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. ' 2009 UICC

Metastasis, the life-threatening aspect of cancer, is a systemic disease process. Considerable progress has been made in recent years regarding how tumor cells circulating in the blood and lymphatic systems interact with and extravasate into secondary sites, and what determines whether these disseminated tumors cells survive, remain dormant or go on to form macrometastases. New insights into the routes that tumor cells take once leaving the primary tumor have emerged. Novel concepts regarding early seeding of metastases coupled to parallel progression, self-seeding of primary tumors by circulating tumor cells and the induction of premetastatic niches in distant organs by primary tumors have come to the fore. The perceived role of the lymphatic system in determining patterns of metastasis formation in distant organs has been reassessed. Together these new insights have the potential to offer new therapeutic options. In particular, the regulation of tumor cell dormancy emerges as a key event in metastasis formation, and therapeutic control of dormancy holds the promise of rendering cancer a chronic rather than life-threatening disease.Cancer patient prognosis is determined in the main by the emergence of metastases from disseminated tumor cells (DTCs) that lodge and grow out as secondary tumors in distant organs. For most tumor types the diagnosis of metastatic cancer is regarded as terminal, and the effects of metastatic growth, for example impairment of vital organ function and increasing tumor burden to lethal levels are thought to be responsible for more than 90% of deaths of cancer patients. [1][2][3] While metastasis by direct extension into body cavities is a feature of some types of cancer, 4 most metastases develop from tumor cells disseminated through the circulatory system. Although metastasis is a systemic disease process, the majority of research efforts in this area since the advent of the molecular era have focused on understanding the process of local invasion. Changes in cell adhesion, activation of proteolysis and the acquisition of motile properties by tumor cells are now well accepted as key events in local invasion and entry into the vascular system. 4,5 The activation of endogenous morphogenetic programmes such as EMT is also thought to play a role. 6 Intravital imaging has proffered an unparalleled glimpse into how tumor cells invade through tissues and enter capillaries. [7][8][9][10]