Functional Imaging of Tumor-Associated Lymphatics

肿瘤相关淋巴管的功能成像

• 批准号: 8244272
• 负责人: Sunkuk Kwon
• 金额: $ 19.58万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-01 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8244272
• 关键词: Acceleration; Adjuvant; Architecture; Biopsy; Blocking Antibodies; Clinical; Clinical Trials; Critical Pathways; Data; Diagnostic; Diagnostic Neoplasm Staging; Disseminated Malignant Neoplasm; Drainage procedure; Evaluation; Experimental Animal Model; Fluorescence; Foundations; Functional Imaging; Image; Imaging Techniques; Indocyanine Green; Institutes; Lead; Lymph; Lymph Node Involvement; Lymphangiogenesis; Lymphatic; Lymphatic System; Lymphatic vessel; Malignant Neoplasms; Metastatic Neoplasm to Lymph Nodes; Methods; Modeling; Molecular Medicine; Morbidity - disease rate; Mus; Neoplasm Metastasis; Nodal; Pathway interactions; Pattern; Permeability; Phenotype; Process; Prognostic Marker; Research; Research Proposals; Role; Route; Staging; Testing; Therapeutic; Therapeutic Intervention; Time; Transgenic Organisms; Translating; Translations; Tumor Cell Line; Vascular Endothelial Growth Factor Receptor; Work; Xenograft procedure; base; bevacizumab; cancer cell; clinical practice; fluorescence imaging; fluorophore; implantation; in vivo; intradermal injection; lymph flow; lymph nodes; malignant breast neoplasm; melanoma; neutralizing antibody; novel diagnostics; novel therapeutics; pre-clinical; response; subcutaneous; therapeutic target; tumor; tumor growth; tumor progression

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.

描述（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发挥着重要作用，但人们对肿瘤相关淋巴管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，我们首次证明了使用动态近红外（NIR）荧光成像并皮内注射非特异性近红外荧光团吲哚菁绿（ICG）对小鼠淋巴收缩功能进行非侵入性定量成像的能力。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观察淋巴引流路径和淋巴收缩活动的图像改变。根据我们的初步发现，我们建议使用非侵入性、动态功能性近红外荧光成像对肿瘤相关淋巴管进行纵向成像，以检验我们的工作假设，即癌症转移伴随着淋巴管收缩功能和淋巴流模式的短暂变化。具体来说，我们的目标是： 1. 在不同的癌症实验动物模型中，对淋巴收缩功能和引流通路的时空变化进行纵向成像，以响应肿瘤生长和淋巴结转移，以阐明异常的淋巴功能和淋巴流模式是否是转移的预后标志；2. 对淋巴管响应于肿瘤生长和淋巴结转移的时空变化进行成像。 抗VEGF受体（VEGFR）-32。成像淋巴管响应抗 VEGF 受体 (VEGFR)-3 阻断抗体或抗 VEGFR-2 和 -3 阻断抗体组合的空间和时间变化，作为改善荷瘤小鼠最早的肿瘤淋巴管生成并降低转移率的手段。该项目如果成功，可能会促进肿瘤淋巴结转移（TNM）分期的新诊断方法的转化，并加速针对淋巴管的新兴疗法的临床试验。 公共卫生相关性：淋巴功能和流动异常与许多病理状况有关，包括癌症转移。然而，尽管淋巴管作为癌症转移的关键途径发挥着重要作用，但人们对肿瘤相关淋巴管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。在这项工作中，我们开发了一种使用近红外荧光成像技术对淋巴收缩功能和流动模式的瞬时变化进行非侵入性定量成像的方法，以响应肿瘤的进展和转移。