VEGFs in tumor lymphatic metastasis

VEGF在肿瘤淋巴转移中的作用

• 批准号: 8295008
• 负责人: HAROLD FISHER DVORAK
• 金额: $ 45.25万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-16 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8295008
• 关键词: Adult; Affect; Blood Vessels; Chronic; Data; Dependency; Development; Ear; Family member; Goals; Health; In Vitro; Incidence; Inflammation; Investigation; Light; Lung; Lymphangiogenesis; Lymphatic; Lymphatic Metastasis; Lymphatic vessel; Lymphedema; Malignant Neoplasms; Mediating; Modeling; Molecular; Mus; Neoplasm Metastasis; Nude Mice; Pathology; Pathway interactions; Play; Process; Reporting; Role; Route; Sentinel Lymph Node; Signal Pathway; Signal Transduction; Sirolimus; Skin; Structure; Testing; Therapeutic; Translating; Vascular Endothelial Growth Factor C; Vascular Endothelial Growth Factor Receptor-2; Vascular Endothelial Growth Factor Receptor-3; Vascular Endothelial Growth Factors; Wound Healing; adenoviral-mediated; angiogenesis; cancer therapy; human FRAP1 protein; in vivo; insight; lymph nodes; mTOR Inhibitor; macrophage; malignant breast neoplasm; melanoma; neoplastic cell; neutralizing antibody; novel; overexpression; receptor structure function; response; tumor; tumor growth

DESCRIPTION (provided by applicant): There is mounting evidence that lymphatic angiogenesis plays an important role in tumor metastasis. While we know a little bit about the VEGF family members that stimulate lymphangiogensis, there is still much we don't know. This application proposes to study VEGF-A and VEGF-C with respect to the effects they have on lymphatic structure and function, the receptors that are utilized, and to explore observations of differential use of the Akt pathway in their signaling. With this information we will then ask how these processes impact metastasis in melanoma models and how they are impacted by emerging therapeutics in the Akt-mTOR pathway. The specific aims of this project are to: 1. Test the hypothesis that the differences in lymphangiogenesis (structure and function) induced by VEGF-A and VEGF-C are contributed to by differential Akt pathway utilization 2. Identify the survival factor(s) and/or survival pathway(s) that bring about the long-term persistence of the VEGF-A164-induced lymphatics. 3. In the context of melanoma where lymphatics are the primary route of metastasis, test whether VEGF- A and VEGF-C have equivalent potential to produce peritumoral lymphangiogensis, lymph node lymphangiogenesis and lymph node and lung metastasis. In addition we will explore the therapeutic impact on this process from TORC1 and TORC1/2 inhibition. PUBLIC HEALTH RELEVANCE: There is compelling evidence that many tumors, including melanoma and breast cancer, can induce lymphangiogenesis at the tumor-stroma interface, and that such lymphangiogenesis is correlated with the incidence of sentinel lymph node metastases. VEGF-A and VEGF-C, released by tumor cells and/or by tumor-associated macrophages, likely represent the major lymphangiogenic factors involved in these processes. This application is focused on understanding the mechanisms that these factors use to induce lymphangiogenesis and metastasis in melanoma, as well as how these mechanisms impact emerging cancer therapies.

描述（由申请人提供）：越来越多的证据表明淋巴血管生成在肿瘤转移中发挥重要作用。虽然我们对刺激淋巴管生成的 VEGF 家族成员了解一些，但仍有很多我们不知道的地方。本申请拟研究 VEGF-A 和 VEGF-C 对淋巴结构和功能、所利用受体的影响，并探索 Akt 通路在其信号传导中的差异使用的观察结果。有了这些信息，我们将询问这些过程如何影响黑色素瘤模型中的转移，以及 Akt-mTOR 通路中的新兴疗法如何影响它们。该项目的具体目标是： 1. 检验 VEGF-A 和 VEGF-C 诱导的淋巴管生成（结构和功能）差异是由 Akt 途径利用差异造成的假设 2. 确定导致 VEGF-A164 诱导的淋巴管长期持续存在的存活因子和/或存活途径。 3. 在淋巴管是主要转移途径的黑色素瘤的情况下，测试VEGF-A和VEGF-C是否具有产生瘤周淋巴管生成、淋巴结淋巴管生成以及淋巴结和肺转移的同等潜力。此外，我们将探讨 TORC1 和 TORC1/2 抑制对此过程的治疗影响。公共卫生相关性：有令人信服的证据表明，许多肿瘤，包括黑色素瘤和乳腺癌，可以在肿瘤-基质界面诱导淋巴管生成，并且这种淋巴管生成与前哨淋巴结转移的发生率相关。由肿瘤细胞和/或肿瘤相关巨噬细胞释放的 VEGF-A 和 VEGF-C 可能代表了这些过程中涉及的主要淋巴管生成因子。该应用的重点是了解这些因子用于诱导黑色素瘤淋巴管生成和转移的机制，以及这些机制如何影响新兴的癌症疗法。