Targeting APLN/APLNR improves anti-angiogenic efficiency and blunts pro-invasive side effects of VEGFA/VEGFR2-blockade in glioblastoma

TY - JOUR

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 -