Recent advances in understanding the biology of lymphangiogenesis, the new growth of lymphatic vessels, have cast new light on the molecular basis of
metastasis to regional lymph nodes. The
receptor tyrosine kinase VEGFR-3 is virtually exclusively expressed on lymphatic but not blood endothelium in the adult, and activation of
VEGFR-3 by its
ligands VEGF-C and
VEGF-D is sufficient to induce lymphangiogenesis. Correlative studies with human
tumors and functional studies using animal
tumor models show that increased levels of
VEGF-C or
VEGF-D in
tumors lead to enhanced numbers of lymphatic vessels in the vicinity of
tumors, which in turn promotes
metastasis to regional lymph nodes by providing a greater number of entry sites into the lymphatic system for invading
tumor cells. These findings have prompted studies to investigate whether inhibitors of
VEGFR-3 activation might represent novel therapeutic agents for the suppression of
metastasis. However, a number of points regarding the therapeutic potential of anti-lymphangiogenic treatments in the context of
cancer remain to be addressed. The spectrum and relative importance of molecules that induce lymphangiogenesis and the regulation of their expression during
tumor progression, the reversibility of
tumor-induced lymphangiogenesis, and possible side-effects of anti-lymphangiogenesis-based
therapies all need to be investigated. Most importantly, the extent to which
lymph node metastases contribute to the formation of
metastases in other organs remains to be elucidated. These aspects are the focus of this review, and their investigation should serve as a roadmap to possible translational application.