VEGF-C sustains VEGFR2 activation under bevacizumab therapy and promotes glioblastoma maintenance

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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

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.

Original languageEnglish
Issue number11
Pages (from-to)1462-1474
Publication statusPublished - 2018

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