Department of Medicine, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.
Cancer Biol Ther. 2010 Dec 15;10(12):1326-33. doi: 10.4161/cbt.10.12.14009.
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 antagonist.
血管内皮生长因子 (VEGF) A 是肿瘤血管生成的主要促进因子，也是抗血管生成癌症治疗的主要靶点。为了研究内皮细胞信号转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，以检测激活的 ERK、STAT3 和 AKT 在血管内皮中的表达。正常器官内皮中的磷酸化 (p)-ERK 和 p-STAT3 表达可以忽略不计，但在肿瘤内皮中显著升高。p-AKT 在肿瘤和正常内皮中均存在显著且相当的水平。在诱导表达更多 VEGF 的 K1735 肿瘤中，内皮 p-ERK、p-STAT3 和 p-AKT 增加，伴随着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 的表达，伴随着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）可以区分肿瘤血管和正常血管，并且这两种信号转导中间物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。
