Neurology, Universitätsmedizin Charité, Berlin
  • Wolfgang Wick - Department of Neurooncology, University Hospital Heidelberg, Heidelberg
  • Peter Vajkoczy - Department of Neurosurgery, Universitätsmedizin Charité, Berlin
  • Marcus Czabanka - Department of Neurosurgery, Universitätsmedizin Charité, Berlin

Deutsche Gesellschaft für Neurochirurgie. 65. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC). Dresden, 11.-14.05.2014. Düsseldorf: German Medical Science GMS Publishing House; 2014. DocMO.10.05

doi: 10.3205/14dgnc056, urn:nbn:de:0183-14dgnc0560

Published: May 13, 2014

© 2014 Broggini 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

Text

Objective: The mTOR pathway plays a pivotal role in glioma pathophysiology. N-myc downstream regulated gene 1 (NDRG1) represents a mTOR complex2 (mTORC2) downstream target, which is significantly upregulated during hypoxia. Hypoxia represents a driving force in glioma angiogenesis. It was the aim to analyse the role of NDRG1 in glioma angiogenesis and to elucidate its effects on the efficacy of antiangiogenic treatment.

Method: NDRG1 overexpressing and control (empty vector) U87MG glioma cells were stereotactically implanted in mice (N=5 per group). Tumor growth was analyzed using repetitive MR imaging. Histological analysis included PECAM/Desmin, Ki67 and phospho-Histone staining. Genetic expression of various angiogenesis associated targets was performed. Sunitinib (80 mg/kg BW, N=5 per group, 6 day treatment period) treatment was applied ip 21 days after stereotactic tumor cell implantation. Tumor size was monitored using MR imaging.

Results: NDRG1 overexpressing tumors showed significantly reduced tumor growth compared to controls (120±62 mm3 vs 80±21 mm3). Vessel density (control: 128±25; NDRG1: 95±6) and pericyte-endothelial cell interactions (control: 0,6±0,05; NDRG1: 0,4±0,08) were significantly reduced under NDRG1 overexpression. Molecular analysis revealed 30fold and 10fold overexpression of endogenous VEGF inhibitors TNFSF15 and maspin. Antiangiogenic treatment induced significant reduction of tumor growth in control and NDRG1 overexpressing tumors. No difference in sunitinib response was observed between control and NDRG1 tumors (control: 23±19 mm3; NDRG1: 21±20 mm3).

Conclusions: NDRG1 overexpression limits glioma angiogenesis and vascular maturation probably via upregulation of endogenous VEGF inhibitors maspin and TNFSF15. Antiangiogenic treatment yields effective results also in NDRG1 overexpressing glioma despite reduced angiogenic activity in these tumors.