| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
© 2005 Oxford University Press
ARTICLE |
Complete and Specific Inhibition of Adult Lymphatic Regeneration by a Novel VEGFR-3 Neutralizing Antibody
Affiliations of authors: Molecular and Cellular Biology, ImClone Systems, New York, NY (BP, KP, LW); Biomedical Engineering Department, Northwestern University, Evanston, IL (JG, KCB, MAS); Experimental Therapeutics, ImClone Systems, New York, NY (YW, DJH); Derald H. Ruttenberg Cancer Center, Mt. Sinai School of Medicine, New York, NY (MS)
Correspondence to: Melody A. Swartz, PhD, Assistant Professor, Institute for Biological Engineering and Biotechnology, School of Life Sciences/LMBM/AAB041, Swiss Federal Institute of Technology Lausanne (EPFL), 1015 Lausanne, Switzerland (e-mail: melody.swartz{at}epfl.ch)
Background: New lymphatic growth may contribute to tumor metastasis. Activation of vascular endothelial growth factor receptor 3 (VEGFR-3) by its ligands VEGF-C and -D is necessary for embryonic and tumor lymphangiogenesis. However, the exact role of VEGFR-3 signaling in adult lymphangiogenesis and in lymphatic vessel survival and regeneration is unclear. Methods: A novel rat monoclonal antibody to murine VEGFR-3, mF4-31C1, which potently antagonizes the binding of VEGF-C to VEGFR-3, was developed. We tested the effects of systemic mF4-31C1 administration in a mouse tail skin model of lymphatic regeneration, either with or without local overexpression of VEGF-C, and we observed lymphatic and blood vessel regeneration over time using microlymphangiography and immunostaining. Results: Normal mice regenerated complete and functional lymphatic vessels within 60 days of surgery. In athymic mice implanted with VEGF-C-overexpressing human breast carcinoma cells, lymphatic regeneration took place over 25 days and resulted in hyperplastic vessels. Under either condition, no lymphatic regeneration occurred in mice receiving mF4-31C1 during the regeneration period. Blood angiogenesis and preexisting lymphatic vessels were unaffected, both in morphology and in function. Conclusions: Blocking VEGFR-3 completely and specifically prevented both physiologically normal and tumor VEGF-C-enhanced lymphangiogenesis in the adult mouse but had no effect on either blood angiogenesis or the survival or function of existing lymphatic vessels. Thus, targeting VEGFR-3 with specific inhibitors may block new lymphatic growth exclusively.
CiteULike 
Connotea 
Del.icio.us What's this?
Editorial about this Article
- Lymphatic Regeneration: New Insights From VEGFR-3 Blockade
- Yoshiyasu Aoki and Giovanna Tosato
J Natl Cancer Inst 2005 97: 2-3.[Extract] [Full Text] [PDF]
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]
|
|
|
|
 |
|
 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]
|
|
|
|
 |
|
 T. Holopainen, H. Huang, C. Chen, K. E. Kim, L. Zhang, F. Zhou, W. Han, C. Li, J. Yu, J. Wu, et al. Angiopoietin-1 Overexpression Modulates Vascular Endothelium to Facilitate Tumor Cell Dissemination and Metastasis Establishment Cancer Res., June 1, 2009; 69(11): 4656 - 4664. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Lahdenranta, J. Hagendoorn, T. P. Padera, T. Hoshida, G. Nelson, S. Kashiwagi, R. K. Jain, and D. Fukumura Endothelial Nitric Oxide Synthase Mediates Lymphangiogenesis and Lymphatic Metastasis Cancer Res., April 1, 2009; 69(7): 2801 - 2808. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Conrad, H. Niess, R. Huss, S. Huber, I. von Luettichau, P. J. Nelson, H. C. Ott, K.-W. Jauch, and C. J. Bruns Multipotent Mesenchymal Stem Cells Acquire a Lymphendothelial Phenotype and Enhance Lymphatic Regeneration In Vivo Circulation, January 20, 2009; 119(2): 281 - 289. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Schomber, A. Zumsteg, K. Strittmatter, I. Crnic, H. Antoniadis, A. Littlewood-Evans, J. Wood, and G. Christofori Differential effects of the vascular endothelial growth factor receptor inhibitor PTK787/ZK222584 on tumor angiogenesis and tumor lymphangiogenesis Mol. Cancer Ther., January 1, 2009; 8(1): 55 - 63. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. W. Clavin, T. Avraham, J. Fernandez, S. V. Daluvoy, M. A. Soares, A. Chaudhry, and B. J. Mehrara TGF-{beta}1 is a negative regulator of lymphatic regeneration during wound repair Am J Physiol Heart Circ Physiol, November 1, 2008; 295(5): H2113 - H2127. [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]
|
|
|
|
 |
|
 D. Hos, F. Bock, T. Dietrich, J. Onderka, F. E. Kruse, K.-H. Thierauch, and C. Cursiefen Inflammatory Corneal (Lymph)angiogenesis Is Blocked by VEGFR-Tyrosine Kinase Inhibitor ZK 261991, Resulting in Improved Graft Survival after Corneal Transplantation Invest. Ophthalmol. Vis. Sci., May 1, 2008; 49(5): 1836 - 1842. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. V. Benest, S. J. Harper, S. Y. Herttuala, K. Alitalo, and D. O. Bates VEGF-C induced angiogenesis preferentially occurs at a distance from lymphangiogenesis Cardiovasc Res, May 1, 2008; 78(2): 315 - 323. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Uzarski, M. B. Drelles, S. E. Gibbs, E. L. Ongstad, J. C. Goral, K. K. McKeown, A. M. Raehl, M. A. Roberts, B. Pytowski, M. R. Smith, et al. The resolution of lymphedema by interstitial flow in the mouse tail skin Am J Physiol Heart Circ Physiol, March 1, 2008; 294(3): H1326 - H1334. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Choi and J.N. Myers Molecular Pathogenesis of Oral Squamous Cell Carcinoma: Implications for Therapy Journal of Dental Research, January 1, 2008; 87(1): 14 - 32. [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]
|
|
|
|
|
|
S. Jackowski, M. Janusch, E. Fiedler, W. C. Marsch, E. J. Ulbrich, G. Gaisbauer, J. Dunst, D. Kerjaschki, and P. Helmbold Radiogenic Lymphangiogenesis in the Skin Am. J. Pathol., July 1, 2007; 171(1): 338 - 348. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Wirzenius, T. Tammela, M. Uutela, Y. He, T. Odorisio, G. Zambruno, J. A. Nagy, H. F. Dvorak, S. Yla-Herttuala, M. Shibuya, et al. Distinct vascular endothelial growth factor signals for lymphatic vessel enlargement and sprouting J. Exp. Med., June 11, 2007; 204(6): 1431 - 1440. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Goldman, K. A. Conley, A. Raehl, D. M. Bondy, B. Pytowski, M. A. Swartz, J. M. Rutkowski, D. B. Jaroch, and E. L. Ongstad Regulation of lymphatic capillary regeneration by interstitial flow in skin Am J Physiol Heart Circ Physiol, May 1, 2007; 292(5): H2176 - H2183. [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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
J. M. Rutkowski, K. C. Boardman, and M. A. Swartz Characterization of lymphangiogenesis in a model of adult skin regeneration Am J Physiol Heart Circ Physiol, September 1, 2006; 291(3): H1402 - H1410. [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]
|
|
|
|
|
|
T. Karpanen, M. Wirzenius, T. Makinen, T. Veikkola, H. J. Haisma, M. G. Achen, S. A. Stacker, B. Pytowski, S. Yla-Herttuala, and K. Alitalo Lymphangiogenic Growth Factor Responsiveness Is Modulated by Postnatal Lymphatic Vessel Maturation Am. J. Pathol., August 1, 2006; 169(2): 708 - 718. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Cursiefen, L. Chen, M. Saint-Geniez, P. Hamrah, Y. Jin, S. Rashid, B. Pytowski, K. Persaud, Y. Wu, J. W. Streilein, et al. Nonvascular VEGF receptor 3 expression by corneal epithelium maintains avascularity and vision PNAS, July 25, 2006; 103(30): 11405 - 11410. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Roberts, B. Kloos, M. Cassella, S. Podgrabinska, K. Persaud, Y. Wu, B. Pytowski, and M. Skobe Inhibition of VEGFR-3 Activation with the Antagonistic Antibody More Potently Suppresses Lymph Node and Distant Metastases than Inactivation of VEGFR-2. Cancer Res., March 1, 2006; 66(5): 2650 - 2657. [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]
|
|
|
|
 |
|
 G. Breier Lymphangiogenesis in Regenerating Tissue: Is VEGF-C Sufficient? Circ. Res., June 10, 2005; 96(11): 1132 - 1134. [Full Text] [PDF]
|
|
|
|
|
|
J. Goldman, T. X. Le, M. Skobe, and M. A. Swartz Overexpression of VEGF-C Causes Transient Lymphatic Hyperplasia but Not Increased Lymphangiogenesis in Regenerating Skin Circ. Res., June 10, 2005; 96(11): 1193 - 1199. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Cursiefen, S. Ikeda, P. M. Nishina, R. S. Smith, A. Ikeda, D. Jackson, J.-S. Mo, L. Chen, M. R. Dana, B. Pytowski, et al. Spontaneous Corneal Hem- and Lymphangiogenesis in Mice with Destrin-Mutation Depend on VEGFR3 Signaling Am. J. Pathol., May 1, 2005; 166(5): 1367 - 1377. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Aoki and G. Tosato Lymphatic Regeneration: New Insights From VEGFR-3 Blockade J Natl Cancer Inst, January 5, 2005; 97(1): 2 - 3. [Full Text] [PDF]
|
|