Functional Imaging of Tumor-Associated Lymphatics

描述（由申请人提供）：淋巴浸润是转移性癌细胞扩散的主要途径。然而，尽管淋巴作为癌症转移的关键途径发挥着重要作用，但由于无法直接成像体内淋巴，人们对肿瘤相关淋巴功能的了解相对较少。最近，我们首次证明了通过皮内注射非特异性近红外荧光团吲哚菁绿（ICG），使用动态近红外（NIR）荧光成像对小鼠淋巴收缩功能进行非侵入性定量成像的能力。随后，同样的方法应用于广泛淋巴结（LN）转移的小鼠，以改变淋巴引流通路和淋巴收缩活动的图像。基于我们的初步发现，我们建议使用非侵入性的动态功能近红外荧光成像来纵向成像肿瘤相关淋巴管，以验证我们的工作假设，即癌症转移伴随着淋巴收缩功能和淋巴流动模式的短暂改变。具体来说，我们的目标是：1。在不同的肿瘤实验动物模型中，肿瘤生长和淋巴结转移时淋巴收缩功能和引流通路纵向的时空变化，以阐明异常的淋巴功能和淋巴流动模式是否是转移的预后标志；抗vegf受体(VEGFR)-32对淋巴管图像时空变化的影响抗vegf受体(VEGFR)-3阻断抗体或抗VEGFR-2和-3阻断抗体联合应用可改善荷瘤小鼠早期肿瘤淋巴管生成，降低肿瘤转移率。这个项目，如果成功的话，可能会促进一种新的肿瘤淋巴结转移（TNM）分期诊断的翻译，并加速针对淋巴系统的新兴治疗方法的临床试验。

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. PUBLIC HEALTH RELEVANCE: Abnormal lymphatic function and flow are implicated in a number of pathological conditions, including cancer metastasis. 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. In this work, we develop an approach to non-invasively and quantitatively image transient changes of lymphatic contractile function and flow patterns in response to tumor progression and metastasis using a near-infrared fluorescence imaging technique.