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Vascular Endothelial Growth Factor C Promotes Tumor Lymphangiogenesis and Intralymphatic Tumor Growth¹

Molecular/Cancer Biology Laboratory, Haartman Institute and Ludwig Institute for Cancer Research, FIN-00014 University of Helsinki, Finland [T. K., M. J. K., H. K., K. A.]; Apoptosis Laboratory, Danish Cancer Society, DK-2100 Copenhagen, Denmark [M. E., M. J.]; and A. I. Virtanen Institute, University of Kuopio, FIN-70211 Kuopio, Finland [S. Y-H.]

Many solid tumors produce vascular endothelial growth factor C (VEGF-C), and its receptor, VEGFR-3, is expressed in tumor blood vessels. To study the role of VEGF-C in tumorigenesis, we implanted MCF-7 human breast carcinoma cells overexpressing recombinant VEGF-C orthotopically into severe combined immunodeficient mice. VEGF-C increased tumor growth, but unlike VEGF, it had little effect on tumor angiogenesis. Instead, VEGF-C strongly promoted the growth of tumor-associated lymphatic vessels, which in the tumor periphery were commonly infiltrated with the tumor cells. These effects of VEGF-C were inhibited by a soluble VEGFR-3 fusion protein. Our data suggest that VEGF-C facilitates tumor metastasis via the lymphatic vessels and that tumor spread can be inhibited by blocking the interaction between VEGF-C and its receptor.

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				H. Kubo, R. Cao, E. Brakenhielm, T. Makinen, Y. Cao, and K. Alitalo Blockade of vascular endothelial growth factor receptor-3 signaling inhibits fibroblast growth factor-2-induced lymphangiogenesis in mouse cornea PNAS, June 25, 2002; 99(13): 8868 - 8873. [Abstract] [Full Text] [PDF]

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				Y. He, K.-i. Kozaki, T. Karpanen, K. Koshikawa, S. Yla-Herttuala, T. Takahashi, and K. Alitalo Suppression of Tumor Lymphangiogenesis and Lymph Node Metastasis by Blocking Vascular Endothelial Growth Factor Receptor 3 Signaling J Natl Cancer Inst, June 5, 2002; 94(11): 819 - 825. [Abstract] [Full Text] [PDF]

				G. Oliver and M. Detmar The rediscovery of the lymphatic system: old and new insights into the development and biological function of the lymphatic vasculature Genes & Dev., April 1, 2002; 16(7): 773 - 783. [Full Text] [PDF]

				R. K. Jain and B. T. Fenton Intratumoral Lymphatic Vessels: A Case of Mistaken Identity or Malfunction? J Natl Cancer Inst, March 20, 2002; 94(6): 417 - 421. [Full Text] [PDF]

				O. Straume and L. A. Akslen Importance of Vascular Phenotype by Basic Fibroblast Growth Factor, and Influence of the Angiogenic Factors Basic Fibroblast Growth Factor/Fibroblast Growth Factor Receptor-1 and Ephrin-A1/EphA2 on Melanoma Progression Am. J. Pathol., March 1, 2002; 160(3): 1009 - 1019. [Abstract] [Full Text] [PDF]

				T. MAKINEN and K. ALITALO Molecular Mechanisms of Lymphangiogenesis Cold Spring Harb Symp Quant Biol, January 1, 2002; 67(0): 189 - 196. [Abstract] [PDF]

				J. F. Wang, X.-F. Zhang, and J. E. Groopman Stimulation of beta 1 Integrin Induces Tyrosine Phosphorylation of Vascular Endothelial Growth Factor Receptor-3 and Modulates Cell Migration J. Biol. Chem., November 2, 2001; 276(45): 41950 - 41957. [Abstract] [Full Text] [PDF]

				T. Karpanen and K. Alitalo Lymphatic Vessels as Targets of Tumor Therapy? J. Exp. Med., September 17, 2001; 194(6): f37 - f42. [Full Text] [PDF]

				M. Skobe, L. M. Hamberg, T. Hawighorst, M. Schirner, G. L. Wolf, K. Alitalo, and M. Detmar Concurrent Induction of Lymphangiogenesis, Angiogenesis, and Macrophage Recruitment by Vascular Endothelial Growth Factor-C in Melanoma Am. J. Pathol., September 1, 2001; 159(3): 893 - 903. [Abstract] [Full Text] [PDF]