Tumor-associated lymphatic vessels act as a conduit by which disseminating tumor cells access regional lymph nodes and form metastases there. Lymph node metastasis is of major prognostic significance for many types of cancer, although lymph node metastases are themselves rarely life-threatening. These observations focus our attention on understanding how tumor cells interact with the lymphatic vasculature, and why this interaction is so significant for prognosis. Tumors interact with the lymphatic vasculature in a number of ways, including vessel co-option, chemotactic migration and invasion into lymphatic vessels and induction of lymphangiogenesis. Tumor-induced lymphangiogenesis both locally and in regional lymph nodes has been correlatively and functionally associated with metastasis formation and poor prognosis. The investigation of the molecular regulation of lymphangiogenesis has identified ways of interfering with prolymphangiogenic signaling. Blockade of tumor-induced lymphangiogenesis in preclinical models inhibits metastasis formation in lymph nodes and often also in other organs, suggesting that blocking the lymphatic route of dissemination might suppress metastasis formation not only in lymph nodes but also in other organs. However, randomized clinical trials that have investigated the efficacy of therapeutic removal of lymph nodes have concluded that lymph node metastases act only as indicators that primary tumors have developed metastatic potential, and do not govern the further spread of metastatic cells. To reconcile these apparently paradoxical observations we suggest a model in which tumor-induced lymphangiogenesis and lymph node metastasis formation act as indicators that tumors are producing factors that can act systemically to promote metastasis formation in distant organs.
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