This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Mazure, N. M. Articles by Giaccia, A. J. Search for Related Content PubMed PubMed Citation Articles by Mazure, N. M. Articles by Giaccia, A. J.

Oncogenic Transformation and Hypoxia Synergistically Act to Modulate Vascular Endothelial Growth Factor Expression¹

Cancer Biology Research Laboratory, Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California 94305-5468 [N. M. M., E. Y. C., P. Y., A. J. G.], and SRI International Life Sciences, Menlo Park, California 94250 [K. R. L.]

Hypoxia can select for cells that have lost their apoptotic potential, thereby making them resistant to adverse conditions. However, long-term survival of transformed cells which have diminished apoptotic sensitivity when exposed to low oxygen conditions would require the activation of their angiogenic program to compensate for an insufficient oxygen supply. In this report, we show that the activity of oncogenic Ha-ras, either constitutively or transiently, enhances the induction of the angiogenic mitogen, vascular endothelial growth factor (VEGF), by hypoxia. Analysis of the 5' flanking region of the VEGF promoter indicates that a HIF-1-like sequence is to promote a 15-fold increase in reporter gene activity in Ha-ras-transformed cells when exposed to hypoxia, whereas mutations in the same site totally inhibited VEGF induction. Under low oxygen conditions, VEGF induction is inhibited in cells expressing a mutant inhibitory allele of Ha-ras (RasN17), indicating a direct role for Ras in modulating VEGF activity. We propose that the angiogenic switch in Ras-transformed cells may be physiologically promoted by the tumor microenvironment through VEGF induction.

¹ This work was supported by NIH Grants PO1CA67166 (to A. J. G., K. R. L.) and CA57333 (to K. R. L.), the American Cancer Society, and Howard Hughes grants and Naomi Van den Horn Cancer Research Fund (to A. J. G.), E. C. was supported by NIH Predoctoral Training Grant 5T32CA09302.

² To whom requests for reprints should be addressed.

Received 5/ 1/96. Accepted 6/14/96.

This article has been cited by other articles:

				I. Helfrich, L. Edler, A. Sucker, M. Thomas, S. Christian, D. Schadendorf, and H. G. Augustin Angiopoietin-2 Levels Are Associated with Disease Progression in Metastatic Malignant Melanoma Clin. Cancer Res., February 15, 2009; 15(4): 1384 - 1392. [Abstract] [Full Text] [PDF]

				M.-C. Lauzier, G. A. Robitaille, D. A. Chan, A. J. Giaccia, and D. E. Richard (2R)-[(4-Biphenylylsulfonyl)amino]-N-hydroxy-3-phenylpropionamide (BiPS), a Matrix Metalloprotease Inhibitor, Is a Novel and Potent Activator of Hypoxia-Inducible Factors Mol. Pharmacol., July 1, 2008; 74(1): 282 - 288. [Abstract] [Full Text] [PDF]

				G. G. Van den Eynden, M. Smid, S. J. Van Laere, C. G. Colpaert, I. Van der Auwera, T. X. Bich, P. van Dam, M. A. den Bakker, L. Y. Dirix, E. A. Van Marck, et al. Gene Expression Profiles Associated with the Presence of a Fibrotic Focus and the Growth Pattern in Lymph Node-Negative Breast Cancer Clin. Cancer Res., May 15, 2008; 14(10): 2944 - 2952. [Abstract] [Full Text] [PDF]

				B. A. Bryan, T. E. Walshe, D. C. Mitchell, J. S. Havumaki, M. Saint-Geniez, A. S. Maharaj, A. E. Maldonado, and P. A. D'Amore Coordinated Vascular Endothelial Growth Factor Expression and Signaling During Skeletal Myogenic Differentiation Mol. Biol. Cell, March 1, 2008; 19(3): 994 - 1006. [Abstract] [Full Text] [PDF]

				T. Klatte, D. B. Seligson, S. B. Riggs, J. T. Leppert, M. K. Berkman, M. D. Kleid, H. Yu, F. F. Kabbinavar, A. J. Pantuck, and A. S. Belldegrun Hypoxia-Inducible Factor 1{alpha} in Clear Cell Renal Cell Carcinoma Clin. Cancer Res., December 15, 2007; 13(24): 7388 - 7393. [Abstract] [Full Text] [PDF]

				S. M. Nemetski and L. B. Gardner Hypoxic Regulation of Id-1 and Activation of the Unfolded Protein Response Are Aberrant in Neuroblastoma J. Biol. Chem., January 5, 2007; 282(1): 240 - 248. [Abstract] [Full Text] [PDF]

				Q. Zhou, L.-Z. Liu, B. Fu, X. Hu, X. Shi, J. Fang, and B.-H. Jiang Reactive oxygen species regulate insulin-induced VEGF and HIF-1{alpha} expression through the activation of p70S6K1 in human prostate cancer cells Carcinogenesis, January 1, 2007; 28(1): 28 - 37. [Abstract] [Full Text] [PDF]

				E. A. V. Jones, F. le Noble, and A. Eichmann What Determines Blood Vessel Structure? Genetic Prespecification vs. Hemodynamics. Physiology, December 1, 2006; 21(6): 388 - 395. [Abstract] [Full Text] [PDF]

				N. Pore, S. Liu, H.-K. Shu, B. Li, D. Haas-Kogan, D. Stokoe, J. Milanini-Mongiat, G. Pages, D. M. O'Rourke, E. Bernhard, et al. Sp1 Is Involved in Akt-mediated Induction of VEGF Expression through an HIF-1-independent Mechanism Mol. Biol. Cell, November 1, 2004; 15(11): 4841 - 4853. [Abstract] [Full Text] [PDF]

				U. E. Knies-Bamforth, S. B. Fox, R. Poulsom, G. I. Evan, and A. L. Harris c-Myc Interacts with Hypoxia to Induce Angiogenesis In vivo by a Vascular Endothelial Growth Factor-Dependent Mechanism Cancer Res., September 15, 2004; 64(18): 6563 - 6570. [Abstract] [Full Text] [PDF]

				J. Fang, Z. Cao, Y. C. Chen, E. Reed, and B.-H. Jiang 9-{beta}-D-Arabinofuranosyl-2-fluoroadenine Inhibits Expression of Vascular Endothelial Growth Factor through Hypoxia-Inducible Factor-1 in Human Ovarian Cancer Cells Mol. Pharmacol., July 1, 2004; 66(1): 178 - 186. [Abstract] [Full Text] [PDF]

				S. T. Palayoor, P. J. Tofilon, and C. N. Coleman Ibuprofen-mediated Reduction of Hypoxia-inducible Factors HIF-1{alpha} and HIF-2{alpha} in Prostate Cancer Cells Clin. Cancer Res., August 1, 2003; 9(8): 3150 - 3157. [Abstract] [Full Text] [PDF]

				M. C. A. Duyndam, S. T. M. Hulscher, E. van der Wall, H. M. Pinedo, and E. Boven Evidence for a Role of p38 Kinase in Hypoxia-inducible Factor 1-independent Induction of Vascular Endothelial Growth Factor Expression by Sodium Arsenite J. Biol. Chem., February 21, 2003; 278(9): 6885 - 6895. [Abstract] [Full Text] [PDF]

				J. M.L. Ebos, J. Tran, Z. Master, D. Dumont, J. V. Melo, E. Buchdunger, and R. S. Kerbel Imatinib Mesylate (STI-571) Reduces Bcr-Abl-Mediated Vascular Endothelial Growth Factor Secretion in Chronic Myelogenous Leukemia Mol. Cancer Res., December 1, 2002; 1(2): 89 - 95. [Abstract] [Full Text] [PDF]

				S. A. Woods, C. J. McGlade, and A. Guha Phosphatidylinositol 3'-kinase and MAPK/ERK kinase 1/2 differentially regulate expression of vascular endothelial growth factor in human malignant astrocytoma cells Neuro-oncol, October 1, 2002; 4(4): 242 - 252. [Abstract] [PDF]

				A. Gasmi, C. Bourcier, Z. Aloui, N. Srairi, S. Marchetti, C. Gimond, S. R. Wedge, L. Hennequin, and J. Pouyssegur Complete Structure of an Increasing Capillary Permeability Protein (ICPP) Purified from Vipera lebetina Venom. ICPP IS ANGIOGENIC VIA VASCULAR ENDOTHELIAL GROWTH FACTOR RECEPTOR SIGNALING J. Biol. Chem., August 9, 2002; 277(33): 29992 - 29998. [Abstract] [Full Text] [PDF]

				N. M. Mazure, C. Chauvet, B. Bois-Joyeux, M.-A. Bernard, H. Nacer-Cherif, and J.-L. Danan Repression of {alpha}-Fetoprotein Gene Expression under Hypoxic Conditions in Human Hepatoma Cells: Characterization of a Negative Hypoxia Response Element That Mediates Opposite Effects of Hypoxia Inducible Factor-1 and c-Myc Cancer Res., February 1, 2002; 62(4): 1158 - 1165. [Abstract] [Full Text] [PDF]

				C. Blancher, J. W. Moore, N. Robertson, and A. L. Harris Effects of ras and von Hippel-Lindau (VHL) Gene Mutations on Hypoxia-inducible Factor (HIF)-1{alpha}, HIF-2{alpha}, and Vascular Endothelial Growth Factor Expression and Their Regulation by the Phosphatidylinositol 3'-Kinase/Akt Signaling Pathway Cancer Res., October 1, 2001; 61(19): 7349 - 7355. [Abstract] [Full Text] [PDF]

				Q. Shi, X. Le, J. L. Abbruzzese, Z. Peng, C.-N. Qian, H. Tang, Q. Xiong, B. Wang, X.-C. Li, and K. Xie Constitutive Sp1 Activity Is Essential for Differential Constitutive Expression of Vascular Endothelial Growth Factor in Human Pancreatic Adenocarcinoma Cancer Res., May 1, 2001; 61(10): 4143 - 4154. [Abstract] [Full Text]

				J. L. Yu, J. W. Rak, P. Carmeliet, A. Nagy, R. S. Kerbel, and B. L. Coomber Heterogeneous Vascular Dependence of Tumor Cell Populations Am. J. Pathol., April 1, 2001; 158(4): 1325 - 1334. [Abstract] [Full Text] [PDF]

				C. J. Green, P. Lichtlen, N. T. Huynh, M. Yanovsky, K. R. Laderoute, W. Schaffner, and B. J. Murphy Placenta Growth Factor Gene Expression Is Induced by Hypoxia in Fibroblasts: A Central Role for Metal Transcription Factor-1 Cancer Res., March 1, 2001; 61(6): 2696 - 2703. [Abstract] [Full Text]

				C. Robinson and S. Stringer The splice variants of vascular endothelial growth factor (VEGF) and their receptors J. Cell Sci., January 3, 2001; 114(5): 853 - 865. [Abstract] [PDF]

				C. Blancher, J. W. Moore, K. L. Talks, S. Houlbrook, and A. L. Harris Relationship of Hypoxia-inducible Factor (HIF)-1{{alpha}} and HIF-2{{alpha}} Expression to Vascular Endothelial Growth Factor Induction and Hypoxia Survival in Human Breast Cancer Cell Lines Cancer Res., December 1, 2000; 60(24): 7106 - 7113. [Abstract] [Full Text]

				K. Salnikow, M. Costa, W. D. Figg, and M. V. Blagosklonny Hyperinducibility of Hypoxia-responsive Genes without p53/p21-dependent Checkpoint in Aggressive Prostate Cancer Cancer Res., October 1, 2000; 60(20): 5630 - 5634. [Abstract] [Full Text]

				R. A. Brekken, J. P. Overholser, V. A. Stastny, J. Waltenberger, J. D. Minna, and P. E. Thorpe Selective Inhibition of Vascular Endothelial Growth Factor (VEGF) Receptor 2 (KDR/Flk-1) Activity by a Monoclonal Anti-VEGF Antibody Blocks Tumor Growth in Mice Cancer Res., September 1, 2000; 60(18): 5117 - 5124. [Abstract] [Full Text]

				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]

				L. Liu, L. Liu, W. F. Anderson, R. W. Beart, E. M. Gordon, and F. L. Hall Incorporation of Tumor Vasculature Targeting Motifs into Moloney Murine Leukemia Virus Env Escort Proteins Enhances Retrovirus Binding and Transduction of Human Endothelial Cells J. Virol., June 1, 2000; 74(11): 5320 - 5328. [Abstract] [Full Text]

				R. E. Favoni and A. De Cupis The Role of Polypeptide Growth Factors in Human Carcinomas: New Targets for a Novel Pharmacological Approach Pharmacol. Rev., June 1, 2000; 52(2): 179 - 206. [Abstract] [Full Text] [PDF]

				A. BIROCCIO, A. CANDILORO, M. MOTTOLESE, O. SAPORA, A. ALBINI, G. ZUPI, and D. DEL BUFALO Bcl-2 overexpression and hypoxia synergistically act to modulate vascular endothelial growth factor expression and in vivo angiogenesis in a breast carcinoma line FASEB J, April 1, 2000; 14(5): 652 - 660. [Abstract] [Full Text]

				S. J. Reshkin, A. Bellizzi, V. Albarani, L. Guerra, M. Tommasino, A. Paradiso, and V. Casavola Phosphoinositide 3-Kinase Is Involved in the Tumor-specific Activation of Human Breast Cancer Cell Na+/H+ Exchange, Motility, and Invasion Induced by Serum Deprivation J. Biol. Chem., February 25, 2000; 275(8): 5361 - 5369. [Abstract] [Full Text] [PDF]

				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]

				M. K. Jones, R. M. Itani, H. Wang, M. Tomikawa, I. J. Sarfeh, S. Szabo, and A. S. Tarnawski Activation of VEGF and Ras genes in gastric mucosa during angiogenic response to ethanol injury Am J Physiol Gastrointest Liver Physiol, June 1, 1999; 276(6): G1345 - G1355. [Abstract] [Full Text] [PDF]

				K. R. Laderoute, H. L. Mendonca, J. M. Calaoagan, A. M. Knapp, A. J. Giaccia, and P. J. S. Stork Mitogen-activated Protein Kinase Phosphatase-1 (MKP-1) Expression Is Induced by Low Oxygen Conditions Found in Solid Tumor Microenvironments. A CANDIDATE MKP FOR THE INACTIVATION OF HYPOXIA-INDUCIBLE STRESS-ACTIVATED PROTEIN KINASE/c-Jun N-TERMINAL PROTEIN KINASE ACTIVITY J. Biol. Chem., April 30, 1999; 274(18): 12890 - 12897. [Abstract] [Full Text] [PDF]

				J. Grunstein, W. G. Roberts, O. Mathieu-Costello, D. Hanahan, and R. S. Johnson Tumor-derived Expression of Vascular Endothelial Growth Factor Is a Critical Factor in Tumor Expansion and Vascular Function Cancer Res., April 1, 1999; 59(7): 1592 - 1598. [Abstract] [Full Text] [PDF]

				J.-P. Theurillat, J. Hainfellner, A. Maddalena, J. Weissenberger, and A. Aguzzi Early Induction of Angiogenetic Signals in Gliomas of GFAP-v-src Transgenic Mice Am. J. Pathol., February 1, 1999; 154(2): 581 - 590. [Abstract] [Full Text] [PDF]

				M. V. Blagosklonny, W. G. An, L. Y. Romanova, J. Trepel, T. Fojo, and L. Neckers p53 Inhibits Hypoxia-inducible Factor-stimulated Transcription J. Biol. Chem., May 15, 1998; 273(20): 11995 - 11998. [Abstract] [Full Text] [PDF]

				F. Okada, J. W. Rak, B. St. Croix, B. Lieubeau, M. Kaya, L. Roncari, S. Shirasawa, T. Sasazuki, and R. S. Kerbel Impact of oncogenes in tumor angiogenesis: Mutant K-ras up-regulation of vascular endothelial growth factor/vascular permeability factor is necessary, but not sufficient for tumorigenicity of human colorectal carcinoma cells PNAS, March 31, 1998; 95(7): 3609 - 3614. [Abstract] [Full Text] [PDF]

				N. M. Mazure, E. Y. Chen, K. R. Laderoute, and A. J. Giaccia Induction of Vascular Endothelial Growth Factor by Hypoxia Is Modulated by a Phosphatidylinositol 3-Kinase/Akt Signaling Pathway in Ha-ras-Transformed Cells Through a Hypoxia Inducible Factor-1 Transcriptional Element Blood, November 1, 1997; 90(9): 3322 - 3331. [Abstract] [Full Text] [PDF]

				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]

				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]

				C. Chen, N. Pore, A. Behrooz, F. Ismail-Beigi, and A. Maity Regulation of glut1 mRNA by Hypoxia-inducible Factor-1. INTERACTION BETWEEN H-ras AND HYPOXIA J. Biol. Chem., March 16, 2001; 276(12): 9519 - 9525. [Abstract] [Full Text] [PDF]