Lymph node metastasis as a new target for cancer treatment

The presence of lymph node metastasis is predictive of poor prognosis in solid tumors. Demonstration of specific markers of lymphatic endothelial cells has facilitated the study of the molecular mechanisms of metastasis, particularly lymphangiogenesis. The vascular endothelial growth factor (VEGF)-C/VEGF-D/VEGF receptor (VEGFR)-3 axis has been the most extensively studied, but other molecular pathways are also involved, such as fibroblast growth factor (FGF)-2, platelet-derived growth factor (PDGF)-BB, angiopoietin-1, VEGF-A, hepatocyte growth factor (HGF), insulin-like growth factor (IGF)-1 and -1R, and cyclooxygenase-2. Several strategies are currently being developed to prevent lymphatic metastasis, mainly targeting the VEGF-C/VEGF-D/VEGFR-3 axis: inhibiting maturation and activation of VEGF-C and VEGF-D by successive proteolyses, inhibiting binding of ligands to their receptor, and using tyrosine kinase inhibitors. Many questions remain and will be discussed in this article, particularly the role of lymph node metastasis in the development of visceral metastases, possible toxicities of antilymphangiogenic treatments, and their possible interactions with intratumoral penetration of other anticancer agents.