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Expression of VEGFR3 in glioma endothelium correlates with tumor grade

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Abstract

Angiogenic processes are regulated by vascular endothelial growth factors (VEGFs) and their receptors VEGFR1 (Flt-1), 2 (Flk-1) and 3 (Flt-4). While VEGFR2 is thought to play a central role in tumor angiogenesis, anti-angiogenic therapies targeting VEGFR2 in glioma models can show escape phenomena with secondary onset of angiogenesis. The purpose of this study was to find explanations for these processes by searching for alternative pathways regulating glioma angiogenesis and reveal a correlation with tumor grade. Thus, VEGFR3, which is not expressed in normal brain, and its ligands VEGF-C and -D, were assessed in high grade (WHO°IV, glioblastomas, GBM) and low grade gliomas [WHO°II astrocytomas (AII)]. In all GBM, a strong protein expression of VEGFR3 was found on tumor endothelium, VEGF-C and -D expression was found on numerous cells in areas of high vascularization. On RNA level, a significant up-regulation of VEGFR3 was detected in GBM compared to AII and non-neoplastic brain. In AII, only very moderate VEGFR3, VEGF-C and -D expression was found on protein and RNA level indicating a correlation of VEGFR3 expression with tumor grade. VEGFR3 signal in both grades was found predominantly on endothelial cells, confirmed by VEGFR3 expression on isolated CD31 positive cells and the expression of various endothelial markers on VEGFR3-positive cells isolated from GBM. The demonstration of a complete angiogenic signaling system that is dependent on tumor grade may influence the traditional paradigm of glioma angiogenesis and may provide a basis for more effective anti-angiogenic treatment strategies.

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Acknowledgments

The authors want to thank Stefanie Lange for her practical help with cell culture, Anke Mojaat for expert assistance with TaqMan analysis and appreciate the work of Christoph Barth in assembling the figures. Work was supported in part by DFG grant NE 648/2-1 and SFB 571 to P.J.N.

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Authors and Affiliations

  1. Department of Neurosurgery, Klinikum Großhadern, Ludwig-Maximilians-University Munich, Marchioninistr. 15, 81373 , Munich, Germany

    S. J. Grau, F. Trillsch, N. Thon, J. -C. Tonn & R. Goldbrunner

  2. Medizinische Poliklinik, Ludwig-Maximilians-University Munich, Munich, Germany

    F. Trillsch & P. J. Nelson

  3. Center for Neuropathology and Prion Research, Ludwig-Maximilians-University Munich, Munich, Germany

    J. Herms

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  1. S. J. Grau
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  2. F. Trillsch
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  3. J. Herms
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  4. N. Thon
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  6. J. -C. Tonn
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Correspondence to S. J. Grau.

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Grau, S.J., Trillsch, F., Herms, J. et al. Expression of VEGFR3 in glioma endothelium correlates with tumor grade. J Neurooncol 82, 141–150 (2007). https://doi.org/10.1007/s11060-006-9272-4

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  • DOI: https://doi.org/10.1007/s11060-006-9272-4

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