Fernando Stephen, Fletcher Bradley S
Department of Pharmacology and Therapeutics, College of Medicine, University of Florida, Gainesville, FL 32610-0267, USA.
Cancer Res. 2009 Jun 15;69(12):5126-32. doi: 10.1158/0008-5472.CAN-09-0725.
Tumor endothelial marker 8 (TEM8) is a recently described protein that is preferentially expressed within tumor endothelium. We have developed a fusion protein that targets TEM8 and disrupts tumor vasculature by promoting localized thrombosis. Fusion protein specificity and function were evaluated using Western blot analysis, ELISA, and enzymatic assays. A xenograft model of colorectal carcinoma was used to test the efficacy of targeted and control fusion proteins. Mice treated with the gene encoding anti-TEM8/truncated tissue factor exhibited a 53% reduction in tumor volume when compared with the untreated animals (P < 0.0001; n = 10) and achieved a 49% increase in tumor growth delay by Kaplan-Meier analysis (P = 0.0367; n = 6). Immunohistochemistry confirmed tumor endothelial expression of TEM8, fusion protein homing to tumor vasculature, decrease in vessel density, and localized areas of thrombosis. These data support the hypothesis that targeting TEM8 can be an effective approach to influence tumor development by disrupting tumor vasculature.
肿瘤内皮标志物8（TEM8）是一种最近被描述的蛋白，它优先表达于肿瘤内皮细胞。我们开发了一种靶向TEM8的融合蛋白，通过促进局部血栓形成来破坏肿瘤血管。使用蛋白质印迹分析、酶联免疫吸附测定和酶活性测定评估融合蛋白的特异性和功能。利用结直肠癌异种移植模型来测试靶向融合蛋白和对照融合蛋白的疗效。与未治疗的动物相比，用编码抗TEM8/截短组织因子的基因治疗的小鼠肿瘤体积减少了53%（P < 0.0001；n = 10），通过Kaplan-Meier分析，肿瘤生长延迟增加了49%（P = 0.0367；n = 6）。免疫组织化学证实了TEM8在肿瘤内皮细胞中的表达、融合蛋白归巢至肿瘤血管、血管密度降低以及局部血栓形成区域。这些数据支持这样的假设，即靶向TEM8可能是一种通过破坏肿瘤血管来影响肿瘤发展的有效方法。
