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- Geretti, Elena, et al.
(författare)
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A mutated soluble neuropilin-2 B domain antagonizes vascular endothelial growth factor bioactivity and inhibits tumor progression
- 2010
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Ingår i: Molecular Cancer Research. - 1541-7786 .- 1557-3125. ; 8:8, s. 1063-1073
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Tidskriftsartikel (refereegranskat)abstract
- Neuropilins (NRP1 and NRP2) are coreceptors for vascular endothelial growth factor (VEGF) and mediate angiogenesis and tumor progression. VEGF binds to the NRP1 and NRP2 B domains. Previously, it was shown that mutagenesis of the soluble NRP2 B domain (MutB-NRP2) increased affinity to VEGF by 8-fold. Here, we show that MutB-NRP2 inhibited (125)I-VEGF binding to NRP1, NRP2, and VEGFR-2. It antagonized VEGF-induced VEGFR-2/NRP2 complex formation and inhibited VEGF-induced activation of AKT, a mediator of cell survival, without affecting activation of VEGFR-2. In three-dimensional embryoid bodies, a model of VEGF-induced angiogenesis, MutB-NRP2 inhibited VEGF-induced sprouting. When overexpressed in human melanoma cells, MutB-NRP2 inhibited tumor growth compared with control tumors. Avastin (bevacizumab), a monoclonal antibody to VEGF, inhibited VEGF interactions with VEGFR-2, but not with NRPs. The combination of MutB-NRP2 and Avastin resulted in an enhanced inhibition of human melanoma tumor growth compared with MutB-NRP2 treatment only or Avastin treatment only. In conclusion, these results indicate that MutB-NRP2 is a novel antagonist of VEGF bioactivity and tumor progression.
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