Tumor Angiogenic Marker Expression Levels during Tumor Growth: Longitudinal Assessment with Molecularly Targeted Microbubbles and US Imaging
Tumor Angiogenic Marker Expression Levels during Tumor Growth: Longitudinal Assessment with Molecularly Targeted Microbubbles and US Imaging
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DOI：
10.1148/radiol.10101079
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发表时间：
2011-03-01
期刊：
影响因子：
19.7
通讯作者：
Willmann, Juergen K.
中科院分区：
文献类型：
--
作者：
Deshpande, Nirupama;Ren, Ying;Willmann, Juergen K.
目的：评价分子靶向微泡（MB）和超声（US）在无创评估肿瘤生长过程中体内肿瘤血管内皮细胞上三种血管生成标志物α（v）β（3）整合素、内皮糖蛋白和血管内皮生长因子受体（VEGFR）2表达水平中的应用。材料和方法：使用实验动物的所有程序均由实验动物护理机构管理小组批准。在流动剪切应力条件下在细胞培养物中测试三种类型的靶向MB（MB整联蛋白、MB内皮糖蛋白、MBVEGFR 2）的结合特异性。在小鼠（n = 54）的三种皮下癌异种移植物（乳腺癌、卵巢癌、胰腺癌）中，在三个肿瘤阶段（小、中、大）测量使用三种MB类型的体内靶向造影剂增强的US成像信号。体内US成像信号与离体血管生成标记物表达相关。显着差异进行了评估，通过使用学生t，方差分析，Wilcoxon，Tukey诚实显着差异tests.Results：细胞附着的所有三种MB类型是显着（P = 0.016）高于对照MBs相比，这种附着可以显着（P = 0.026）减少封闭抗体。与阴性对照细胞相比，血管生成标志物表达细胞显著（P = 0.003）结合更多靶向MB，MB附着显著（P <0.001）与细胞上的标志物表达水平相关（rho = 0.87）。在早期乳腺癌和卵巢癌中，体内靶向对比增强超声显示出显著性（P = .07）。相关性良好（rho >= 0.63; P
Purpose: To evaluate the use of molecularly targeted microbubbles (MBs) and ultrasonography (US) in the noninvasive assessment of the level of expression of three angiogenic markers, alpha(v)beta(3) integrin, endoglin, and vascular endothelial growth factor receptor (VEGFR) 2, on tumor vascular endothelial cells in vivo during tumor growth.Materials and Methods: All procedures using laboratory animals were approved by the Institutional Administrative Panel on Laboratory Animal Care. Binding specificity of three types of targeted MBs (MBIntegrin, MBEndoglin, MBVEGFR2) was tested in cell culture under flow shear stress conditions. In vivo targeted contrast material-enhanced US imaging signal using the three MB types was measured at three tumor stages (small, medium, large) in three subcutaneous cancer xenografts (breast, ovarian, pancreatic cancer) in mice (n = 54). In vivo US imaging signal was correlated with ex vivo angiogenic marker expression. Significant differences were evaluated by using the Student t, analysis of variance, Wilcoxon, and Tukey Honest Significant Difference tests.Results: Cell attachment of all three MB types was significantly (P = .016) higher compared with control MBs, and this attachment could be significantly (P = .026) decreased by blocking antibodies. Angiogenic marker-expressing cells bound significantly (P = .003) more targeted MBs than negative control cells, and MB attachment significantly (P < .001) correlated with marker expression levels on cells (rho = 0.87). In early stage breast and ovarian cancers, in vivo targeted contrast-enhanced US demonstrated significantly (P = .07). There was good correlation (rho >= 0.63; P