Signaling for lymphangiogenesis via VEGFR-3 is required for the early events of metastasis

• DOI: 10.1007/s10585-013-9581-x
• Publication Date: 2013-04-16T09:45:39Z
• Authors: Masataka Matsumoto; Sally Roufail; Rachael Inder; Carol Caesar; Tara Karnezis; Ramin Shayan; Rae H. Farnsworth; Teruhiko Sato; Marc G. Achen; G. Bruce Mann; Steven A. Stacker
• Keywords: 0301 basic medicine; Vascular Endothelial Growth Factor D; 610; Neovascularization, Physiologic; 600; Mice, SCID; Vascular Endothelial Growth Factor Receptor-3; Vascular Endothelial Growth Factor Receptor-2; 3. Good health; Mice; 03 medical and health sciences; Cell Line, Tumor; Lymphatic Metastasis; Animals; Humans; Female; Lymphangiogenesis; Lymphatic Vessels; Signal Transduction

Metastasis to regional lymph nodes is an important and early event in many tumors. Vascular endothelial growth factor-C (VEGF-C), VEGF-D and their receptor VEGFR-3, play a role in tumor spread via the lymphatics, although the timing of their involvement is not understood. In contrast, VEGFR-2, activated by VEGF-A, VEGF-C and VEGF-D, is a mediator of angiogenesis and drives primary tumor growth. We demonstrate the critical role for VEGFR-3, but not VEGFR-2, in the early events of metastasis. In a tumor model exhibiting both VEGF-D-dependent angiogenesis and lymphangiogenesis, an antibody to VEGFR-2 (DC101) was capable of inhibiting angiogenesis (79 % reduction in PECAM + blood vessels) and growth (93 % reduction in tumor volume). However, unlike an anti-VEGFR-3 Mab (mF4-31C1), DC101 was not capable of eliminating either tumor lymphangiogenesis or lymphogenous metastasis (60 % reduction of lymph node metastasis by DC101 vs 95 % by mF4-31C1). Early excision of the primary tumors demonstrated that VEGF-D-mediated tumor spread precedes angiogenesis-induced growth. Small but highly metastatic primary human breast cancers had significantly higher lymphatic vessel density (23.1 vessels/mm(2)) than size-matched (11.7) or larger non-metastatic tumors (12.4) thus supporting the importance of lymphatic vessels, as opposed to angiogenesis-mediated primary tumor growth, for nodal metastasis. These results suggest that lymphangiogenesis via VEGF-D is more critical than angiogenesis for nodal metastasis.