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

doi:10.1093/neuonc/noy103

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

22 Citations (Scopus)

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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.

Original language	English
Journal	Neuro-Oncology
Volume	20
Issue number	11
Pages (from-to)	1462-1474
ISSN	1522-8517
DOIs	https://doi.org/10.1093/neuonc/noy103
Publication status	Published - 9 Oct 2018

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Michaelsen, S. R., Staberg, M., Pedersen, H., Jensen, K. E., Majewski, W., Broholm, H., Nedergaard, M. K., Meulengracht, C., Urup, T., Villingshøj, M., Lukacova, S., Skjøth-Rasmussen, J., Brennum, J., Kjær, A., Lassen, U., Stockhausen, M-T., Poulsen, H. S., & Hamerlik, P. (2018). VEGF-C sustains VEGFR2 activation under bevacizumab therapy and promotes glioblastoma maintenance. Neuro-Oncology, 20(11), 1462-1474. https://doi.org/10.1093/neuonc/noy103

Michaelsen, SR, Staberg, M, Pedersen, H, Jensen, KE, Majewski, W, Broholm, H, Nedergaard, MK, Meulengracht, C, Urup, T, Villingshøj, M, Lukacova, S, Skjøth-Rasmussen, J, Brennum, J, Kjær, A , Lassen, U, Stockhausen, M-T, Poulsen, HS & Hamerlik, P 2018, 'VEGF-C sustains VEGFR2 activation under bevacizumab therapy and promotes glioblastoma maintenance', Neuro-Oncology, vol. 20, no. 11, pp. 1462-1474. https://doi.org/10.1093/neuonc/noy103

@article{8f653a1200e3443080be22d961514630,

title = "VEGF-C sustains VEGFR2 activation under bevacizumab therapy and promotes glioblastoma maintenance",

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.",

author = "Michaelsen, {Signe R} and Mikkel Staberg and Henriette Pedersen and Jensen, {Kamilla E} and Wiktor Majewski and Helle Broholm and Nedergaard, {Mette K} and Christopher Meulengracht and Thomas Urup and Mette Villingsh{\o}j and Sl{\'a}vka Lukacova and Jane Skj{\o}th-Rasmussen and Jannick Brennum and Andreas Kj{\ae}r and Ulrik Lassen and Marie-Th{\'e}r{\'e}se Stockhausen and Poulsen, {Hans S} and Petra Hamerlik",

year = "2018",

month = oct,

day = "9",

doi = "10.1093/neuonc/noy103",

language = "English",

volume = "20",

pages = "1462--1474",

journal = "Neuro-Oncology",

issn = "1522-8517",

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number = "11",

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T1 - VEGF-C sustains VEGFR2 activation under bevacizumab therapy and promotes glioblastoma maintenance

AU - Michaelsen, Signe R

AU - Staberg, Mikkel

AU - Pedersen, Henriette

AU - Jensen, Kamilla E

AU - Majewski, Wiktor

AU - Broholm, Helle

AU - Nedergaard, Mette K

AU - Meulengracht, Christopher

AU - Urup, Thomas

AU - Villingshøj, Mette

AU - Lukacova, Slávka

AU - Skjøth-Rasmussen, Jane

AU - Brennum, Jannick

AU - Kjær, Andreas

AU - Lassen, Ulrik

AU - Stockhausen, Marie-Thérése

AU - Poulsen, Hans S

AU - Hamerlik, Petra

PY - 2018/10/9

Y1 - 2018/10/9

N2 - 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.

AB - 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.

U2 - 10.1093/neuonc/noy103

DO - 10.1093/neuonc/noy103

M3 - Journal article

C2 - 29939339

SN - 1522-8517

VL - 20

SP - 1462

EP - 1474

JO - Neuro-Oncology

JF - Neuro-Oncology

IS - 11

ER -

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

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