VEGF-C Sustains VEGFR2 Activation under Bevacizumab Therapy and Promotes Glioblastoma Maintenance

Signe R Michaelsen, Mikkel Staberg, Henriette Pedersen, Kamilla E Jensen, Wiktor Majewski, Helle Broholm, Mette K Nedergaard, Christopher Meulengracht, Thomas Urup, Mette Villingshøj, Slávka Lukacova, Jane Skjøth-Rasmussen, Jannick Brennum, Andreas Kjær, Ulrik Lassen, Marie-Thérése Stockhausen, Hans S Poulsen, Petra Hamerlik

63 Citationer (Scopus)

Abstract

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 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.

OriginalsprogEngelsk
TidsskriftNeuro-Oncology
Vol/bind20
Udgave nummer11
Sider (fra-til)1462-74
ISSN1522-8517
DOI
StatusUdgivet - 2018

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