The anti-vascular endothelial growth factor receptor-1 monoclonal antibody D16F7 inhibits invasiveness of human glioblastoma and glioblastoma stem cells.
The anti-vascular endothelial growth factor receptor-1 monoclonal antibody D16F7 inhibits invasiveness of human glioblastoma and glioblastoma stem cells.
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DOI：
10.1186/s13046-017-0577-2
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发表时间：
2017-08-10
期刊：
影响因子：
--
通讯作者：
Graziani G
中科院分区：
文献类型：
--
作者：
Atzori MG;Tentori L;Ruffini F;Ceci C;Lisi L;Bonanno E;Scimeca M;Eskilsson E;Daubon T;Miletic H;Ricci Vitiani L;Pallini R;Navarra P;Bjerkvig R;D'Atri S;Lacal PM;Graziani G
胶质母细胞瘤（GBM）是一种高度迁移性、侵袭性和血管生成性的脑肿瘤。与血管内皮生长因子-A（VEGF-A）一样，胎盘生长因子（PlGF）促进GBM血管生成。VEGF-A是VEGF受体-1（VEGFR-1）和VEGFR-2的配体，而PlGF仅与VEGFR-1相互作用。我们最近产生了新的抗VEGFR-1单克隆抗体（mAb）D16 F7，其减少VEGFR-1同源二聚化/活化，而不影响VEGF-A和PlGF结合。在本研究中，我们通过免疫组织化学评估了人GBM组织样品（n = 42）中VEGFR-1的表达，通过qRT-PCR和/或蛋白质印迹分析评估了细胞系（n = 6）和GBM干细胞（GSC）（n = 18）中VEGFR-1的表达。在VEGFR-1阳性GBM或GSC中，我们还分析了D16 F7响应VEGF-A和PlGF抑制GBM侵袭的能力。大多数GBM标本对VEGFR-1染色呈阳性，除一种GBM细胞系外，所有细胞系均表达VEGFR-1。另一方面，在GSC中，受体的表达是异质性的。D16 F7减少了响应于VEGF-A和PlGF的VEGFR-1阳性GBM细胞系和患者来源的GSC的迁移和侵袭。有趣的是，在转染过表达野生型EGFR（EGFRwt+）或突变型EGFR（配体结合结构域缺陷型EGFRvIII+）的VEGFR-1阳性GSC中也观察到这种效应。此外，D16 F7通过减少受体配体诱导的酪氨酸1213处的受体自磷酸化和下游Erk 1/2活化来抑制VEGFR-1过表达GBM细胞中的细胞内信号转导。这项研究的结果表明，VEGFR-1是GBM治疗的相关靶标，D16 F7衍生的人源化mAb值得进一步研究。本文的在线版本（doi：10.1186/s13046-017-0577-2）包含补充材料，可供授权用户使用。
Glioblastoma (GBM) is a highly migratory, invasive, and angiogenic brain tumor. Like vascular endothelial growth factor-A (VEGF-A), placental growth factor (PlGF) promotes GBM angiogenesis. VEGF-A is a ligand for both VEGF receptor-1 (VEGFR-1) and VEGFR-2, while PlGF interacts exclusively with VEGFR-1. We recently generated the novel anti-VEGFR-1 monoclonal antibody (mAb) D16F7 that diminishes VEGFR-1 homodimerization/activation without affecting VEGF-A and PlGF binding. In the present study, we evaluated the expression of VEGFR-1 in human GBM tissue samples (n = 42) by immunohistochemistry, in cell lines (n = 6) and GBM stem cells (GSCs) (n = 18) by qRT-PCR and/or western blot analysis. In VEGFR-1 positive GBM or GSCs we also analyzed the ability of D16F7 to inhibit GBM invasiveness in response to VEGF-A and PlGF. Most of GBM specimens stained positively for VEGFR-1 and all but one GBM cell lines expressed VEGFR-1. On the other hand, in GSCs the expression of the receptor was heterogeneous. D16F7 reduced migration and invasion of VEGFR-1 positive GBM cell lines and patient-derived GSCs in response to VEGF-A and PlGF. Interestingly, this effect was also observed in VEGFR-1 positive GSCs transfected to over-express wild-type EGFR (EGFRwt+) or mutant EGFR (ligand binding domain-deficient EGFRvIII+). Furthermore, D16F7 suppressed intracellular signal transduction in VEGFR-1 over-expressing GBM cells by reducing receptor auto-phosphorylation at tyrosine 1213 and downstream Erk1/2 activation induced by receptor ligands. The results from this study suggest that VEGFR-1 is a relevant target for GBM therapy and that D16F7-derived humanized mAbs warrant further investigation. The online version of this article (doi:10.1186/s13046-017-0577-2) contains supplementary material, which is available to authorized users.
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影响因子：
10.5
作者：
Inda, Maria-del-Mar;Bonavia, Rudy;Furnari, Frank
通讯作者：
Furnari, Frank
影响因子：
16.6
作者：
Cudmore, Melissa J.;Hewett, Peter W.;Ahmed, Asif
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影响因子：
--
作者：
D'Alessio A;Proietti G;Lama G;Biamonte F;Lauriola L;Moscato U;Vescovi A;Mangiola A;Angelucci C;Sica G
通讯作者：
Sica G
影响因子：
82.9
作者：
Autiero, M;Waltenberger, J;Carmeliet, P
通讯作者：
Carmeliet, P
影响因子：
7.3
作者：
Anisimov, Andrey;Leppanen, Veli-Matti;Alitalo, Kari
通讯作者：
Alitalo, Kari