Effect of VEGF and VEGF Trap on vascular endothelial cell signaling in tumors
Effect of VEGF and VEGF Trap on vascular endothelial cell signaling in tumors
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DOI：
10.4161/cbt.10.12.14009
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发表时间：
2010-12-15
影响因子：
3.6
通讯作者：
Lee, William M. F.
中科院分区：
文献类型：
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作者：
Lassoued, Wiem;Murphy, Danielle;Lee, William M. F.
血管内皮生长因子 (VEGF) A 是肿瘤血管生成的主要促进剂，也是抗血管生成癌症治疗的主要靶点。为了检查内皮细胞信号传导是否可以提供体内血管生成和 VEGF 活性的组织学生物标志物，我们对正常小鼠器官和多种肿瘤模型进行了免疫组织化学研究，以了解激活的 ERK、STAT3 和 AKT 的内皮表达。 Phospho(p)-ERK 和 p-STAT3 的表达在正常器官的内皮细胞中可以忽略不计，但在肿瘤内皮细胞中显着升高。 p-AKT 在肿瘤和正常内皮细胞中均以显着且可比较的水平存在。在 K1735 肿瘤中，诱导表达更多 VEGF，内皮 p-ERK、p-STAT3 和 p-AKT 增加，并伴有加速血管生成的迹象。用 VEGF 抑制剂 VEGF Trap（阿柏西普）治疗 K1735 和 Colo-205 肿瘤，可降低肿瘤内皮 p-ERK、p-STAT3 和 p-AKT 表达，并伴有抗血管生成作用的迹象。这些结果表明内皮 p-ERK 和 p-STAT3（但不是 p-AKT）将肿瘤与正常血管区分开来，并且这两种信号中间体的存在可能是肿瘤血管生成活性和 VEGF 拮抗剂抑制血管生成的有用指标。
Vascular endothelial growth factor (VEGF) A is a major promoter of tumor angiogenesis and a prime target of antiangiogenic cancer therapy. To examine whether endothelial cell signaling might provide histological biomarkers of angiogenesis and VEGF activity in vivo, normal mouse organs and multiple tumor models were studied immunohistochemically for endothelial expression of activated ERK, STAT3 and AKT. Phospho(p)-ERK and p-STAT3 expression was negligible in the endothelia of normal organs but was significantly elevated in tumor endothelium. p-AKT was present at significant and comparable levels in both tumor and normal endothelia. In K1735 tumors induced to express more VEGF, endothelial p-ERK, p-STAT3 and p-AKT increased accompanied by signs of accelerated angiogenesis. Treatment of K1735 and Colo-205 tumors with the VEGF inhibitor, VEGF Trap (aflibercept), decreased tumor endothelial p-ERK, p-STAT3 and p-AKT expression accompanied by signs of antiangiogenic effect. These results show that endothelial p-ERK and p-STAT3 (but not p-AKT) distinguish tumor from normal vessels and that the presence of these two signaling intermediates may be useful indicators of tumor angiogenic activity and angiogenesis inhibition by VEGF antagonists.