VEGF-C sustains VEGFR2 activation under bevacizumab therapy and promotes glioblastoma maintenance. Issue 11 (25th June 2018)

• Record Type: Journal Article
• Authors: Michaelsen, Signe R; Staberg, Mikkel; Pedersen, Henriette; Jensen, Kamilla E; Majewski, Wiktor; Broholm, Helle; Nedergaard, Mette K; Meulengracht, Christopher; Urup, Thomas; Villingshøj, Mette; Lukacova, Slávka; Skjøth-Rasmussen, Jane; Brennum, Jannick; Kjær, Andreas; Lassen, Ulrik; Stockhausen, Marie-Thérése; Poulsen, Hans S; Hamerlik, Petra
• Is Part Of: Neuro-oncology. Volume 20:Issue 11(2018)
• Page Start: 1462
• Page End: 1474
• Publication Date: 2018-06-25
• Subjects: bevacizumab -- glioblastoma -- VEGF -- VEGF-C -- VEGFR2; Brain Neoplasms -- Periodicals; Brain -- Tumors -- Periodicals; Brain -- Cancer -- Periodicals; Nervous system -- Cancer -- Periodicals; 616.99481
• DOI: 10.1093/neuonc/noy103
• Languages: English
• ISSNs: 1522-8517

Abstract

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 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.