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）：有越来越多的证据表明淋巴血管生成在肿瘤转移中起重要作用。虽然我们对刺激淋巴管的VEGF家庭成员有所了解，但我们仍然不知道。该应用建议研究VEGF-A和VEGF-C关于它们对淋巴结结构和功能的影响，所使用的受体，并探索AKT途径在信号传导中的差异使用的观察结果。然后，我们将询问这些过程如何影响黑色素瘤模型中的转移，以及它们如何受到Akt-MTOR途径中新兴治疗剂的影响。该项目的具体目的是：1。检验以下假设：VEGF-A和VEGF-C诱导的淋巴管生成（结构和功能）的差异是由差异AKT途径使用2。确定生存因子（s）和/或生存途径，这些途径带来了长期的persistence vegffff-a164644-a16464-a。 3。在黑色素瘤的背景下，淋巴管是转移的主要途径，测试VEGFA和VEGF-C是否具有产生肿瘤性淋巴管菌的等效潜力，淋巴结淋巴结淋巴管生成，淋巴结和淋巴结和肺转移。此外，我们将探讨TORC1和TORC1/2抑制对这一过程的治疗影响。公共卫生相关性：有令人信服的证据表明，包括黑色素瘤和乳腺癌在内的许多肿瘤都可以在肿瘤细胞瘤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/或与肿瘤相关的巨噬细胞释放的VEGF-A和VEGF-C可能代表了这些过程中涉及的主要淋巴管植物因子。该应用的重点是了解这些因素用于诱导黑色素瘤中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。