Lymphangiogenesis and tumor metastasis: myth or reality?

The metastatic spread of tumor cells is responsible for the majority of cancer deaths, and with few exceptions, all cancers can metastasize. Clinical findings have long suggested that by providing a pathway for tumor cell dissemination, tumor-associated lymphatics are a key component of metastatic spread. It is not known, however, whether pre-existing vessels are sufficient to serve this function, or whether tumor cell dissemination requires de novo lymphatic formation (lymphangiogenesis) or an increase in lymphatic size. Lymphangiogenesis has traditionally been overshadowed by the greater emphasis placed on the blood vascular system (angiogenesis). This is due in part to the lack of identification of lymphangiogenic factors, as well as suitable markers that distinguish blood from lymphatic vascular endothelium. This scenario is changing rapidly after the identification of the first lymphangiogenic factor, vascular endothelial growth factor C (VEGF-C). Increased expression of VEGF-C in primary tumors correlates with increased dissemination of tumor cells to regional lymph nodes in a variety of human carcinomas. Here I will review what is known about the mechanisms of lymphangiogenesis, particularly in the context of metastatic tumor spread, and will critically examine the role of VEGF-C in this process. However, despite recent progress in this field, it remains to be determined whether inhibition of lymphangiogenesis is a realistic therapeutic strategy for inhibiting tumor cell dissemination and the formation of metastasis.