Artikel
VEGFR-3 pathway as a possible escape mechanism from anti-VEGF-A therapy in glioblastoma
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Autoren
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Jun Thorsteinsdottir
- Neurochirurgische Klinik und Poliklinik, Klinikum der Universität München-Großhadern, Deutschland
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Jörg-Christian Tonn
- Neurochirurgische Klinik und Poliklinik, Klinikum der Universität München-Großhadern, Deutschland
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Christian Schichor
- Neurochirurgische Klinik und Poliklinik, Klinikum der Universität München-Großhadern, Deutschland
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Stefan Grau
- Neurochirurgische Klinik und Poliklinik, Klinikum der Universität München-Großhadern, Deutschland
| Veröffentlicht: | 16. September 2010 |
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Gliederung
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Objective: Neo-angiogenesis in gliomas is related to the expression of VEGF-A and its receptor VEGFR-2. Anti-VEGF-A therapy in combination with chemotherapy is an emerging treatment concept for malignant glioma. In various animal glioma models, anti-VEGF-A-therapy, e.g. with bevacizumab, a neutralizing antibody against VEGF-A, normalized pathological architecture of tumor vasculature and increased response to chemotherapy and radiation. However, this phenomenon was transient. The underlying causes for the observed secondary onset of re-angiogenesis are unclear. VEGFR-3, the receptor for VEGF-C and -D, is expressed in glioma endothelium in a tumor grade dependent manner. Thus we investigated the role of this receptor and its ligands in respect to anti-VEGF-A therapy.
Methods: Human glioblastoma cells (U87, U251), endothelial cells (HBMEC) and isolated endothelial cells (EC) from glioblastoma were treated with bevacizumab (Avastin®) for 5 and 14 days respectively. The influence of anti-VEGF-A-therapy regarding the activity of the VEGFR-3 pathway by means of proliferation, secretion of VEGF-A, -C and -D, endothelial tube formation and intracellular signal mechanisms such as MAP kinase phosphorylation were investigated.
Results: Short-time treatment with bevacizumab showed no effect on tumor or endothelial cells. Long-term treatment (10 to 14 days) reduced tumor cell and EC proliferation significantly (p<0.01). The absence of VEGF-A did not affect the phosphorylation status of VEGFR-3, but it induced cellular reactivity of tumor and endothelial cells to VEGF-C, -D and -C156s (a specific ligand for VEGFR-3) by means of increased proliferation and EC tube formation (p<0.01). In tumor cells, bevacizumab induced up-regulation of VEGF-C and -D on the mRNA level and the secretion of VEGF-D, whereas secretion of VEGF-A was down-regulated. Furthermore, anti-VEGF-A treatment changed the activation of intracellular pathways, showing increased activation of p38MAPK in EC and SAPK/JNK in tumor cells.
Conclusions: These findings support the theory of activation of redundant pro-angiogenic signalling systems during anti-VEGF-A treatment. The VEGFR-3 pathway with its ligands and intracellular pathways may (amongst other molecules) serve as an alternative pathway to overcome the impact of anti-VEGF-A treatment. This may help in understanding complex changes observed during anti-VEGF-A therapy.
