Journal
NEURO-ONCOLOGY
Volume 20, Issue 11, Pages 1462-1474Publisher
OXFORD UNIV PRESS INC
DOI: 10.1093/neuonc/noy103
Keywords
bevacizumab; glioblastoma; VEGF; VEGF-C; VEGFR2.
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Funding
- Danish Cancer Society
- NovoNordisk
- Bjarne Saxhofs
- Arvid Nilssons
- Torben Alice Frimodts
- King Christian IX's
- Dansk Kraeftforsknings
- Fabrikant Ejner Willumsens Memorial
- Roche A/S
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Background. Glioblastoma ranks among the most lethal cancers, with current therapies offering only palliation. Paracrine vascular endothelial growth factor (VEGF) signaling has been targeted using anti-angiogenic agents, whereas autocrine VEGF/VEGF receptor 2 (VEGFR2) signaling is poorly understood. Bevacizumab resistance of VEGFR2-expressing glioblastoma cells prompted interrogation of autocrine VEGF-C/VEGFR2 signaling in glioblastoma. Methods. Autocrine VEGF-C/VEGFR2 signaling was functionally investigated using RNA interference and exogenous ligands in patient-derived xenograft lines and primary glioblastoma cell cultures in vitro and in vivo. VEGF-C expression and interaction with VEGFR2 in a matched pre-and post-bevacizumab treatment cohort were analyzed by immunohistochemistry and proximity ligation assay. Results. VEGF-C was expressed by patient-derived xenograft glioblastoma lines, primary cells, and matched surgical specimens before and after bevacizumab treatment. VEGF-C activated autocrine VEGFR2 signaling to promote cell survival, whereas targeting VEGF-C expression reprogrammed cellular transcription to attenuate survival and cell cycle progression. Supporting potential translational significance, targeting VEGF-C impaired tumor growth in vivo, with superiority to bevacizumab treatment. Conclusions. Our results demonstrate VEGF-C serves as both a paracrine and an autocrine pro-survival cytokine in glioblastoma, promoting tumor cell survival and tumorigenesis. VEGF-C permits sustained VEGFR2 activation and tumor growth, where its inhibition appears superior to bevacizumab therapy in improving tumor control.
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