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Max-Planck-Institut für Biochemie, Am Klopferspitz 18A, 82125 Martinsried, Germany [B. M., A. U.]; Klinikum der Albert-Ludwigs-Universität, Abteilung Neuropathologie im Neurozentrum, Breisacherstrasse 64, 79106 Freiburg, Germany [K. H. P.]; Max-Planck-Institut für Physiologische und Klinische Forschung, W. G. Kerchoff-Institut, Abteilung Molekulare Zellbiologie, Parkstrasse 1, 61231 Bad Nauheim, Germany [W. R.]; and SUGEN, Inc., Redwood City, California 94063 [M. P. L., L. K. S., L. M. S.]
Angiogenesis, the sprouting of new blood vessels from existing vessels, occurs in many physiological and pathological processes, including embryonic development, wound healing, and tumor growth. It is required for tumor growth because new blood vessel formation is necessary for tumors to expand beyond a minimum volume. Several growth factor receptor tyrosine kinases have been implicated in angiogenesis, including receptors for epidermal, fibroblast, and platelet-derived growth factors, as well as the receptors Flk-1/KDR, Flt-1, Tek/Tie-2, and Tie-1. Endothelial cells in the vessels of tumors express Flk-1/KDR, a receptor for vascular endothelial growth factor. Flk-1 was previously shown to play a role in angiogenesis and tumor formation of s.c. xenografts of C6 glioma cells using dominant-negative methodology. We now demonstrate that Flk-1 seems to be generally involved in the growth of a wide range of solid tumors, including mammary, ovarian, and lung carcinoma, as well as glioblastoma. Furthermore, survival times in rats bearing intracerebral tumors were prolonged using the same dominant-negative methodology. The involvement of Flk-1 in a variety of tumor types suggests an important role for Flk-1 in tumor angiogenesis.
1 Present address: Pennie and Edmonds, 2730 Sand Hill Road, Menlo Park, CA 94025.
2 To whom requests for reprints should be addressed, at SUGEN, Inc., 515 Galveston Drive, Redwood City, CA 94063.
Received 10/18/95. Accepted 2/ 1/96.
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C. K. Goldman, R. L. Kendall, G. Cabrera, L. Soroceanu, Y. Heike, G. Y. Gillespie, G. P. Siegal, X. Mao, A. J. Bett, W. R. Huckle, et al. Paracrine expression of a native soluble vascular endothelial growth factor receptor inhibits tumor growth, metastasis, and mortality rate PNAS, July 21, 1998; 95(15): 8795 - 8800. [Abstract] [Full Text] [PDF]
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P. Lin, J. A. Buxton, A. Acheson, C. Radziejewski, P. C. Maisonpierre, G. D. Yancopoulos, K. M. Channon, L. P. Hale, M. W. Dewhirst, S. E. George, et al. Antiangiogenic gene therapy targeting the endothelium-specific receptor tyrosine kinase Tie2 PNAS, July 21, 1998; 95(15): 8829 - 8834. [Abstract] [Full Text] [PDF]
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D. R. Senger, K. P. Claffey, J. E. Benes, C. A. Perruzzi, A. P. Sergiou, and M. Detmar Angiogenesis promoted by vascular endothelial growth factor: Regulation through alpha 1beta 1 and alpha 2beta 1 integrins PNAS, December 9, 1997; 94(25): 13612 - 13617. [Abstract] [Full Text] [PDF]
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Y. S. Schiffenbauer, R. Abramovitch, G. Meir, N. Nevo, M. Holzinger, A. Itin, E. Keshet, and M. Neeman Loss of ovarian function promotes angiogenesis in human ovarian carcinoma PNAS, November 25, 1997; 94(24): 13203 - 13208. [Abstract] [Full Text] [PDF]
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 D. S. Winlaw Angiogenesis in the Pathobiology and Treatment of Vascular and Malignant Diseases Ann. Thorac. Surg., October 1, 1997; 64(4): 1204 - 1211. [Abstract] [Full Text]
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L. E. Benjamin and E. Keshet Conditional switching of vascular endothelial growth factor (VEGF) expression in tumors: Induction of endothelial cell shedding and regression of hemangioblastoma-like vessels by VEGF withdrawal PNAS, August 5, 1997; 94(16): 8761 - 8766. [Abstract] [Full Text] [PDF]
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R. Yabkowitz, S. Meyer, D. Yanagihara, D. Brankow, T. Staley, G. Elliott, S. Hu, and B. Ratzkin Regulation of Tie Receptor Expression on Human Endothelial Cells by Protein Kinase C-Mediated Release of Soluble Tie Blood, July 15, 1997; 90(2): 706 - 715. [Abstract] [Full Text] [PDF]
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 R. O SCHLINGEMANN and V. W M VAN HINSBERGH Role of vascular permeability factor/vascular endothelial growth factor in eye disease Br J Ophthalmol, June 1, 1997; 81(6): 501 - 512. [Full Text] [PDF]
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N. Ferrara and T. Davis-Smyth The Biology of Vascular Endothelial Growth Factor Endocr. Rev., February 1, 1997; 18(1): 4 - 25. [Abstract] [Full Text]
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H. Gille, J. Kowalski, B. Li, J. LeCouter, B. Moffat, T. F. Zioncheck, N. Pelletier, and N. Ferrara Analysis of Biological Effects and Signaling Properties of Flt-1 (VEGFR-1) and KDR (VEGFR-2). A REASSESSMENT USING NOVEL RECEPTOR-SPECIFIC VASCULAR ENDOTHELIAL GROWTH FACTOR MUTANTS J. Biol. Chem., January 26, 2001; 276(5): 3222 - 3230. [Abstract] [Full Text] [PDF]
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M. E. Baldwin, B. Catimel, E. C. Nice, S. Roufail, N. E. Hall, K. L. Stenvers, M. J. Karkkainen, K. Alitalo, S. A. Stacker, and M. G. Achen The Specificity of Receptor Binding by Vascular Endothelial Growth Factor-D Is Different in Mouse and Man J. Biol. Chem., May 25, 2001; 276(22): 19166 - 19171. [Abstract] [Full Text] [PDF]
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M. L. Gagnon, D. R. Bielenberg, Z.'e. Gechtman, H.-Q. Miao, S. Takashima, S. Soker, and M. Klagsbrun Identification of a natural soluble neuropilin-1 that binds vascular endothelial growth factor: In vivo expression and antitumor activity PNAS, March 14, 2000; 97(6): 2573 - 2578. [Abstract] [Full Text] [PDF]
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M. Papetti and I. M. Herman Mechanisms of normal and tumor-derived angiogenesis Am J Physiol Cell Physiol, May 1, 2002; 282(5): C947 - C970. [Abstract] [Full Text] [PDF]
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