VEGFs in tumor lymphatic metastasis

描述(申请人提供)：越来越多的证据表明淋巴管生成在肿瘤转移中起重要作用。虽然我们对刺激淋巴管生成的血管内皮生长因子家族成员有一些了解，但仍有许多我们不知道的东西。本申请建议研究血管内皮生长因子-A和血管内皮生长因子-C对淋巴结构和功能的影响，以及所使用的受体，并探索Akt通路在其信号转导中的不同使用情况。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途径中的新兴疗法如何影响它们。本项目的具体目的是：1.验证血管内皮生长因子-A和血管内皮生长因子-C诱导的淋巴管生成(结构和功能)的差异是通过对Akt通路的不同利用所致的假说。2.确定导致血管内皮生长因子-A164诱导的淋巴管长期持续存在的生存因素(S)和/或生存路径(S)。3.在淋巴管是主要转移途径的黑色素瘤的背景下，测试血管内皮生长因子-A和血管内皮生长因子-C在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方面是否具有相同的潜能。此外，我们还将探讨抑制TORC1和TORC1/2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，许多肿瘤，包括黑色素瘤和乳腺癌，可以在肿瘤-间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可能是参与这些过程的主要淋巴管生成因子。这项应用的重点是了解这些因素用来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治疗。

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.