Vessel fractions in tumor xenografts depicted by flow- or contrast-sensitive three-dimensional high-frequency Doppler ultrasound respond differently to antiangiogenic treatment
Vessel fractions in tumor xenografts depicted by flow- or contrast-sensitive three-dimensional high-frequency Doppler ultrasound respond differently to antiangiogenic treatment
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DOI：
10.1158/0008-5472.can-08-0285
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发表时间：
2008-09-01
期刊：
影响因子：
11.2
通讯作者：
Kiessling, Fabian
中科院分区：
文献类型：
--
作者：
Palmowski, Moritz;Huppert, Jochen;Kiessling, Fabian
高频体积功率多普勒超声（HF-VPDU）捕获血管中的血流依赖信号，可用于评估啮齿动物肿瘤的抗血管生成治疗效果。然而，敏感性仅限于比毛细血管大的血管。对比度增强的HF-VPDU通过评估分解微泡的受激声发射来显示所有灌注血管。因此，我们研究了血流敏感和对比增强的HF-VPDU是否可以描述不同的血管部分，并评估它们对抗血管生成治疗的早期反应。用HF-VPDU对A431肿瘤小鼠给予聚氰丙烯酸丁酯微泡前后进行扫描。动物接受抗血管生成治疗。（SU11248）或对照物质，并在9天内反复成像。在每个时间点切除肿瘤进行免疫组织化学分析。在未经治疗的肿瘤生长过程中，血流敏感和增强扫描显示血管化相应减少。与对照组相比，治疗组血管化程度明显下降（P < 0.05），增强扫描结果更为明显。令人惊讶的是，尽管在对比增强扫描中血管化仍然很低，但在第6天之后，血流敏感超声显示血管化再次增加，并且在第9天时血管化高于对照组。组织学评估表明，未成熟血管在治疗中明显降解，而肿瘤周围的大成熟血管更耐治疗，并且由于肿瘤缩小而更紧密。总之，对比增强的HF-VPDU和血流敏感的HF-VPDU都能够评估抗血管生成治疗的效果。由于对比敏感超声对未成熟的小血管更敏感，而血流敏感超声主要捕获肿瘤周围的大血管，因此两种方法的结合可以提供肿瘤血管成熟的证据。
High-frequency volumetric Power Doppler ultrasound (HF-VPDU) captures flow-dependent signals in blood vessels and can be used to assess antiangiogenic therapy effects in rodent tumors. However, the sensitivity is limited to vessels larger than capillaries. Contrast-enhanced HF-VPDU reveals all perfused vessels by assessing stimulated acoustic emissions from disintegrating microbubbles. Thus, we investigated whether flow-sensitive and contrast-enhanced HF-VPDU can depict different vessel fractions and assess their early response to antiangiogenic therapy. Mice with A431 tumors were scanned before and after administration of polybutylcyanoacrylate microbubbles by HF-VPDU. Animals received either antiangiogenic treatment. (SU11248) or a control substance and were imaged repeatedly over 9 days. At each time point, tumors were removed for immunohistochemical analysis. During growth of untreated tumors, vascularization decreased correspondingly on flow-sensitive and contrast-enhanced scans. Treated tumors showed it significantly (P < 0.05) stronger decline in vascularization than controls, which was more pronounced in contrast-enhanced scans. Surprisingly, whereas vascularization remained low in contrast-enhanced scans, flow-sensitive ultrasound indicated a reincrease after day 6 with a higher vascularization than the controls at day 9. Histologic evaluation indicated that immature vessels degraded markedly on therapy, whereas large mature vessels on the tumor periphery were more therapy resistant and drew closer due to tumor shrinkage. In conclusion, contrast-enhanced HF-VPDU and flow-sensitive HF-VPDU are both capable of assessing the effects of antiangiogenic therapy. Because contrast-sensitive ultrasound is more sensitive for small immature vessels and flow-sensitive ultrasound mostly captures large vessels at the tumor periphery, the combination of both methods can pro-vide evidence of vascular maturity in tumors.