| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Cell and Tumor Biology |
1 Molecular/Cancer Biology Laboratory and Ludwig Institute for Cancer Research, Biomedicum Helsinki and Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland; 2 A.I. Virtanen Institute, University of Kuopio, Kuopio, Finland; 3 Cell Genesys, Inc., South San Francisco, California; and 4 Division of Molecular Carcinogenesis, Center for Neurological Disease and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan
Requests for reprints: Kari Alitalo, Molecular/Cancer Biology Laboratory and Ludwig Institute for Cancer Research, Biomedicum Helsinki and Helsinki University Central Hospital, University of Helsinki, P.O. Box 63 (Haartmaninkatu 8), 00014 Helsinki, Finland. Phone: 358-9191-25511; Fax: 358-9-912-25510; E-mail: kari.alitalo{at}helsinki.fi.
Lymphangiogenic growth factors vascular endothelial growth factor (VEGF)-C and VEGF-D have been shown to promote lymphatic metastasis by inducing tumor-associated lymphangiogenesis. In this study, we have investigated how tumor cells gain access into lymphatic vessels and at what stage tumor cells initiate metastasis. We show that VEGF-C produced by tumor cells induced extensive lymphatic sprouting towards the tumor cells as well as dilation of the draining lymphatic vessels, suggesting an active role of lymphatic endothelial cells in lymphatic metastasis. A significant increase in lymphatic vessel growth occurred between 2 and 3 weeks after tumor xenotransplantation, and lymph node metastasis occurred at the same stage. These processes were blocked dose-dependently by inhibition of VEGF receptor 3 (VEGFR-3) signaling by systemic delivery of a soluble VEGFR-3-immunoglobulin (Ig) fusion protein via adenoviral or adeno-associated viral vectors. However, VEGFR-3-Ig did not suppress lymph node metastasis when the treatment was started at a later stage after the tumor cells had already spread out, suggesting that tumor cell entry into lymphatic vessels is a key step during tumor dissemination via the lymphatics. Whereas lymphangiogenesis and lymph node metastasis were significantly inhibited by VEGFR-3-Ig, some tumor cells were still detected in the lymph nodes in some of the treated mice. This indicates that complete blockade of lymphatic metastasis may require the targeting of both tumor lymphangiogenesis and tumor cell invasion.
This article has been cited by other articles:
|
|
 |
|
  T. P. Padera, A. H. Kuo, T. Hoshida, S. Liao, J. Lobo, K. R. Kozak, D. Fukumura, and R. K. Jain Differential response of primary tumor versus lymphatic metastasis to VEGFR-2 and VEGFR-3 kinase inhibitors cediranib and vandetanib Mol. Cancer Ther., August 1, 2008; 7(8): 2272 - 2279. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Marttila-Ichihara, R. Turja, M. Miiluniemi, M. Karikoski, M. Maksimow, J. Niemela, L. Martinez-Pomares, M. Salmi, and S. Jalkanen Macrophage mannose receptor on lymphatics controls cell trafficking Blood, July 1, 2008; 112(1): 64 - 72. [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]
|
|
|
|
 |
|
 S. S. Sundar and T. S. Ganesan Role of Lymphangiogenesis in Cancer J. Clin. Oncol., September 20, 2007; 25(27): 4298 - 4307. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Qin, Y. Wan, M. Li, X. Xue, S. Wu, C. Zhang, Y. You, W. Wang, C. Jiang, Y. Liu, et al. Identification of a Novel Peptide Ligand of Human Vascular Endothelia Growth Factor Receptor 3 for Targeted Tumour Diagnosis and Therapy J. Biochem., July 1, 2007; 142(1): 79 - 85. [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]
|
|
|
|
 |
|
 R. R. Langley and I. J. Fidler Tumor Cell-Organ Microenvironment Interactions in the Pathogenesis of Cancer Metastasis Endocr. Rev., May 1, 2007; 28(3): 297 - 321. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Goldman, J. M. Rutkowski, J. D. Shields, M. C. Pasquier, Y. Cui, H. G. Schmokel, S. Willey, D. J. Hicklin, B. Pytowski, and M. A. Swartz Cooperative and redundant roles of VEGFR-2 and VEGFR-3 signaling in adult lymphangiogenesis FASEB J, April 1, 2007; 21(4): 1003 - 1012. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. I. Harrell, B. M. Iritani, and A. Ruddell Tumor-Induced Sentinel Lymph Node Lymphangiogenesis and Increased Lymph Flow Precede Melanoma Metastasis Am. J. Pathol., February 1, 2007; 170(2): 774 - 786. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Hirakawa, L. F. Brown, S. Kodama, K. Paavonen, K. Alitalo, and M. Detmar VEGF-C-induced lymphangiogenesis in sentinel lymph nodes promotes tumor metastasis to distant sites Blood, February 1, 2007; 109(3): 1010 - 1017. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Laakkonen, M. Waltari, T. Holopainen, T. Takahashi, B. Pytowski, P. Steiner, D. Hicklin, K. Persaud, J. R. Tonra, L. Witte, et al. Vascular Endothelial Growth Factor Receptor 3 Is Involved in Tumor Angiogenesis and Growth Cancer Res., January 15, 2007; 67(2): 593 - 599. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Zeng, K. Opeskin, J. Goad, and E. D. Williams Tumor-Induced Activation of Lymphatic Endothelial Cells via Vascular Endothelial Growth Factor Receptor-2 Is Critical for Prostate Cancer Lymphatic Metastasis Cancer Res., October 1, 2006; 66(19): 9566 - 9575. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Shayan, M. G. Achen, and S. A. Stacker Lymphatic vessels in cancer metastasis: bridging the gaps Carcinogenesis, September 1, 2006; 27(9): 1729 - 1738. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Hoshida, N. Isaka, J. Hagendoorn, E. di Tomaso, Y.-L. Chen, B. Pytowski, D. Fukumura, T. P. Padera, and R. K. Jain Imaging Steps of Lymphatic Metastasis Reveals That Vascular Endothelial Growth Factor-C Increases Metastasis by Increasing Delivery of Cancer Cells to Lymph Nodes: Therapeutic Implications Cancer Res., August 15, 2006; 66(16): 8065 - 8075. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. L. Iruela-Arispe When It Comes to Blocking Lymphatics, It Is All a Question of Time Am. J. Pathol., August 1, 2006; 169(2): 347 - 350. [Full Text] [PDF]
|
|
|
|
 |
|
 J. Kreuger, I. Nilsson, D. Kerjaschki, T. Petrova, K. Alitalo, and L. Claesson-Welsh Early Lymph Vessel Development From Embryonic Stem Cells Arterioscler. Thromb. Vasc. Biol., May 1, 2006; 26(5): 1073 - 1078. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Y. Wong, H. Haack, D. Crowley, M. Barry, R. T. Bronson, and R. O. Hynes Tumor-Secreted Vascular Endothelial Growth Factor-C Is Necessary for Prostate Cancer Lymphangiogenesis, but Lymphangiogenesis Is Unnecessary for Lymph Node Metastasis Cancer Res., November 1, 2005; 65(21): 9789 - 9798. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Cancer Research | Clinical Cancer Research |
| Cancer Epidemiology Biomarkers & Prevention | Molecular Cancer Therapeutics |
| Molecular Cancer Research | Cancer Prevention Research |
| Cancer Prevention Journals Portal | Cancer Reviews Online |
| Annual Meeting Education Book | Meeting Abstracts Online |
