Physics for Medicine Paris, Inserm, ESPCI Paris, CNRS, PSL Research University, Paris, France; Inserm Accélérateur de Recherche Technologique en Ultrasons biomédicaux, Paris, France.
Sorbonnne Université, CNRS, INSERM, Laboratoire d'Imagerie Biomédicale, Paris, France.
Ultrasound Med Biol. 2019 May;45(5):1284-1296. doi: 10.1016/j.ultrasmedbio.2018.12.010. Epub 2019 Feb 22.
Angiogenesis, the formation of new vessels, is one of the key mechanisms in tumor development and an appealing target for therapy. Non-invasive, high-resolution, high-sensitivity, quantitative 3-D imaging techniques are required to correctly depict tumor heterogeneous vasculature over time. Ultrafast Doppler was recently introduced and provides an unprecedented combination of resolution, penetration depth and sensitivity without requiring any contrast agents. The technique was further extended to three dimensions with ultrafast Doppler tomography (UFD-T). In this work, UFD-T was applied to the monitoring of tumor angiogenesis in vivo, providing structural and functional information at different stages of development. UFD-T volume renderings revealed that our murine model's vasculature stems from pre-existing vessels and sprouts to perfuse the whole volume as the tumor grows until a critical size is reached. Then, as the network becomes insufficient, the tumor core is no longer irrigated because the vasculature is concentrated mainly in the periphery. In addition to spatial distribution and growth patterns, UFD-T allowed a quantitative analysis of vessel size and length, revealing that the diameter distribution of vessels remained relatively constant throughout tumor growth. The network is dominated by small vessels at all stages of tumor development, with more than 74% of the vessels less than 200 µm in diameter. This study also found that cumulative vessel length is more closely related to tumor radius than volume, indicating that the vascularization becomes insufficient when a critical mass is reached. UFD-T was also compared with dynamic contrast-enhanced ultrasound and found to provide complementary information regarding the link between structure and perfusion. In conclusion, UFD-T is capable of in vivo quantitative assessment of the development of tumor vasculature (vessels with blood speed >1 mm/s [sensitivity limit] assessed with a resolution limit of 80 µm) in 3 dimensions. The technique has very interesting potential as a tool for treatment monitoring, response assessment and treatment planning for optimal drug efficiency.
血管生成，即新血管的形成，是肿瘤发展的关键机制之一，也是治疗的一个有吸引力的靶点。需要非侵入性、高分辨率、高灵敏度、定量的 3D 成像技术来正确描绘随时间推移的肿瘤异质性血管。最近引入的超快速多普勒提供了前所未有的分辨率、穿透深度和灵敏度的组合，而无需任何造影剂。该技术进一步扩展到三维，具有超快速多普勒层析成像（UFD-T）。在这项工作中，UFD-T 应用于体内肿瘤血管生成的监测，提供了不同发育阶段的结构和功能信息。UFD-T 体绘制显示，我们的鼠模型的血管来源于预先存在的血管，并在肿瘤生长过程中长出分支以灌注整个体积，直到达到临界大小。然后，由于网络变得不足，肿瘤核心不再被灌溉，因为血管主要集中在周围。除了空间分布和生长模式外，UFD-T 还允许对血管大小和长度进行定量分析，结果表明，血管直径分布在整个肿瘤生长过程中相对保持不变。该网络在肿瘤发展的所有阶段都由小血管主导，超过 74%的血管直径小于 200 µm。这项研究还发现，累积血管长度与肿瘤半径比体积更密切相关，这表明当达到临界质量时，血管化变得不足。UFD-T 还与动态对比增强超声进行了比较，结果发现它提供了关于结构和灌注之间联系的补充信息。总之，UFD-T 能够在 3 维体内定量评估肿瘤血管生成的发展（用 80 µm 的分辨率极限评估的速度大于 1mm/s 的[灵敏度极限]的血管）。该技术具有作为治疗监测、反应评估和治疗计划工具的非常有趣的潜力，以实现最佳药物效率。
