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Mutant ras Oncogenes Upregulate VEGF/VPF Expression: Implications for Induction and Inhibition of Tumor Angiogenesis¹

Division of Cancer Biology Research, Sunnybrook Health Science Centre, Toronto, Ontario M4N 3M5 Canada [J. R., Y. M., L. B., J. F., R. S. K.], and Department of Genetics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan [S. S., T. S.]

The growth of solid tumors in vivo beyond 1–2 mm in diameter requires induction and maintenance of an angiogenic response. This can occur through the release of various angiogenic growth factors from tumor cells. One such factor is vascular endothelial growth factor/vascular permeability factor (VEGF/VPF), a secreted and specific mitogen for vascular endothelial cells. We show that one of the most commonly encountered genetic changes detected in human cancer, i.e., expression of mutant ras oncogenes, is associated with marked up-regulation of VEGF/VPF in transformed epithelial cells. Thus, elevation of the levels of both VEGF/VPF mRNA and secreted functional protein were detected in human and rodent tumor cell lines expressing mutant K-ras or H-ras oncogenes, respectively. Genetic disruption of the mutant K-ras allele in human colon carcinoma cells was associated with a reduction in VEGF/VPF activity. Furthermore, pharmacological disruption of mutant RAS protein function in H-ras transformed rat intestinal epithelial cells by treatment with L-739,749 (a protein farnesyltransferase inhibitor) caused a significant suppression of VEGF/VPF. The results suggest that dominantly acting ras oncogenes may contribute to the growth of solid tumors in vivo not only by a direct effect on tumor cell proliferation but also indirectly, i.e., by facilitating tumor angiogenesis. Hence, pharmacologically targeting mutant ras oncogenes could conceivably suppress solid tumor growth in vivo, in part, by inhibiting tumor-induced angiogenesis.

¹ This work was supported by grants from the Medical Research Council of Canada and the National Institutes of Health, USA (CA-41233) to RSK. RSK is a Terry Fox Scientist of the National Cancer Institute of Canada, supported by funds from the annual Terry Fox Run.

² To whom requests for reprints should be addressed, at Sunnybrook Health Science Centre, Reichmann Research Building, S-218, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5 Canada.

Received 9/ 7/95. Accepted 9/14/95.

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				P. P. Claudio, P. Stiegler, C. M. Howard, C. Bellan, C. Minimo, G. M. Tosi, J. Rak, A. Kovatich, Paola De Fazio, P. Micheli, et al. RB2/p130 Gene-enhanced Expression Down-Regulates Vascular Endothelial Growth Factor Expression and Inhibits Angiogenesis in Vivo Cancer Res., January 1, 2001; 61(2): 462 - 468. [Abstract] [Full Text]

				I. Baba, S. Shirasawa, R. Iwamoto, K. Okumura, T. Tsunoda, M. Nishioka, K. Fukuyama, K. Yamamoto, E. Mekada, and T. Sasazuki Involvement of Deregulated Epiregulin Expression in Tumorigenesis in Vivo through Activated Ki-Ras Signaling Pathway in Human Colon Cancer Cells Cancer Res., December 1, 2000; 60(24): 6886 - 6889. [Abstract] [Full Text]

				K. R. LaMontagne Jr., M. A. Moses, D. Wiederschain, S. Mahajan, J. Holden, H. Ghazizadeh, D. A. Frank, and J. L. Arbiser Inhibition of MAP Kinase Kinase Causes Morphological Reversion and Dissociation between Soft Agar Growth and in Vivo Tumorigenesis in Angiosarcoma Cells Am. J. Pathol., December 1, 2000; 157(6): 1937 - 1945. [Abstract] [Full Text] [PDF]

				J. Grunstein, J. J. Masbad, R. Hickey, F. Giordano, and R. S. Johnson Isoforms of Vascular Endothelial Growth Factor Act in a Coordinate Fashion To Recruit and Expand Tumor Vasculature Mol. Cell. Biol., October 1, 2000; 20(19): 7282 - 7291. [Abstract] [Full Text]

				A. Maity, N. Pore, J. Lee, D. Solomon, and D. M. O’Rourke Epidermal Growth Factor Receptor Transcriptionally Up-Regulates Vascular Endothelial Growth Factor Expression in Human Glioblastoma Cells via a Pathway Involving Phosphatidylinositol 3'-Kinase and Distinct from That Induced by Hypoxia Cancer Res., October 1, 2000; 60(20): 5879 - 5886. [Abstract] [Full Text]

				L. M. Ellis and G. E. Gallick Promiscuous Transcription of Vascular Endothelial Growth Factor and Survival of Tumors J Natl Cancer Inst, July 5, 2000; 92(13): 1030 - 1031. [Full Text] [PDF]

				E. A. Sheta, M. A. Harding, M. R. Conaway, and D. Theodorescu Focal Adhesion Kinase, Rap1, and Transcriptional Induction of Vascular Endothelial Growth Factor J Natl Cancer Inst, July 5, 2000; 92(13): 1065 - 1073. [Abstract] [Full Text] [PDF]

				K. R. Laderoute, R. M. Alarcon, M. D. Brody, J. M. Calaoagan, E. Y. Chen, A. M. Knapp, Z. Yun, N. C. Denko, and A. J. Giaccia Opposing Effects of Hypoxia on Expression of the Angiogenic Inhibitor Thrombospondin 1 and the Angiogenic Inducer Vascular Endothelial Growth Factor Clin. Cancer Res., July 1, 2000; 6(7): 2941 - 2950. [Abstract] [Full Text]

				C. J. Bruns, C. C. Solorzano, M. T. Harbison, S. Ozawa, R. Tsan, D. Fan, J. Abbruzzese, P. Traxler, E. Buchdunger, R. Radinsky, et al. Blockade of the Epidermal Growth Factor Receptor Signaling by a Novel Tyrosine Kinase Inhibitor Leads to Apoptosis of Endothelial Cells and Therapy of Human Pancreatic Carcinoma Cancer Res., June 1, 2000; 60(11): 2926 - 2935. [Abstract] [Full Text] [PDF]

				C. J. Bruns, M. T. Harbison, D. W. Davis, C. A. Portera, R. Tsan, D. J. McConkey, D. B. Evans, J. L. Abbruzzese, D. J. Hicklin, and R. Radinsky Epidermal Growth Factor Receptor Blockade with C225 Plus Gemcitabine Results in Regression of Human Pancreatic Carcinoma Growing Orthotopically in Nude Mice by Antiangiogenic Mechanisms Clin. Cancer Res., May 1, 2000; 6(5): 1936 - 1948. [Abstract] [Full Text] [PDF]

				C. V. Ngo, M. Gee, N. Akhtar, D. Yu, O. Volpert, R. Auerbach, and A. Thomas-Tikhonenko An in Vivo Function for the Transforming Myc Protein: Elicitation of the Angiogenic Phenotype Cell Growth Differ., April 1, 2000; 11(4): 201 - 210. [Abstract] [Full Text]

				J. L. Arbiser, H. Larsson, L. Claesson-Welsh, X. Bai, K. LaMontagne, S. W. Weiss, S. Soker, E. Flynn, and L. F. Brown Overexpression of VEGF 121 in Immortalized Endothelial Cells Causes Conversion to Slowly Growing Angiosarcoma and High Level Expression of the VEGF Receptors VEGFR-1 and VEGFR-2 in Vivo Am. J. Pathol., April 1, 2000; 156(4): 1469 - 1476. [Abstract] [Full Text] [PDF]

				R. S. Kerbel Tumor angiogenesis: past, present and the near future Carcinogenesis, March 1, 2000; 21(3): 505 - 515. [Abstract] [Full Text] [PDF]

				S. R. Wedge, D. J. Ogilvie, M. Dukes, J. Kendrew, J. O. Curwen, L. F. Hennequin, A. P. Thomas, E. S. E. Stokes, B. Curry, G. H. P. Richmond, et al. ZD4190: An Orally Active Inhibitor of Vascular Endothelial Growth Factor Signaling with Broad-Spectrum Antitumor Efficacy Cancer Res., February 1, 2000; 60(4): 970 - 975. [Abstract] [Full Text]

				J. Rak, Y. Mitsuhashi, C. Sheehan, A. Tamir, A. Viloria-Petit, J. Filmus, S. J. Mansour, N. G. Ahn, and R. S. Kerbel Oncogenes and Tumor Angiogenesis: Differential Modes of Vascular Endothelial Growth Factor Up-Regulation in ras-transformed Epithelial Cells and Fibroblasts Cancer Res., January 1, 2000; 60(2): 490 - 498. [Abstract] [Full Text]

				E. K. Rowinsky, J. J. Windle, and D. D. Von Hoff Ras Protein Farnesyltransferase: A Strategic Target for Anticancer Therapeutic Development J. Clin. Oncol., November 1, 1999; 17(11): 3631 - 3652. [Abstract] [Full Text] [PDF]

				L. Angelov, B. Salhia, L. Roncari, G. McMahon, and A. Guha Inhibition of Angiogenesis by Blocking Activation of the Vascular Endothelial Growth Factor Receptor 2 Leads to Decreased Growth of Neurogenic Sarcomas Cancer Res., November 1, 1999; 59(21): 5536 - 5541. [Abstract] [Full Text] [PDF]

				Y. D. Jung, K. Nakano, W. Liu, G. E. Gallick, and L. M. Ellis Extracellular Signal-regulated Kinase Activation Is Required for Up-Regulation of Vascular Endothelial Growth Factor by Serum Starvation in Human Colon Carcinoma Cells Cancer Res., October 1, 1999; 59(19): 4804 - 4807. [Abstract] [Full Text] [PDF]

				X. Peng, J. W. Griffith, R. Han, C. M. Lang, and J. W. Kreider Development of Keratoacanthomas and Squamous Cell Carcinomas in Transgenic Rabbits with Targeted Expression of EJras Oncogene in Epidermis Am. J. Pathol., July 1, 1999; 155(1): 315 - 324. [Abstract] [Full Text] [PDF]