Functional Imaging of Tumor-Associated Lymphatics

描述（由申请人提供）：淋巴侵袭是转移性癌细胞扩散的主要途径。然而，尽管淋巴管作为癌症转移的关键途径具有重要作用，但对肿瘤相关淋巴功能的了解相对较少，部分原因是无法直接对体内淋巴管进行成像。最近，我们证明了第一次的能力，非侵入性和定量图像淋巴收缩功能的小鼠使用动态近红外（NIR）荧光成像与皮内注射的非特异性近红外荧光团，吲哚菁绿色（ICG）。随后，在具有广泛淋巴结（LN）转移的小鼠中采用相同的方法来成像淋巴引流途径和淋巴收缩活性的改变。基于我们的初步研究结果，我们建议使用非侵入性的，动态功能近红外荧光成像纵向图像肿瘤相关的淋巴细胞，以测试我们的工作假设，即癌症转移伴随着淋巴收缩功能和淋巴流动模式的短暂变化。具体而言，我们的目标是：1。在不同的实验性肿瘤动物模型中，对淋巴管收缩功能和引流途径的纵向变化进行成像，以阐明异常的淋巴管功能和淋巴流模式是否是转移的预后标志。图像的空间和时间变化的血管内皮生长因子受体（VEGFR）-32。成像抗VEGF受体（VEGFR）-3阻断抗体或抗VEGFR-2和-3阻断抗体的组合作为改善荷瘤小鼠最早期肿瘤淋巴管生成和降低转移率的手段时，肿瘤的空间和时间变化。该项目如果成功，可以促进肿瘤淋巴结转移（TNM）分期的新诊断方法的翻译，并加速靶向肿瘤的新兴疗法的临床试验。

DESCRIPTION (provided by applicant): Lymphatic invasion is a major route for the spread of metastatic cancer cells. Yet despite the important role of lymphatics as a critical pathway for cancer metastasis, relatively little is known about tumor-associated lymphatic function, due in part to the inability to directly image the lymphatics in vivo. Recently, we demonstrated for the first time the ability to non-invasively and quantitatively image lymphatic contractile function in mice using dynamic near-infrared (NIR) fluorescence imaging with intradermal injection of a nonspecific NIR fluorophore, indocyanine green (ICG). Subsequently, the same approach was employed in mice with extensive lymph node (LN) metastasis to image alteration of lymphatic drainage pathways and lymphatic contractile activity. Based upon our initial findings, we propose to use non-invasive, dynamic functional NIR fluorescence imaging to longitudinally image tumor-associated lymphatics to test our working hypothesis that cancer metastasis is accompanied by transient changes of lymphatic contractile function and lymph flow patterns. Specifically, our aims are to: 1. Image spatial and temporal changes in lymphatic contractile function and drainage pathways longitudinally in response to tumor growth and LN metastasis in different experimental animal models of cancer in order to elucidate whether aberrant lymphatic function and lymph flow patterns are a prognostic marker of metastasis and, 2. Image spatial and temporal changes of the lymphatics in response to the anti-VEGF receptor (VEGFR)-32. Image spatial and temporal changes of the lymphatics in response to the anti-VEGF receptor (VEGFR)-3 blocking antibody or a combination of anti-VEGFR-2 and -3 blocking antibodies as a means to ameliorate the earliest tumor lymphangiogenesis and reduce the rate of metastasis in tumor-bearing mice. This project, if successful, could motivate translation of a new diagnostic for tumor-node- metastasis (TNM) staging and acceleration of clinical trials of emerging therapeutics that target the lymphatics.