SDF-1 Blockade Enhances Anti-VEGF Therapy of Glioblastoma and Can Be Monitored by MRI.
SDF-1 Blockade Enhances Anti-VEGF Therapy of Glioblastoma and Can Be Monitored by MRI.
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DOI：
10.1016/j.neo.2016.11.010
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发表时间：
2017-01
期刊：
影响因子：
4.8
通讯作者：
Brown, J. Martin
中科院分区：
文献类型：
--
作者：
Deng, Lei;Stafford, Jason H.;Liu, Shie-Chau;Chernikova, Sophia B.;Merchant, Milton;Recht, Lawrence;Brown, J. Martin
尽管抗血管生成疗法已被批准用于多形性胶质母细胞瘤（GBM）患者，但生存获益仍然有限。抗血管生成治疗的耐药机制之一是基质衍生因子（SDF）-1α（CXCL-12）诱导缺氧和随后的巨噬细胞募集。在这项研究中，我们测试了一种新型SDF-1α抑制剂olaptesed pegol（OLA-PEG，NOX-A12）是否可以逆转巨噬细胞的募集并增强抗血管内皮生长因子（VEGF）治疗的抗肿瘤作用。我们还测试了磁共振成像（MRI）与ferumoxytol作为造影剂是否可以提供早期的巨噬细胞阻滞的信息。采用裸鼠原位人G12胶质母细胞瘤和大鼠C6胶质母细胞瘤作为动物模型。用贝伐单抗或B-20（均为抗VEGF抗体）治疗。用ferumoxytol对大鼠进行MR成像，用于巨噬细胞检测。VEGF阻断后肿瘤缺氧和SDF-1α表达增加。与单独抗VEGF治疗相比，将OLA-PEG加入贝伐单抗或B-20显著延长了携带颅内GBM的啮齿动物的生存期。VEGF阻断可增加肿瘤内CD 68+肿瘤相关巨噬细胞（TAM），但与单独VEGF阻断相比，OLA-PEG + VEGF阻断的组合显著降低TAM水平。与单独VEGF阻断相比，使用ferumoxytol作为造影剂的MRI非侵入性地证实了OLA-PEG +抗VEGF治疗的大鼠中巨噬细胞减少。总之，用OLA-PEG抑制SDF-1可通过VEGF阻断抑制TAM的募集，并增强其在GBM中的抗肿瘤功效。使用ferumoxytol作为造影剂的非侵入性MRI提供了关于OLA-PEG减少TAM的作用的早期信息。
Despite the approval of antiangiogenic therapy for glioblastoma multiforme (GBM) patients, survival benefits are still limited. One of the resistance mechanisms for antiangiogenic therapy is the induction of hypoxia and subsequent recruitment of macrophages by stromal-derived factor (SDF)-1α (CXCL-12). In this study, we tested whether olaptesed pegol (OLA-PEG, NOX-A12), a novel SDF-1α inhibitor, could reverse the recruitment of macrophages and potentiate the antitumor effect of anti–vascular endothelial growth factor (VEGF) therapy. We also tested whether magnetic resonance imaging (MRI) with ferumoxytol as a contrast agent could provide early information on macrophage blockade. Orthotopic human G12 glioblastomas in nude mice and rat C6 glioblastomas were employed as the animal models. These were treated with bevacizumab or B-20, both anti-VEGF antibodies. Rats were MR imaged with ferumoxytol for macrophage detection. Tumor hypoxia and SDF-1α expression were elevated by VEGF blockade. Adding OLA-PEG to bevacizumab or B-20 significantly prolonged the survival of rodents bearing intracranial GBM compared with anti-VEGF therapy alone. Intratumoral CD68+ tumor associated macrophages (TAMs) were increased by VEGF blockade, but the combination of OLA-PEG + VEGF blockade markedly lowered TAM levels compared with VEGF blockade alone. MRI with ferumoxytol as a contrast agent noninvasively demonstrated macrophage reduction in OLA-PEG + anti-VEGF–treated rats compared with VEGF blockade alone. In conclusion, inhibition of SDF-1 with OLA-PEG inhibited the recruitment of TAMs by VEGF blockage and potentiated its antitumor efficacy in GBM. Noninvasive MRI with ferumoxytol as a contrast agent provides early information on the effect of OLA-PEG in reducing TAMs.
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影响因子：
50.3
作者：
Ahn, G-One;Brown, J. Martin
通讯作者：
Brown, J. Martin
影响因子：
11.2
作者：
Daly, Christopher;Eichten, Alexandra;Thurston, Gavin
通讯作者：
Thurston, Gavin
肿瘤相关巨噬细胞的细胞和分子起源。
DOI：
10.1126/science.1252510
发表时间：
2014-05-23
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Franklin RA;Liao W;Sarkar A;Kim MV;Bivona MR;Liu K;Pamer EG;Li MO
通讯作者：
Li MO
DOI：
10.1038/nrc2442
发表时间：
2008-08
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
通讯作者：
--
影响因子：
11.2
作者：
Hughes R;Qian BZ;Rowan C;Muthana M;Keklikoglou I;Olson OC;Tazzyman S;Danson S;Addison C;Clemons M;Gonzalez-Angulo AM;Joyce JA;De Palma M;Pollard JW;Lewis CE
通讯作者：
Lewis CE