Department of Ophthalmology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
Oncogene. 2013 Nov 14;32(46):5369-76. doi: 10.1038/onc.2012.622. Epub 2013 Jan 21.
Understanding tumor-induced angiogenesis is a challenging problem with important consequences for the diagnosis and treatment of cancer. In this study, we define a novel function for epithelial membrane protein-2 (EMP2) in the control of angiogenesis. EMP2 functions as an oncogene in endometrial cancer, and its expression has been linked to decreased survival. Using endometrial cancer xenografts, modulation of EMP2 expression resulted in profound changes to the tumor microvasculature. Under hypoxic conditions, upregulation of EMP2 promoted vascular endothelial growth factors (VEGF) expression through a HIF-1α-dependent pathway and resulted in successful capillary-like tube formation. In contrast, reduction of EMP2 correlated with reduced HIF-1α and VEGF expression with the net consequence of poorly vascularized tumors in vivo. We have previously shown that targeting of EMP2 using diabodies in endometrial cancer resulted in a reduction of tumor load, and since then we have constructed a fully human EMP2 IgG1. Treatment of endometrial cancer cells with EMP2-IgG1 reduced tumor load with a significant improvement in survival. These results support the role of EMP2 in the control of the tumor microenvironment and confirm the cytotoxic effects observed by EMP2 treatment in vivo.
了解肿瘤诱导的血管生成是一个具有重要诊断和治疗癌症意义的挑战性问题。在这项研究中，我们定义了上皮膜蛋白-2（EMP2）在控制血管生成中的一个新功能。EMP2在子宫内膜癌中作为癌基因发挥作用，其表达与生存率降低有关。使用子宫内膜癌异种移植物，调节 EMP2 的表达导致肿瘤微血管发生深刻变化。在缺氧条件下，EMP2 的上调通过 HIF-1α 依赖性途径促进血管内皮生长因子（VEGF）的表达，导致成功的毛细血管样管形成。相比之下，EMP2 的减少与 HIF-1α 和 VEGF 表达的减少相关，导致体内肿瘤血管生成不良。我们之前已经表明，使用双抗体靶向子宫内膜癌中的 EMP2 导致肿瘤负荷减少，此后我们构建了完全人源的 EMP2 IgG1。用 EMP2-IgG1 处理子宫内膜癌细胞减少了肿瘤负荷，显著提高了生存率。这些结果支持 EMP2 在控制肿瘤微环境中的作用，并证实了 EMP2 在体内治疗中观察到的细胞毒性作用。
