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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Special Emphasis Panel (ZRG1-ONC-M (02))
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Mohla, Suresh
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Beth Israel Deaconess Medical Center
United States
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Dvorak, Harold F (2015) Tumor Stroma, Tumor Blood Vessels, and Antiangiogenesis Therapy. Cancer J 21:237-43
Dvorak, Harold F (2015) Tumors: wounds that do not heal-redux. Cancer Immunol Res 3:1-11
Qin, Liuliang; Zhao, Dezheng; Xu, Jianfeng et al. (2013) The vascular permeabilizing factors histamine and serotonin induce angiogenesis through TR3/Nur77 and subsequently truncate it through thrombospondin-1. Blood 121:2154-64
Sitohy, Basel; Nagy, Janice A; Dvorak, Harold F (2012) Anti-VEGF/VEGFR therapy for cancer: reassessing the target. Cancer Res 72:1909-14
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Sitohy, Basel; Nagy, Janice A; Jaminet, Shou-Ching Shih et al. (2011) Tumor-surrogate blood vessel subtypes exhibit differential susceptibility to anti-VEGF therapy. Cancer Res 71:7021-8
Dvorak, Harold F; Weaver, Valerie M; Tlsty, Thea D et al. (2011) Tumor microenvironment and progression. J Surg Oncol 103:468-74