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Vascular Endothelial Growth Factor Receptor 3 Is Involved in Tumor Angiogenesis and Growth

¹ Molecular/Cancer Biology Research Program and Ludwig Institute for Cancer Research, Biomedicum Helsinki, Haartman Institute and Helsinki University Central Hospital, University of Helsinki, Finland; ² ImClone Systems, New York, New York; and ³ Division of Molecular Carcinogenesis, Center for Nuerological Disease and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan

Requests for reprints: Kari Alitalo, Molecular/Cancer Biology Research Program and Ludwig Institute for Cancer Research, Biomedicum Helsinki, Haartman Institute and Helsinki University Central Hospital, P.O. Box 63, Haartmaninkatu 8, FI-00014 Helsinki, Finland. Phone: 358-9-191-25511; Fax: 358-9-191-25510; E-mail: kari.alitalo{at}helsinki.fi.

Vascular endothelial growth factor receptor 3 (VEGFR-3) binds VEGF-C and VEGF-D and is essential for the development of the lymphatic vasculature. Experimental tumors that overexpress VEGFR-3 ligands induce lymphatic vessel sprouting and enlargement and show enhanced metastasis to regional lymph nodes and beyond, whereas a soluble form of VEGFR-3 that blocks receptor signaling inhibits these changes and metastasis. Because VEGFR-3 is also essential for the early blood vessel development in embryos and is up-regulated in tumor angiogenesis, we wanted to determine if an antibody targeting the receptor that interferes with VEGFR-3 ligand binding can inhibit primary tumor growth. Our results show that antibody interference with VEGFR-3 function can inhibit the growth of several human tumor xenografts in immunocompromised mice. Immunohistochemical analysis showed that the blood vessel density of anti-VEGFR-3–treated tumors was significantly decreased and hypoxic and necrotic tumor tissue was increased when compared with tumors treated with control antibody, indicating that blocking of the VEGFR-3 pathway inhibits angiogenesis in these tumors. As expected, the anti-VEGFR-3–treated tumors also lacked lymphatic vessels. These results suggest that the VEGFR-3 pathway contributes to tumor angiogenesis and that effective inhibition of tumor progression may require the inhibition of multiple angiogenic targets. [Cancer Res 2007;67(2):593–9]

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