Brain Tumor Center, Department of Neuro-Oncology, Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Neuro Oncol. 2012 Nov;14(11):1379-92. doi: 10.1093/neuonc/nos158. Epub 2012 Sep 10.
Vascular endothelial growth factor (VEGF) is a critical regulator of angiogenesis. Inhibiting the VEGF-VEGF 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.
血管内皮生长因子（VEGF）是血管生成的关键调节因子。最近的研究表明，抑制胶质母细胞瘤中的 VEGF-VEGF 受体（R）信号转导通路可以延迟肿瘤进展，但抗 VEGF 治疗和 VEGFR 抑制剂的相对益处以及反应和失败的机制尚不清楚。我们研究的目的是评估 VEGF 隔离和/或 VEGFR 抑制对原位肿瘤生长的相对有效性，以及治疗抵抗的机制。我们不仅评估了抗 VEGF 治疗（贝伐单抗）、抗 VEGFR 治疗（舒尼替尼）和联合治疗对荷瘤小鼠存活的影响，还通过流式细胞术和免疫组织化学评估了这些治疗对肿瘤血管生成、细胞增殖、间充质和干细胞标志物以及髓样细胞浸润的差异影响。贝伐单抗与对照组或单独使用舒尼替尼相比，显著延长了生存期。两种抗血管生成药物最初均减少了巨噬细胞和肿瘤血管的浸润。然而，多靶点 VEGFR 抑制，而不是 VEGF 隔离，迅速造成血管梯度，并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。贝伐单抗和舒尼替尼联合治疗与单独使用贝伐单抗治疗相比，改善了动物的存活率。然而，在肿瘤进展时，观察到 CD11b(+)/Gr1(+)粒细胞浸润显著增加，肿瘤表现出侵袭性的间充质特征和干细胞标志物表达增加。总的来说，我们的结果表明，贝伐单抗比舒尼替尼更能长时间降低肿瘤血管生成，与缺氧的发展延迟和浸润的髓样细胞的持续减少有关。
