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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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Z. Gombos, X. Xu, C. S. Chu, P. J. Zhang, and G. Acs Peritumoral Lymphatic Vessel Density and Vascular Endothelial Growth Factor C Expression in Early-Stage Squamous Cell Carcinoma of the Uterine Cervix Clin. Cancer Res., December 1, 2005; 11(23): 8364 - 8371. [Abstract] [Full Text] [PDF] |
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F. Renyi-Vamos, J. Tovari, J. Fillinger, J. Timar, S. Paku, I. Kenessey, G. Ostoros, L. Agocs, I. Soltesz, and B. Dome Lymphangiogenesis Correlates with Lymph Node Metastasis, Prognosis, and Angiogenic Phenotype in Human Non-Small Cell Lung Cancer Clin. Cancer Res., October 15, 2005; 11(20): 7344 - 7353. [Abstract] [Full Text] [PDF] |
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J. Lin, A. S. Lalani, T. C. Harding, M. Gonzalez, W.-W. Wu, B. Luan, G. H. Tu, K. Koprivnikar, M. J. VanRoey, Y. He, et al. Inhibition of Lymphogenous Metastasis Using Adeno-Associated Virus-Mediated Gene Transfer of a Soluble VEGFR-3 Decoy Receptor Cancer Res., August 1, 2005; 65(15): 6901 - 6909. [Abstract] [Full Text] [PDF] |
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G. Breier Lymphangiogenesis in Regenerating Tissue: Is VEGF-C Sufficient? Circ. Res., June 10, 2005; 96(11): 1132 - 1134. [Full Text] [PDF] |
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Y. He, I. Rajantie, K. Pajusola, M. Jeltsch, T. Holopainen, S. Yla-Herttuala, T. Harding, K. Jooss, T. Takahashi, and K. Alitalo Vascular Endothelial Cell Growth Factor Receptor 3-Mediated Activation of Lymphatic Endothelium Is Crucial for Tumor Cell Entry and Spread via Lymphatic Vessels Cancer Res., June 1, 2005; 65(11): 4739 - 4746. [Abstract] [Full Text] [PDF] |
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S. Hirakawa, S. Kodama, R. Kunstfeld, K. Kajiya, L. F. Brown, and M. Detmar VEGF-A induces tumor and sentinel lymph node lymphangiogenesis and promotes lymphatic metastasis J. Exp. Med., April 4, 2005; 201(7): 1089 - 1099. [Abstract] [Full Text] [PDF] |
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T. Tammela, C. Heckman, and K. Alitalo Lymphangiogenesis and Metastasis Am. Assoc. Cancer Res. Educ. Book, April 1, 2005; 2005(1): 67 - 73. [Full Text] [PDF] |
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M. E. Baldwin, M. M. Halford, S. Roufail, R. A. Williams, M. L. Hibbs, D. Grail, H. Kubo, S. A. Stacker, and M. G. Achen Vascular Endothelial Growth Factor D Is Dispensable for Development of the Lymphatic System Mol. Cell. Biol., March 15, 2005; 25(6): 2441 - 2449. [Abstract] [Full Text] [PDF] |
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X. Jimenez, D. Lu, L. Brennan, K. Persaud, M. Liu, H. Miao, L. Witte, and Z. Zhu A recombinant, fully human, bispecific antibody neutralizes the biological activities mediated by both vascular endothelial growth factor receptors 2 and 3 Mol. Cancer Ther., March 1, 2005; 4(3): 427 - 434. [Abstract] [Full Text] [PDF] |
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V. Schacht, S. S. Dadras, L. A. Johnson, D. G. Jackson, Y.-K. Hong, and M. Detmar Up-Regulation of the Lymphatic Marker Podoplanin, a Mucin-Type Transmembrane Glycoprotein, in Human Squamous Cell Carcinomas and Germ Cell Tumors Am. J. Pathol., March 1, 2005; 166(3): 913 - 921. [Abstract] [Full Text] [PDF] |
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T. Tammela, B. Enholm, K. Alitalo, and K. Paavonen The biology of vascular endothelial growth factors Cardiovasc Res, February 15, 2005; 65(3): 550 - 563. [Abstract] [Full Text] [PDF] |
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M I Koukourakis, A Giatromanolaki, E Sivridis, C Simopoulos, K C Gatter, A L Harris, and D G Jackson LYVE-1 immunohistochemical assessment of lymphangiogenesis in endometrial and lung cancer J. Clin. Pathol., February 1, 2005; 58(2): 202 - 206. [Abstract] [Full Text] [PDF] |
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V. Kaushal, P. Mukunyadzi, R. A. Dennis, E. R. Siegel, D. E. Johnson, and M. Kohli Stage-Specific Characterization of the Vascular Endothelial Growth Factor Axis in Prostate Cancer: Expression of Lymphangiogenic Markers Is Associated with Advanced-Stage Disease Clin. Cancer Res., January 15, 2005; 11(2): 584 - 593. [Abstract] [Full Text] [PDF] |
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B. Pytowski, J. Goldman, K. Persaud, Y. Wu, L. Witte, D. J. Hicklin, M. Skobe, K. C. Boardman, and M. A. Swartz Complete and Specific Inhibition of Adult Lymphatic Regeneration by a Novel VEGFR-3 Neutralizing Antibody J Natl Cancer Inst, January 5, 2005; 97(1): 14 - 21. [Abstract] [Full Text] [PDF] |
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K. Alitalo, S. Mohla, and E. Ruoslahti Lymphangiogenesis and Cancer: Meeting Report Cancer Res., December 15, 2004; 64(24): 9225 - 9229. [Full Text] [PDF] |
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H. Kurahara, S. Takao, K. Maemura, H. Shinchi, S. Natsugoe, and T. Aikou Impact of Vascular Endothelial Growth Factor-C and -D Expression in Human Pancreatic Cancer: Its Relationship to Lymph Node Metastasis Clin. Cancer Res., December 15, 2004; 10(24): 8413 - 8420. [Abstract] [Full Text] [PDF] |
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I. Crnic, K. Strittmatter, U. Cavallaro, L. Kopfstein, L. Jussila, K. Alitalo, and G. Christofori Loss of Neural Cell Adhesion Molecule Induces Tumor Metastasis by Up-regulating Lymphangiogenesis Cancer Res., December 1, 2004; 64(23): 8630 - 8638. [Abstract] [Full Text] [PDF] |
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A. Hoeben, B. Landuyt, M. S. Highley, H. Wildiers, A. T. Van Oosterom, and E. A. De Bruijn Vascular Endothelial Growth Factor and Angiogenesis Pharmacol. Rev., December 1, 2004; 56(4): 549 - 580. [Abstract] [Full Text] [PDF] |
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P. Bono, V.-M. Wasenius, P. Heikkila, J. Lundin, D. G. Jackson, and H. Joensuu High LYVE-1-Positive Lymphatic Vessel Numbers Are Associated with Poor Outcome in Breast Cancer Clin. Cancer Res., November 1, 2004; 10(21): 7144 - 7149. [Abstract] [Full Text] [PDF] |
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Y. Zeng, K. Opeskin, M. E. Baldwin, L. G. Horvath, M. G. Achen, S. A. Stacker, R. L. Sutherland, and E. D. Williams Expression of Vascular Endothelial Growth Factor Receptor-3 by Lymphatic Endothelial Cells Is Associated with Lymph Node Metastasis in Prostate Cancer Clin. Cancer Res., August 1, 2004; 10(15): 5137 - 5144. [Abstract] [Full Text] [PDF] |
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N. Isaka, T. P. Padera, J. Hagendoorn, D. Fukumura, and R. K. Jain Peritumor Lymphatics Induced by Vascular Endothelial Growth Factor-C Exhibit Abnormal Function Cancer Res., July 1, 2004; 64(13): 4400 - 4404. [Abstract] [Full Text] [PDF] |
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M M Vleugel, R Bos, P van der Groep, A E Greijer, A Shvarts, H V Stel, E van der Wall, and P J van Diest Lack of lymphangiogenesis during breast carcinogenesis J. Clin. Pathol., July 1, 2004; 57(7): 746 - 751. [Abstract] [Full Text] [PDF] |
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P. Laakkonen, M. E. Akerman, H. Biliran, M. Yang, F. Ferrer, T. Karpanen, R. M. Hoffman, and E. Ruoslahti Antitumor activity of a homing peptide that targets tumor lymphatics and tumor cells PNAS, June 22, 2004; 101(25): 9381 - 9386. [Abstract] [Full Text] [PDF] |
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Y. He, I. Rajantie, M. Ilmonen, T. Makinen, M. J. Karkkainen, P. Haiko, P. Salven, and K. Alitalo Preexisting Lymphatic Endothelium but not Endothelial Progenitor Cells Are Essential for Tumor Lymphangiogenesis and Lymphatic Metastasis Cancer Res., June 1, 2004; 64(11): 3737 - 3740. [Abstract] [Full Text] [PDF] |
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K. Persaud, J.-C. Tille, M. Liu, Z. Zhu, X. Jimenez, D. S. Pereira, H.-Q. Miao, L. A. Brennan, L. Witte, M. S. Pepper, et al. Involvement of the VEGF receptor 3 in tubular morphogenesis demonstrated with a human anti-human VEGFR-3 monoclonal antibody that antagonizes receptor activation by VEGF-C J. Cell Sci., June 1, 2004; 117(13): 2745 - 2756. [Abstract] [Full Text] [PDF] |
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P. SAHARINEN and T. V. PETROVA Molecular Regulation of Lymphangiogenesis Ann. N.Y. Acad. Sci., April 1, 2004; 1014(1): 76 - 87. [Abstract] [Full Text] [PDF] |
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Y. Nakamura, H. Yasuoka, M. Tsujimoto, Q. Yang, S. Imabun, M. Nakahara, K. Nakao, M. Nakamura, I. Mori, and K. Kakudo Flt-4-Positive Vessel Density Correlates with Vascular Endothelial Growth Factor-D Expression, Nodal Status, and Prognosis in Breast Cancer Clin. Cancer Res., November 1, 2003; 9(14): 5313 - 5317. [Abstract] [Full Text] [PDF] |
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J. Dixelius, T. Makinen, M. Wirzenius, M. J. Karkkainen, C. Wernstedt, K. Alitalo, and L. Claesson-Welsh Ligand-induced Vascular Endothelial Growth Factor Receptor-3 (VEGFR-3) Heterodimerization with VEGFR-2 in Primary Lymphatic Endothelial Cells Regulates Tyrosine Phosphorylation Sites J. Biol. Chem., October 17, 2003; 278(42): 40973 - 40979. [Abstract] [Full Text] [PDF] |
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S. S. Dadras, T. Paul, J. Bertoncini, L. F. Brown, A. Muzikansky, D. G. Jackson, U. Ellwanger, C. Garbe, M. C. Mihm, and M. Detmar Tumor Lymphangiogenesis: A Novel Prognostic Indicator for Cutaneous Melanoma Metastasis and Survival Am. J. Pathol., June 1, 2003; 162(6): 1951 - 1960. [Abstract] [Full Text] [PDF] |
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E. D. Emberley, Y. Niu, E. Leygue, L. Tomes, R. D. Gietz, L. C. Murphy, and P. H. Watson Psoriasin Interacts with Jab1 and Influences Breast Cancer Progression Cancer Res., April 15, 2003; 63(8): 1954 - 1961. [Abstract] [Full Text] [PDF] |
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Y. Tang, D. Zhang, L. Fallavollita, and P. Brodt Vascular Endothelial Growth Factor C Expression and Lymph Node Metastasis Are Regulated by the Type I Insulin-like Growth Factor Receptor Cancer Res., March 15, 2003; 63(6): 1166 - 1171. [Abstract] [Full Text] [PDF] |
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L. Yuan, D. Moyon, L. Pardanaud, C. Breant, M. J. Karkkainen, K. Alitalo, and A. Eichmann Abnormal lymphatic vessel development in neuropilin 2 mutant mice Development, March 12, 2003; 129(20): 4797 - 4806. [Abstract] [Full Text] [PDF] |
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P.-W. Tsai, S.-G. Shiah, M.-T. Lin, C.-W. Wu, and M.-L. Kuo Up-regulation of Vascular Endothelial Growth Factor C in Breast Cancer Cells by Heregulin-beta 1. A CRITICAL ROLE OF p38/NUCLEAR FACTOR-kappa B SIGNALING PATHWAY J. Biol. Chem., February 14, 2003; 278(8): 5750 - 5759. [Abstract] [Full Text] [PDF] |
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J. Krishnan, V. Kirkin, A. Steffen, M. Hegen, D. Weih, S. Tomarev, J. Wilting, and J. P. Sleeman Differential in Vivo and in Vitro Expression of Vascular Endothelial Growth Factor (VEGF)-C and VEGF-D in Tumors and Its Relationship to Lymphatic Metastasis in Immunocompetent Rats Cancer Res., February 1, 2003; 63(3): 713 - 722. [Abstract] [Full Text] [PDF] |
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S. Hirakawa, Y.-K. Hong, N. Harvey, V. Schacht, K. Matsuda, T. Libermann, and M. Detmar Identification of Vascular Lineage-Specific Genes by Transcriptional Profiling of Isolated Blood Vascular and Lymphatic Endothelial Cells Am. J. Pathol., February 1, 2003; 162(2): 575 - 586. [Abstract] |