Complete and specific inhibition of adult lymphatic regeneration by a novel VEGFR-3 neutralizing antibody

被引:197
作者
Pytowski, B
Goldman, J
Persaud, K
Wu, Y
Witte, L
Hicklin, DJ
Skobe, M
Boardman, KC
Swartz, MA
机构
[1] ImClone Syst, Mol & Cellular Biol, New York, NY USA
[2] Northwestern Univ, Dept Biomed Engn, Evanston, IL 60208 USA
[3] ImClone Syst, Expt Therapeut, New York, NY USA
[4] Derald H Ruttenberg Canc Ctr, Mt Sinai Sch Med, New York, NY USA
来源
JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE | 2005年 / 97卷 / 01期
关键词
D O I
10.1093/jnci/dji003
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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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页码:14 / 21
页数:8
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