Vascular endothelial growth factor C (VEGF-C) and VEGF-D are the two central signaling molecules that govern the development and growth of the lymphovascular system. The presence or absence of lymphangiogenesis plays a central and sometimes causative role in a variety of diseases. Therefore, molecules that govern lymphangiogenesis, especially VEGF-C and VEGFR-3, offer the possibility for therapeutic interventions. Although the blockade of lymphangiogenesis does not yet exist as an independent therapeutic concept, a number of anti-lymphangiogenic drugs are now being tested in clinical trials. The rationale is that targeting VEGF-C and VEGF-D can improve the current anti-angiogenic treatment, since tumors may deploy the angiogenic forms of VEGF-C and VEGF-D when VEGF-A-mediated angiogenesis is blocked therapeutically. Despite numerous attempts, no breakthroughs have occurred in pro-angiogenic thera- pies to date. Furthermore, pro-lymphangiogenic, VEGF-C- or VEGF-D-based, therapies have not yet even entered the clinical trial phase. However, one clinical study with VEGF- C is now in preparation, namely in combination with lymph node transplantation for the treatment of postmastectomy edema. Here, we review the roles that VEGF-C, VEGF-D and their receptors play in diseases involving the lymphatic vascular system, and we present possibilities for utilizing these molecules to stimulate lymphatic vessel growth to treat lymphedema, or to block their functions in order to inhibit tumor angiogenesis and tumor lymphangiogenesis.Peer reviewe
