抗血管内皮生长因子受体-1 单克隆抗体 D16F7 抑制人脑胶质瘤和脑胶质瘤干细胞的侵袭性。
The anti-vascular endothelial growth factor receptor-1 monoclonal antibody D16F7 inhibits invasiveness of human glioblastoma and glioblastoma stem cells.
机构信息
Department of Systems Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133, Rome, Italy.
Laboratory of Molecular Oncology, "Istituto Dermopatico dell'Immacolata"-IRCCS, Via dei Monti di Creta, 104, 00167, Rome, Italy.
出版信息
J Exp Clin Cancer Res. 2017 Aug 10;36(1):106. doi: 10.1186/s13046-017-0577-2.
BACKGROUND
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.
METHODS
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.
RESULTS
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.
CONCLUSION
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.
背景
胶质母细胞瘤（GBM）是一种高度迁移、侵袭和血管生成的脑肿瘤。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。我们最近生成了新型抗 VEGFR-1 单克隆抗体（mAb）D16F7，它可减弱 VEGFR-1 同源二聚体/激活，而不影响 VEGF-A 和 PlGF 结合。
方法
在本研究中，我们通过免疫组织化学评估了 42 例人 GBM 组织样本中 VEGFR-1 的表达，通过 qRT-PCR 和/或 Western blot 分析评估了 6 种细胞系和 18 种 GBM 干细胞（GSCs）中 VEGFR-1 的表达。在 VEGFR-1 阳性的 GBM 或 GSCs 中，我们还分析了 D16F7 抑制 GBM 对 VEGF-A 和 PlGF 的侵袭能力的能力。
结果
大多数 GBM 标本 VEGFR-1 染色阳性，除了一种 GBM 细胞系外，所有细胞系均表达 VEGFR-1。另一方面，在 GSCs 中，受体的表达是异质的。D16F7 降低了 VEGFR-1 阳性 GBM 细胞系和患者来源的 GSCs 对 VEGF-A 和 PlGF 的迁移和侵袭。有趣的是，这种效应也在 VEGFR-1 阳性的 GSCs 中转染过表达野生型 EGFR（EGFRwt）或突变型 EGFR（配体结合域缺失的 EGFRvIII）时观察到。此外，D16F7 通过降低受体配体诱导的酪氨酸 1213 自身磷酸化和下游 Erk1/2 激活来抑制 VEGFR-1 过表达 GBM 细胞中的细胞内信号转导。
结论
本研究结果表明，VEGFR-1 是 GBM 治疗的一个相关靶点，D16F7 衍生的人源化 mAb 值得进一步研究。
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