This Article Full Text Full Text (PDF) Supplementary Data Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Laakkonen, P. Articles by Alitalo, K. Search for Related Content PubMed PubMed Citation Articles by Laakkonen, P. Articles by Alitalo, K.

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]

This article has been cited by other articles:

				E.-S. Chung, S. K. Chauhan, Y. Jin, S. Nakao, A. Hafezi-Moghadam, N. van Rooijen, Q. Zhang, L. Chen, and R. Dana Contribution of Macrophages to Angiogenesis Induced by Vascular Endothelial Growth Factor Receptor-3-Specific Ligands Am. J. Pathol., November 1, 2009; 175(5): 1984 - 1992. [Abstract] [Full Text] [PDF]

				A. C. Roman, J. M. Carvajal-Gonzalez, E. M. Rico-Leo, and P. M. Fernandez-Salguero Dioxin Receptor Deficiency Impairs Angiogenesis by a Mechanism Involving VEGF-A Depletion in the Endothelium and Transforming Growth Factor-{beta} Overexpression in the Stroma J. Biol. Chem., September 11, 2009; 284(37): 25135 - 25148. [Abstract] [Full Text] [PDF]

				M. P. Morelli, A. M. Brown, T. M. Pitts, J. J. Tentler, F. Ciardiello, A. Ryan, J. M. Jurgensmeier, and S. G. Eckhardt Targeting vascular endothelial growth factor receptor-1 and -3 with cediranib (AZD2171): effects on migration and invasion of gastrointestinal cancer cell lines Mol. Cancer Ther., September 1, 2009; 8(9): 2546 - 2558. [Abstract] [Full Text] [PDF]

				N. C. Douglas, H. Tang, R. Gomez, B. Pytowski, D. J. Hicklin, C. M. Sauer, J. Kitajewski, M. V. Sauer, and R. C. Zimmermann Vascular Endothelial Growth Factor Receptor 2 (VEGFR-2) Functions to Promote Uterine Decidual Angiogenesis during Early Pregnancy in the Mouse Endocrinology, August 1, 2009; 150(8): 3845 - 3854. [Abstract] [Full Text] [PDF]

				A. Anisimov, A. Alitalo, P. Korpisalo, J. Soronen, S. Kaijalainen, V.-M. Leppanen, M. Jeltsch, S. Yla-Herttuala, and K. Alitalo Activated Forms of VEGF-C and VEGF-D Provide Improved Vascular Function in Skeletal Muscle Circ. Res., June 5, 2009; 104(11): 1302 - 1312. [Abstract] [Full Text] [PDF]

				S. KUEMMEL, A. THOMAS, S. LANDT, A. FUGER, P. SCHMID, M. KRINER, J.-U. BLOHMER, J. SEHOULI, G. SCHALLER, W. LICHTENEGGER, et al. Circulating Vascular Endothelial Growth Factors and their Soluble Receptors in Pre-invasive, Invasive and Recurrent Cervical Cancer Anticancer Res, February 1, 2009; 29(2): 641 - 645. [Abstract] [Full Text] [PDF]

				T. Miyazaki, N. Okada, K. Ishibashi, K. Ogata, T. Ohsawa, T. Ishiguro, H. Nakada, M. Yokoyama, M. Matsuki, H. Kato, et al. Clinical Significance of Plasma Level of Vascular Endothelial Growth Factor-C in Patients with Colorectal Cancer Jpn. J. Clin. Oncol., December 1, 2008; 38(12): 839 - 843. [Abstract] [Full Text] [PDF]

				M. Lohela, H. Helotera, P. Haiko, D. J. Dumont, and K. Alitalo Transgenic Induction of Vascular Endothelial Growth Factor-C Is Strongly Angiogenic in Mouse Embryos but Leads to Persistent Lymphatic Hyperplasia in Adult Tissues Am. J. Pathol., December 1, 2008; 173(6): 1891 - 1901. [Abstract] [Full Text] [PDF]

				M. Kodama, Y. Kitadai, M. Tanaka, T. Kuwai, S. Tanaka, N. Oue, W. Yasui, and K. Chayama Vascular Endothelial Growth Factor C Stimulates Progression of Human Gastric Cancer via Both Autocrine and Paracrine Mechanisms Clin. Cancer Res., November 15, 2008; 14(22): 7205 - 7214. [Abstract] [Full Text] [PDF]

				D. D. Hu-Lowe, H. Y. Zou, M. L. Grazzini, M. E. Hallin, G. R. Wickman, K. Amundson, J. H. Chen, D. A. Rewolinski, S. Yamazaki, E. Y. Wu, et al. Nonclinical Antiangiogenesis and Antitumor Activities of Axitinib (AG-013736), an Oral, Potent, and Selective Inhibitor of Vascular Endothelial Growth Factor Receptor Tyrosine Kinases 1, 2, 3 Clin. Cancer Res., November 15, 2008; 14(22): 7272 - 7283. [Abstract] [Full Text] [PDF]

				L. M. Ellis and D. J. Hicklin Pathways Mediating Resistance to Vascular Endothelial Growth Factor-Targeted Therapy Clin. Cancer Res., October 15, 2008; 14(20): 6371 - 6375. [Abstract] [Full Text] [PDF]

				J. B. Burton, S. J. Priceman, J. L. Sung, E. Brakenhielm, D. S. An, B. Pytowski, K. Alitalo, and L. Wu Suppression of Prostate Cancer Nodal and Systemic Metastasis by Blockade of the Lymphangiogenic Axis Cancer Res., October 1, 2008; 68(19): 7828 - 7837. [Abstract] [Full Text] [PDF]

				A. Ny, M. Koch, W. Vandevelde, M. Schneider, C. Fischer, A. Diez-Juan, E. Neven, I. Geudens, S. Maity, L. Moons, et al. Role of VEGF-D and VEGFR-3 in developmental lymphangiogenesis, a chemicogenetic study in Xenopus tadpoles Blood, September 1, 2008; 112(5): 1740 - 1749. [Abstract] [Full Text] [PDF]

				C. A. Heckman, T. Holopainen, M. Wirzenius, S. Keskitalo, M. Jeltsch, S. Yla-Herttuala, S. R. Wedge, J. M. Jurgensmeier, and K. Alitalo The Tyrosine Kinase Inhibitor Cediranib Blocks Ligand-Induced Vascular Endothelial Growth Factor Receptor-3 Activity and Lymphangiogenesis Cancer Res., June 15, 2008; 68(12): 4754 - 4762. [Abstract] [Full Text] [PDF]

				M. Oka, C. Iwata, H. I. Suzuki, K. Kiyono, Y. Morishita, T. Watabe, A. Komuro, M. R. Kano, and K. Miyazono Inhibition of endogenous TGF-{beta} signaling enhances lymphangiogenesis Blood, May 1, 2008; 111(9): 4571 - 4579. [Abstract] [Full Text] [PDF]

				C.R. Dass, T.M.N. Tran, and P.F.M. Choong Angiogenesis Inhibitors and the Need for Anti-angiogenic Therapeutics Journal of Dental Research, October 1, 2007; 86(10): 927 - 936. [Abstract] [Full Text] [PDF]

				T. P. Padera, M. Ancukiewicz, T. Hoshida, D. Fukumura, and R. K. Jain Anti-VEGFR-3 Therapy and Lymph Node Metastasis Cancer Res., May 15, 2007; 67(10): 5055 - 5055. [Full Text] [PDF]