基因工程小鼠模型中靶向血管内皮生长因子受体2的胰腺癌新生血管对比增强超声检查：早期检测的潜力
Vascular endothelial growth factor receptor type 2-targeted contrast-enhanced US of pancreatic cancer neovasculature in a genetically engineered mouse model: potential for earlier detection.
作者信息
Pysz Marybeth A, Machtaler Steven B, Seeley E Scott, Lee John J, Brentnall Teresa A, Rosenberg Jarrett, Tranquart François, Willmann Jürgen K
机构信息
From the Department of Radiology, Molecular Imaging Program at Stanford (MIPS), Stanford School of Medicine, Stanford University, 300 Pasteur Dr, Room H1307, Stanford, CA 94305 (M.A.P., S.B.M., J.R., J.K.W.); Department of Pathology, University of California at San Francisco, San Francisco, Calif (E.S.S.); Department of Developmental Biology, Institute for Stem Cell Biology and Regenerative Medicine, Howard Hughes Medical Institute, Stanford School of Medicine, Stanford University, Stanford, Calif (J.J.L.); Department of Medicine, University of Washington, Seattle, Wash (T.A.B.); and Bracco Suisse SA, Geneva, Switzerland (F.T.).
出版信息
Radiology. 2015 Mar;274(3):790-9. doi: 10.1148/radiol.14140568. Epub 2014 Oct 14.
PURPOSE
To test ultrasonographic (US) imaging with vascular endothelial growth factor receptor type 2 (VEGFR2)-targeted microbubble contrast material for the detection of pancreatic ductal adenocarcinoma (PDAC) in a transgenic mouse model of pancreatic cancer development.
MATERIALS AND METHODS
Experiments involving animals were approved by the Institutional Administrative Panel on Laboratory Animal Care at Stanford University. Transgenic mice (n = 44; Pdx1-Cre, KRas(G12D), Ink4a(-/-)) that spontaneously develop PDAC starting at 4 weeks of age were imaged by using a dedicated small-animal US system after intravenous injection of 5 × 10(7) clinical-grade VEGFR2-targeted microbubble contrast material. The pancreata in wild-type (WT) mice (n = 64) were scanned as controls. Pancreatic tissue was analyzed ex vivo by means of histologic examination (with hematoxylin-eosin staining) and immunostaining of vascular endothelial cell marker CD31 and VEGFR2. The Wilcoxon rank sum test and linear mixed-effects model were used for statistical analysis.
RESULTS
VEGFR2-targeted US of PDAC showed significantly higher signal intensities (26.8-fold higher; mean intensity ± standard deviation, 6.7 linear arbitrary units [lau] ± 8.5; P < .001) in transgenic mice compared with normal, control pancreata of WT mice (mean intensity, 0.25 lau ± 0.25). The highest VEGFR2-targeted US signal intensities were observed in smaller tumors, less than 3 mm in diameter (30.8-fold higher than control tissue with mean intensity of 7.7 lau ± 9.3 [P < .001]; and 1.7-fold higher than lesions larger than 3 mm in diameter with mean intensity of 4.6 lau ± 5.8 [P < .024]). Ex vivo quantitative VEGFR2 immunofluorescence demonstrated that VEGFR2 expression was significantly higher in pancreatic tumors (P < .001; mean fluorescent intensity, 499.4 arbitrary units [au] ± 179.1) compared with normal pancreas (mean fluorescent intensity, 232.9 au ± 83.7).
CONCLUSION
US with clinical-grade VEGFR2-targeted microbubbles allows detection of small foci of PDAC in transgenic mice.
目的
在胰腺癌发生的转基因小鼠模型中，测试使用靶向血管内皮生长因子受体2（VEGFR2）的微泡造影剂进行超声（US）成像以检测胰腺导管腺癌（PDAC）。
材料与方法
涉及动物的实验经斯坦福大学实验动物护理机构管理小组批准。对4周龄开始自发发生PDAC的转基因小鼠（n = 44；Pdx1-Cre，KRas(G12D)，Ink4a(-/-)）静脉注射5×10⁷临床级靶向VEGFR2的微泡造影剂后，使用专用小动物超声系统进行成像。扫描野生型（WT）小鼠（n = 64）的胰腺作为对照。通过组织学检查（苏木精-伊红染色）以及血管内皮细胞标志物CD31和VEGFR2的免疫染色对胰腺组织进行离体分析。采用Wilcoxon秩和检验和线性混合效应模型进行统计分析。
结果
与WT小鼠正常对照胰腺（平均强度，0.25线性任意单位[lau]±0.25）相比，靶向VEGFR2的PDAC超声在转基因小鼠中显示出明显更高的信号强度（高26.8倍；平均强度±标准差，6.7线性任意单位[lau]±8.5；P <.001）。在直径小于3 mm的较小肿瘤中观察到最高的靶向VEGFR2的超声信号强度（比对照组织高30.8倍，平均强度为7.7 lau±9.3 [P <.001]；比直径大于3 mm的病变高1.7倍，平均强度为4.6 lau±5.8 [P <.024]）。离体定量VEGFR2免疫荧光显示，与正常胰腺（平均荧光强度，232.9任意单位[au]±83.7）相比，胰腺肿瘤中的VEGFR2表达明显更高（P <.001；平均荧光强度，499.4任意单位[au]±179.1）。
结论
使用临床级靶向VEGFR2的微泡进行超声检查可检测转基因小鼠中的小灶性PDAC。
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