Artikel
Glioblastoma angiogenesis and invasion are inhibited by combination treatments directed against VEGFR-2, EGFR and VE-cadherin
Inhibierung der Angiogenese und Invasion von Glioblastomen durch kombinierte Antagonisierung von VEGFR-2, EGFR und VE-Cadherin
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Autoren
Veröffentlicht: | 4. Mai 2005 |
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Gliederung
Text
Objective
Increasing evidence suggests that inhibition of tumour angiogenesis can influence tumour cell invasion and metastasis. We previously showed that systemic antagonisation of vascular endothelial growth factor receptor-2 (VEGFR-2) with the monoclonal antibody (mAb) DC101 inhibited glioblastoma growth in an orthotopic model, but caused increased tumour cell invasion along the preexistent vasculature.
Methods
In human glioblastoma cells signalling through the epidermal growth factor receptor (EGFR) predominantly stimulates tumour cell invasion. Therefore, we attempted to inhibit tumour cell invasion caused by DC101 therapy by combined systemic treatment with a mAb against EGFR (C225). In addition, we analysed whether antagonisation of vascular endothelial (VE)-cadherin as a different anti-angiogenic target can also inhibit glioblastoma growth and whether this also stimulates invasion. Treatments were either initiated on day 1 after intracerebral tumour cell injection or on day 6 when tumours were already established.
Results
Increased tumour cell invasion caused by DC101 monotherapy was inhibited by 50-66% through combined treatment with C225 and DC101. C225 inhibited glioblastoma cell migration in vitro, but had no effect on the volume of the main tumour mass or on tumour cell proliferation or apoptosis in vivo, neither alone nor in combination with DC101. The anti-VE-cadherin mAb E4G10 also inhibited tumour angiogenesis and growth, although with weaker effects than DC101, and the effects of E4G10 were dependent on early initiation of treatment. E4G10 treatment caused increased tumour cell invasion along the host vasculature, although with less effect than DC101.
Conclusions
Our findings show that anti-angiogenic glioblastoma therapy targeting either VEGFR-2 or VE-cadherin can inhibit tumour growth, but can increase tumour cell invasion in an orthotopic model. The increased tumour cell invasion caused by DC101 treatment can be inhibited by simultaneous antagonisation of EGFR which in the context of human glioblastomas has been implicated in tumour cell invasion.