Glioblastoma resistance to anti-VEGF therapy is associated with myeloid cell infiltration, stem cell accumulation, and a mesenchymal phenotype
Glioblastoma resistance to anti-VEGF therapy is associated with myeloid cell infiltration, stem cell accumulation, and a mesenchymal phenotype
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DOI：
10.1093/neuonc/nos158
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发表时间：
2012-11-01
期刊：
影响因子：
15.9
通讯作者：
de Groot, John F.
中科院分区：
文献类型：
--
作者：
Piao, Yuji;Liang, Ji;de Groot, John F.
血管内皮生长因子（VEGF）是血管生成的重要调节因子。抑制胶质母细胞瘤中vegf受体(R)信号转导通路最近被证明可以延缓进展，但抗vegf治疗和VEGFR抑制剂的相对益处、反应和失败机制尚不清楚。本研究的目的是评估VEGF隔离和/或VEGFR抑制对原位肿瘤生长的相对有效性以及治疗耐药的机制。我们不仅评估了抗vegf治疗（贝伐单抗）、抗vegfr治疗（舒尼替尼）及其联合治疗对原位胶质瘤小鼠存活的影响，还利用流式细胞术和免疫组织化学技术评估了两种治疗对肿瘤血管、细胞增殖、间充质和干细胞标志物以及骨髓细胞浸润的差异影响。与对照组或单独舒尼替尼相比，贝伐单抗显著延长了生存期。两种抗血管生成药物最初都能减少巨噬细胞的浸润和肿瘤血管。然而，多靶点VEGFR抑制，而不是VEGF隔离，迅速产生血管梯度，更迅速地诱导肿瘤缺氧。巨噬细胞的再浸润与缺氧的诱导有关。与贝伐单抗单独治疗相比，贝伐单抗和舒尼替尼联合治疗提高了动物存活率。然而，在肿瘤进展时，观察到CD11b/Gr1粒细胞浸润显著增加，肿瘤出现侵袭性间充质特征，干细胞标志物表达增加。总的来说，我们的研究结果表明，与舒尼替尼相比，贝伐单抗治疗肿瘤血管的减少时间更长，这与缺氧发展的延迟和浸润性骨髓细胞的持续减少有关。
Vascular endothelial growth factor (VEGF) is a critical regulator of angiogenesis. Inhibiting the VEGFVEGF receptor (R) signal transduction pathway in glioblastoma has recently been shown to delay progression, but the relative benefit and mechanisms of response and failure of anti-VEGF therapy and VEGFR inhibitors are not well understood. The purpose of our study was to evaluate the relative effectiveness of VEGF sequestration and/or VEGFR inhibition on orthotopic tumor growth and the mechanism(s) of treatment resistance. We evaluated, not only, the effects of anti-VEGF therapy (bevacizumab), anti-VEGFR therapy (sunitinib), and the combination on the survival of mice bearing orthotopic gliomas, but also the differential effects of the treatments on tumor vascularity, cellular proliferation, mesenchymal and stem cell markers, and myeloid cell infiltration using flow cytometry and immunohistochemistry. Bevacizumab significantly prolonged survival compared with the control or sunitinib alone. Both antiangiogenic agents initially reduced infiltration of macrophages and tumor vascularity. However, multitargeted VEGFR inhibition, but not VEGF sequestration, rapidly created a vascular gradient and more rapidly induced tumor hypoxia. Re-infiltration of macrophages was associated with the induction of hypoxia. Combination treatment with bevacizumab and sunitinib improved animal survival compared with bevacizumab therapy alone. However, at the time of tumor progression, a significant increase in CD11b/Gr1 granulocyte infiltration was observed, and tumors developed aggressive mesenchymal features and increased stem cell marker expression. Collectively, our results demonstrate a more prolonged decrease in tumor vascularity with bevacizumab than with sunitinib, associated with a delay in the development of hypoxia and sustained reduction of infiltrated myeloid cells.