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- Title
Complete and Specific Inhibition of Adult Lymphatic Regeneration by a Novel VEGFR-3 Neutralizing Antibody.
- Authors
Pytowski, Bronislaw; Goldman, Jeremy; Persaud, Kris; Yan Wu; Witte, Larry; Hicklin, Daniel J.; Skobe, Mihaela; Boardman, Kendrick C.; Swartz, Melody A.
- Abstract
Background: New lymphatic growth may contribute to tumor metastasis. Activation of vascular endothelial growth factor receptor 3 (VEGFR-3) by its ligands VEGF-C and -D is necessary for embryonic and tumor lymphangiogenesis. However, the exact role of VEGFR-3 signaling in adult lymphangiogenesis and in lymphatic vessel survival and re- generation is unclear. Methods: A novel rat monoclonal antibody to murine VEGFR-3, mF4-31C1, which potently antagonizes the binding of VEGF-C to VEGFR-3, was developed. We tested the effects of systemic mF4-31C1 ad- ministration in a mouse tail skin model of lymphatic regeneration, either with or without local overexpression of VEGF-C, and we observed lymphatic and blood vessel re- generation over time using microlymphangiography and immunostaining. Results: Normal mice regenerated complete and functional lymphatic vessels within 60 days of surgery. In athymic mice implanted with VEGF-C-overexpressing human breast carcinoma cells, lymphatic regeneration took place over 25 days and resulted in hyperplastic vessels. Under either condition, no lymphatic regeneration occurred in mice receiving mF4-31C1 during the regeneration period. Blood angiogenesis and preexisting lymphatic vessels were unaffected, both in morphology and in function. Conclusions: Blocking VEGFR-3 completely and specifically prevented both physiologically normal and tumor VEGF-C-enhanced lymphangiogenesis in the adult mouse but had no effect on either blood angiogenesis or the survival or function of existing lymphatic vessels. Thus, targeting VEGFR-3 with specific inhibitors may block new lymphatic growth exclusively.
- Subjects
LYMPHATICS; VASCULAR endothelial growth factors; MONOCLONAL antibodies; REGENERATION (Biology); ONCOLOGY
- Publication
JNCI: Journal of the National Cancer Institute, 2005, Vol 97, Issue 1, p14
- ISSN
0027-8874
- Publication type
Article
- DOI
10.1093/jnci/dji003