Lymphangiogenesis and cancer
Final Report Abstract
Our work in SPP1190 has focused on understanding how tumors interact with and disseminate through the lymphatic system, how they induce the new growth of lymphatic vessels in the process of lymphangiogenesis, and how these processes contribute to the development of metastases in lymph nodes and vital organs. Specifically, we have generated new tumor models that metastasize via the lymphatics, and have used these both to identify genes that direct metastasis to lymph nodes, as well as to demonstrate that the lymph node microenvironment conditions tumor cells and increases their metastatic potential. We have also developed an innovative genetic switch for marking tumor cells in vivo while they disseminate via the lymphatics, and have used this system to show that a significant number of lung metastasis form from tumor cells that have trafficked through the lymph nodes. Furthermore, we have identified degradation products of the extracellular matric glycosaminoglycan hyaluronic acid that are produced in the tumor context as inducers of lymphatic endothelial cell proliferation and lymphangiogenesis. Finally, we have performed proof of principle studies that identify a number of natural products as inhibitors of lymphangiogenesis that may serve as lead compounds for the development of therapeutically useful lymphangiogenesis inhibitors. Together our activities in SPP1190 have cast new light on the role of the lymphatic system in tumor metastasis, on the regulation of lymphangiogenesis by tumors, and on possible ways of interfering with tumorinduced lymphangiogenesis for therapeutic purposes.
