Lymphatics and cancer: VEGF-C and nitric oxide in lymphatic function, lymphangiogenesis, and metastasis

The lymphatics are a primary route for cancer metastasis and lymph node metastasis is an important clinical prognostic factor. The process of lymphatic metastasis is, however, not well understood. This thesis examines the function of lymphatic vessels in relation to cancer progression and metastasis. The specific aim of these studies is to analyze how vascular endothelial growth factor (VEGF)-C-induced lymphatics function and contribute to metastasis, and what the role of nitric oxide is in these processes. The larger aim of these studies is to determine if these molecular pathways are suitable therapeutic targets in cancer patients and in what clinical stages they would be useful. The experiments use several murine models that allow in vivo observation of the normal and tumor microlymphatic circulation. The results show, first, that abnormal lymphatics already start to occur in early stages of cancer. Second, that VEGF-C-induced tumor lymphatics exhibit abnormal drainage patterns and elevated lymph flow levels, as well as increased delivery of metastatic tumor cells to the lymph nodes. Third, that nitric oxide affects physiological lymph flow and tumor lymph vessel growth. Fourth, that targeting these pathways may be suitable to prevent, but not treat, lymphatic metastasis in a clinical setting.