Soluble Tie2 overrides the heightened invasion induced by anti-angiogenesis therapies in gliomas.
Soluble Tie2 overrides the heightened invasion induced by anti-angiogenesis therapies in gliomas.
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DOI：
10.18632/oncotarget.7550
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发表时间：
2016-03-29
期刊：
影响因子：
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通讯作者：
Gomez-Manzano C
中科院分区：
文献类型：
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作者：
Cortes-Santiago N;Hossain MB;Gabrusiewicz K;Fan X;Gumin J;Marini FC;Alonso MM;Lang F;Yung WK;Fueyo J;Gomez-Manzano C
使用抗血管内皮生长因子（VEGF）药物贝伐珠单抗治疗后胶质母细胞瘤复发的特点是高度浸润和恶性行为，导致手术切除和化疗无效。我们的小组之前曾报道，在抗 VEGF 治疗后，表达 Tie2 的单核细胞 (TEM) 异常地存在于肿瘤/正常脑界面，并且它们在这些肿瘤的侵袭性生长中发挥着重要作用。在这里，我们的目的是进一步了解导致这种促侵袭性肿瘤微环境的机制。对 U87MG 异种神经胶质瘤模型和 GL261 小鼠同基因模型的检查显示，在针对 VEGF 或 VEGF 受体 (VEGFR) 的抗血管生成治疗后，通过免疫组织化学分析、免疫荧光分析和酶联分析评估，血管生成素 2 (Ang2)（Tie2 的天然配体）的肿瘤表达增加。 肿瘤裂解物的免疫吸附测定。迁移和明胶溶解测定表明，Ang2 既可作为 TEM 的化学引诱剂，又可作为其肿瘤重塑特性的增强信号。因此，Ang2体内转导到颅内神经胶质瘤中增加了TEM向肿瘤的募集。为了减少抗血管生成治疗后的侵袭性肿瘤生长，我们使用 Tie2 诱饵受体靶向 Ang-Tie2 轴。使用同基因模型，我们观察到肿瘤内可溶性 Tie2 的过度表达阻止了 TEM 向肿瘤的募集以及抗血管生成治疗后侵袭的发展。总而言之，这些数据表明 Ang2-Tie2 通路在抗血管生成治疗后侵袭性胶质瘤复发中发挥着积极作用，并为在胶质母细胞瘤患者中测试 VEGF 和 Ang-Tie2 通路联合靶向提供了理论基础。
Glioblastoma recurrence after treatment with the anti–vascular endothelial growth factor (VEGF) agent bevacizumab is characterized by a highly infiltrative and malignant behavior that renders surgical excision and chemotherapy ineffective. Our group has previously reported that Tie2-expressing monocytes (TEMs) are aberrantly present at the tumor/normal brain interface after anti-VEGF therapies and their significant role in the invasive outgrowth of these tumors. Here, we aimed to further understand the mechanisms leading to this pro-invasive tumor microenvironment. Examination of a U87MG xenogeneic glioma model and a GL261 murine syngeneic model showed increased tumor expression of angiopoietin 2 (Ang2), a natural ligand of Tie2, after anti-angiogenesis therapies targeting VEGF or VEGF receptor (VEGFR), as assessed by immunohistochemical analysis, immunofluorescence analysis, and enzyme-linked immunosorbent assays of tumor lysates. Migration and gelatinolytic assays showed that Ang2 acts as both a chemoattractant of TEMs and an enhancing signal for their tumor-remodeling properties. Accordingly, in vivo transduction of Ang2 into intracranial gliomas increased recruitment of TEMs into the tumor. To reduce invasive tumor outgrowth after anti-angiogenesis therapy, we targeted the Ang-Tie2 axis using a Tie2 decoy receptor. Using syngeneic models, we observed that overexpression of soluble Tie2 within the tumor prevented the recruitment of TEMs to the tumor and the development of invasion after anti-angiogenesis treatment. Taken together, these data indicate an active role for the Ang2-Tie2 pathway in invasive glioma recurrence after anti-angiogenesis treatment and provide a rationale for testing the combined targeting of VEGF and Ang-Tie2 pathways in patients with glioblastoma.