Targeting APLN/APLNR improves anti-angiogenic efficiency and blunts pro-invasive side effects of VEGFA/VEGFR2-blockade in glioblastoma
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Targeting APLN/APLNR improves anti-angiogenic efficiency and blunts pro-invasive side effects of VEGFA/VEGFR2-blockade in glioblastoma. / Mastrella, Giorgia; Hou, Mengzhuo; Li, Min; Stoecklein, Veit M; Zdouc, Nina; Volmar, Marie N M; Miletic, Hrvoje; Reinhard, Sören; Herold-Mende, Christel C; Kleber, Susanne; Eisenhut, Katharina; Gargiulo, Gaetano; Synowitz, Michael; Vescovi, Angelo Luigi; Harter, Patrick N; Penninger, Josef M; Wagner, Ernst; Mittelbronn, Michel; Bjerkvig, Rolf; Hambardzumyan, Dolores; Schüller, Ulrich; Tonn, Jörg-Christian; Radke, Josefine; Glass, Rainer; Kälin, Roland Eugen.
in: CANCER RES, Jahrgang 79, Nr. 9, 01.05.2019, S. 2298-2313.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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T1 - Targeting APLN/APLNR improves anti-angiogenic efficiency and blunts pro-invasive side effects of VEGFA/VEGFR2-blockade in glioblastoma
AU - Mastrella, Giorgia
AU - Hou, Mengzhuo
AU - Li, Min
AU - Stoecklein, Veit M
AU - Zdouc, Nina
AU - Volmar, Marie N M
AU - Miletic, Hrvoje
AU - Reinhard, Sören
AU - Herold-Mende, Christel C
AU - Kleber, Susanne
AU - Eisenhut, Katharina
AU - Gargiulo, Gaetano
AU - Synowitz, Michael
AU - Vescovi, Angelo Luigi
AU - Harter, Patrick N
AU - Penninger, Josef M
AU - Wagner, Ernst
AU - Mittelbronn, Michel
AU - Bjerkvig, Rolf
AU - Hambardzumyan, Dolores
AU - Schüller, Ulrich
AU - Tonn, Jörg-Christian
AU - Radke, Josefine
AU - Glass, Rainer
AU - Kälin, Roland Eugen
N1 - Copyright ©2019, American Association for Cancer Research.
PY - 2019/5/1
Y1 - 2019/5/1
N2 - Antiangiogenic therapy of glioblastoma (GBM) with bevacizumab, a VEGFA-blocking antibody, may accelerate tumor cell invasion and induce alternative angiogenic pathways. Here we investigate the roles of the proangiogenic apelin receptor APLNR and its cognate ligand apelin in VEGFA/VEGFR2 antiangiogenic therapy against distinct subtypes of GBM. In proneural GBM, apelin levels were downregulated by VEGFA or VEGFR2 blockade. A central role for apelin/APLNR in controlling GBM vascularization was corroborated in a serial implantation model of the angiogenic switch that occurs in human GBM. Apelin and APLNR are broadly expressed in human GBM, and knockdown or knockout of APLN in orthotopic models of proneural or classical GBM subtypes significantly reduced GBM vascularization compared with controls. However, reduction in apelin expression led to accelerated GBM cell invasion. Analysis of stereotactic GBM biopsies from patients as well as from in vitro and in vivo experiments revealed increased dissemination of APLNR-positive tumor cells when apelin levels were reduced. Application of apelin-F13A, a mutant APLNR ligand, blocked tumor angiogenesis and GBM cell invasion. Furthermore, cotargeting VEGFR2 and APLNR synergistically improved survival of mice bearing proneural GBM. In summary, we show that apelin/APLNR signaling controls GBM angiogenesis and invasion and that both pathologic features are blunted by apelin-F13A. We suggest that apelin-F13A can improve the efficiency and reduce the side effects of established antiangiogenic treatments for distinct GBM subtypes. SIGNIFICANCE: Pharmacologic targeting of the APLNR acts synergistically with established antiangiogenic treatments in glioblastoma and blunts therapy resistance to current strategies for antiangiogenesis. See related commentary by Amoozgar et al., p. 2104.
AB - Antiangiogenic therapy of glioblastoma (GBM) with bevacizumab, a VEGFA-blocking antibody, may accelerate tumor cell invasion and induce alternative angiogenic pathways. Here we investigate the roles of the proangiogenic apelin receptor APLNR and its cognate ligand apelin in VEGFA/VEGFR2 antiangiogenic therapy against distinct subtypes of GBM. In proneural GBM, apelin levels were downregulated by VEGFA or VEGFR2 blockade. A central role for apelin/APLNR in controlling GBM vascularization was corroborated in a serial implantation model of the angiogenic switch that occurs in human GBM. Apelin and APLNR are broadly expressed in human GBM, and knockdown or knockout of APLN in orthotopic models of proneural or classical GBM subtypes significantly reduced GBM vascularization compared with controls. However, reduction in apelin expression led to accelerated GBM cell invasion. Analysis of stereotactic GBM biopsies from patients as well as from in vitro and in vivo experiments revealed increased dissemination of APLNR-positive tumor cells when apelin levels were reduced. Application of apelin-F13A, a mutant APLNR ligand, blocked tumor angiogenesis and GBM cell invasion. Furthermore, cotargeting VEGFR2 and APLNR synergistically improved survival of mice bearing proneural GBM. In summary, we show that apelin/APLNR signaling controls GBM angiogenesis and invasion and that both pathologic features are blunted by apelin-F13A. We suggest that apelin-F13A can improve the efficiency and reduce the side effects of established antiangiogenic treatments for distinct GBM subtypes. SIGNIFICANCE: Pharmacologic targeting of the APLNR acts synergistically with established antiangiogenic treatments in glioblastoma and blunts therapy resistance to current strategies for antiangiogenesis. See related commentary by Amoozgar et al., p. 2104.
KW - Journal Article
U2 - 10.1158/0008-5472.CAN-18-0881
DO - 10.1158/0008-5472.CAN-18-0881
M3 - SCORING: Journal article
C2 - 30718358
VL - 79
SP - 2298
EP - 2313
JO - CANCER RES
JF - CANCER RES
SN - 0008-5472
IS - 9
ER -