Converging evidence for efficacy from parallel EphB4-targeted approaches in ovarian carcinoma.
Converging evidence for efficacy from parallel EphB4-targeted approaches in ovarian carcinoma.
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DOI：
10.1158/1535-7163.mct-10-0200
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发表时间：
2010-08
影响因子：
5.7
通讯作者：
Sood AK
中科院分区：
文献类型：
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作者：
Spannuth WA;Mangala LS;Stone RL;Carroll AR;Nishimura M;Shahzad MM;Lee SJ;Moreno-Smith M;Nick AM;Liu R;Jennings NB;Lin YG;Merritt WM;Coleman RL;Vivas-Mejia PE;Zhou Y;Krasnoperov V;Lopez-Berestein G;Gill PS;Sood AK
EphB4是一种跨膜受体酪氨酸激酶，在神经可塑性和血管生成中发挥重要作用。EphB4在卵巢癌中过度表达，并预示着不良的临床结果。然而，EphB4在卵巢癌中的生物学意义尚不清楚，也是目前研究的重点。在这里，我们使用几个卵巢癌模型研究了两种不同的EphB4靶向方法(一种新的单抗EphB4-131或siRNA)的生物学效应。EphB4基因沉默显著增加肿瘤细胞的凋亡率，减少迁移(p<；0.001)和侵袭(p<；0.001)。与对照组相比，在A2780-CP20(48%，p<；0.05)和IGROV-AF1(61%，p<；0.05)模型中，EphB4 siRNA-DOPC单独显著降低了肿瘤生长。在A2780-CP20和IGROV-AF1模型中，EphB4 siRNA-DOPC和多西紫杉醇的联合治疗导致了肿瘤重量的最大减轻(与对照组相比减少了89-95%；两组均为0.05)。在A2780-CP20和IGROV-AF1模型中，EphB4-131抗体降低了EphB4蛋白水平，使肿瘤生长减少了80%-83%(p<；两种模型均为0.01)。在A2780-CP20和IGROV-AF1模型中，EphB4-131和多西紫杉醇的联合应用导致了最大的肿瘤减少(与对照组相比减少了94-98%；P<；两组均为0.05)。与对照组相比，EphB4靶向导致肿瘤血管生成减少(p<；0.001)，增殖减少(p<；0.001)，肿瘤细胞凋亡率增加(p<；0.001)，这可能是通过调节PI3K信号发生的。总而言之，这些数据确定EphB4是卵巢癌的有价值的治疗靶点，并为进一步开发提供了两种新的策略。
EphB4 is a transmembrane receptor tyrosine kinase that plays an important role in neural plasticity and angiogenesis. EphB4 is overexpressed in ovarian cancer and is predictive of poor clinical outcome. However, the biological significance of EphB4 in ovarian cancer is not known and is the focus of the current study. Here, we examined the biological effects of two different methods of EphB4 targeting (a novel monoclonal antibody, EphB4-131 or siRNA) using several ovarian cancer models. EphB4 gene silencing significantly increased tumor cell apoptosis, and decreased migration (p<0.001) and invasion (p<0.001). Compared to controls, EphB4 siRNA-DOPC alone significantly reduced tumor growth in the A2780-cp20 (48%, p<0.05) and IGROV-af1 (61%, p<0.05) models. Combination therapy with EphB4 siRNA-DOPC and docetaxel resulted in the greatest reduction in tumor weight in both A2780-cp20 and IGROV-af1 models (89-95% reduction versus controls; p<0.05 for both groups). The EphB4-131 antibody, which reduced EphB4 protein level, decreased tumor growth by 80-83% (p<0.01 for both models) in the A2780-cp20 and IGROV-af1 models. Combination of EphB4-131 and docetaxel resulted in the greatest tumor reduction in both A2780-cp20 and IGROV-af1 models (94-98% reduction versus controls; p<0.05 for both groups). Compared to controls, EphB4 targeting resulted in reduced tumor angiogenesis (p<0.001), proliferation (p<0.001), and increased tumor cell apoptosis (p<0.001), which likely occurs through modulation of PI3K signaling. Collectively, these data identify EphB4 as a valuable therapeutic target in ovarian cancer and offer two new strategies for further development.