Tumor-induced lymphangiogenesis: a target for cancer therapy?

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.