Complete and specific inhibition of adult lymphatic regeneration by a novel VEGFR-3 neutralizing antibody
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 regeneration 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 administration 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 regeneration 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.
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Keywords: Animals ; Antibodies ; Monoclonal/administration & dosage/*pharmacology ; Antineoplastic Agents/administration & dosage/*pharmacology ; Breast Neoplasms/metabolism/*physiopathology ; Female ; Fluorescent Antibody Technique ; Humans ; Immunohistochemistry ; Lymphangiogenesis/*drug effects ; Lymphography ; Mice ; Mice ; Nude ; Phosphorylation ; Rats ; Research Support ; Non-U.S. Gov't ; Research Support ; U.S. Gov't ; P.H.S. ; Tail ; Time Factors ; Up-Regulation ; Vascular Endothelial Growth Factor C/*antagonists & ; inhibitors/metabolism ; Vascular Endothelial Growth Factor Receptor-3/*antagonists & ; inhibitors/metabolism ; Mice ; Research Support
Record created on 2006-08-09, modified on 2016-08-08