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

Abstract

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.

• 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
• Journal: Clinical & experimental metastasis (Clin Exp Metastasis) Vol. 30 Issue 6 Pg. 819-32 (Aug 2013) ISSN: 1573-7276 [Electronic] Netherlands
• PMID: 23591595 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Vascular Endothelial Growth Factor D
• FLT4 protein, human
• Vascular Endothelial Growth Factor Receptor-2
• Vascular Endothelial Growth Factor Receptor-3

Topics

• Animals
• Cell Line, Tumor
• Female
• Humans
• Lymphangiogenesis (physiology)
• Lymphatic Metastasis
• Lymphatic Vessels (pathology)
• Mice
• Mice, SCID
• Neovascularization, Physiologic
• Signal Transduction (physiology)
• Vascular Endothelial Growth Factor D (physiology)
• Vascular Endothelial Growth Factor Receptor-2 (physiology)
• Vascular Endothelial Growth Factor Receptor-3 (physiology)