Hypoxia-inducible Factor-1{{alpha}} Is a Positive Factor in Solid Tumor Growth

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Hypoxia-inducible Factor-1 ${alpha}$ Is a Positive Factor in Solid Tumor Growth

Heather E. Ryan, Michelle Poloni, Wayne McNulty, David Elson, Max Gassmann, Jeffery M. Arbeit and Randall S. Johnson¹

Department of Biology, University of California, San Diego, California 92093 [H. E. R., M. P., W. M., R. S. J.]; Cancer Genetics Program, University of California, San Francisco Comprehensive Cancer Center, San Francisco, California 94143 [D. E., J. M. A.]; and Institute of Physiology, University of Zurich-Irchel, CH-8057 Zurich, Switzerland [M. G.]

Deficiencies in oxygenation are widespread in solid tumors.The transcription factor hypoxia-inducible factor (HIF)-1 ${alpha}$ isan important mediator of the hypoxic response of tumor cellsand controls the up-regulation of a number of factors importantfor solid tumor expansion, including the angiogenic factor vascularendothelial growth factor (VEGF). We have isolated two celllines nullizygous for HIF-1 ${alpha}$ , one from embryos genetically nullfor HIF-1 ${alpha}$ , and the other from embryos carrying loxP-flankedalleles of the gene, which allows for cre-mediated excision.The loss of HIF-1 ${alpha}$ negatively affects tumor growth in these twosets of H-ras-transformed cell lines, and this negative effect isnot due to deficient vascularization. Despite differences inVEGF expression, vascular density is similar in wild-type andHIF-1 ${alpha}$ -null tumors. The evidence from these experiments indicatesthat hypoxic response via HIF-1 ${alpha}$ is an important positive factorin solid tumor growth and that HIF-1 ${alpha}$ affects tumor expansionin ways unrelated to its regulation of VEGF expression.

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J.-P. Piret, E. Minet, J.-P. Cosse, N. Ninane, C. Debacq, M. Raes, and C. Michiels
Hypoxia-inducible Factor-1-dependent Overexpression of Myeloid Cell Factor-1 Protects Hypoxic Cells against tert-Butyl Hydroperoxide-induced Apoptosis
J. Biol. Chem., March 11, 2005; 280(10): 9336 - 9344.
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C. Tan, R. G. de Noronha, A. J. Roecker, B. Pyrzynska, F. Khwaja, Z. Zhang, H. Zhang, Q. Teng, A. C. Nicholson, P. Giannakakou, et al.
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Cancer Res., January 15, 2005; 65(2): 605 - 612.
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A. Hoeben, B. Landuyt, M. S. Highley, H. Wildiers, A. T. Van Oosterom, and E. A. De Bruijn
Vascular Endothelial Growth Factor and Angiogenesis
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D. F. Higgins, M. P. Biju, Y. Akai, A. Wutz, R. S. Johnson, and V. H. Haase
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Am J Physiol Renal Physiol, December 1, 2004; 287(6): F1223 - F1232.
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X. Zhang, T. Kon, H. Wang, F. Li, Q. Huang, Z. N. Rabbani, J. P. Kirkpatrick, Z. Vujaskovic, M. W. Dewhirst, and C.-Y. Li
Enhancement of Hypoxia-Induced Tumor Cell Death In vitro and Radiation Therapy In vivo by Use of Small Interfering RNA Targeted to Hypoxia-Inducible Factor-1{alpha}
Cancer Res., November 15, 2004; 64(22): 8139 - 8142.
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P. Vaupel
The Role of Hypoxia-Induced Factors in Tumor Progression
Oncologist, November 1, 2004; 9(suppl_5): 10 - 17.
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N. T.V. Le and D. R. Richardson
Iron chelators with high antiproliferative activity up-regulate the expression of a growth inhibitory and metastasis suppressor gene: a link between iron metabolism and proliferation
Blood, November 1, 2004; 104(9): 2967 - 2975.
[Abstract] [Full Text] [PDF]

H. D. Skinner, J. Z. Zheng, J. Fang, F. Agani, and B.-H. Jiang
Vascular Endothelial Growth Factor Transcriptional Activation Is Mediated by Hypoxia-inducible Factor 1{alpha}, HDM2, and p70S6K1 in Response to Phosphatidylinositol 3-Kinase/AKT Signaling
J. Biol. Chem., October 29, 2004; 279(44): 45643 - 45651.
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M. P. Biju, A. K. Neumann, S. J. Bensinger, R. S. Johnson, L. A. Turka, and V. H. Haase
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Mol. Cell. Biol., October 15, 2004; 24(20): 9038 - 9047.
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Z. Cao, J. Fang, C. Xia, X. Shi, and B.-H. Jiang
trans-3,4,5'-Trihydroxystibene Inhibits Hypoxia-Inducible Factor 1{alpha} and Vascular Endothelial Growth Factor Expression in Human Ovarian Cancer Cells
Clin. Cancer Res., August 1, 2004; 10(15): 5253 - 5263.
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O. Stoeltzing, M. F. McCarty, J. S. Wey, F. Fan, W. Liu, A. Belcheva, C. D. Bucana, G. L. Semenza, and L. M. Ellis
Role of Hypoxia-Inducible Factor 1{alpha} in Gastric Cancer Cell Growth, Angiogenesis, and Vessel Maturation
J Natl Cancer Inst, June 16, 2004; 96(12): 946 - 956.
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A. M. Arsham, D. R. Plas, C. B. Thompson, and M. C. Simon
Akt and Hypoxia-Inducible Factor-1 Independently Enhance Tumor Growth and Angiogenesis
Cancer Res., May 15, 2004; 64(10): 3500 - 3507.
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J. T. Erler, C. J. Cawthorne, K. J. Williams, M. Koritzinsky, B. G. Wouters, C. Wilson, C. Miller, C. Demonacos, I. J. Stratford, and C. Dive
Hypoxia-Mediated Down-Regulation of Bid and Bax in Tumors Occurs via Hypoxia-Inducible Factor 1-Dependent and -Independent Mechanisms and Contributes to Drug Resistance
Mol. Cell. Biol., April 1, 2004; 24(7): 2875 - 2889.
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G. Hopfl, O. Ogunshola, and M. Gassmann
HIFs and tumors--causes and consequences
Am J Physiol Regulatory Integrative Comp Physiol, April 1, 2004; 286(4): R608 - R623.
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S. Martin-Puig, E. Temes, G. Olmos, D. R. Jones, J. Aragones, and M. O. Landazuri
Role of Iron (II)-2-Oxoglutarate-dependent Dioxygenases in the Generation of Hypoxia-induced Phosphatidic Acid through HIF-1/2 and von Hippel-Lindau-independent Mechanisms
J. Biol. Chem., March 5, 2004; 279(10): 9504 - 9511.
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Y. Mizukami, J. Li, X. Zhang, M. A. Zimmer, O. Iliopoulos, and D. C. Chung
Hypoxia-Inducible Factor-1-Independent Regulation of Vascular Endothelial Growth Factor by Hypoxia in Colon Cancer
Cancer Res., March 1, 2004; 64(5): 1765 - 1772.
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S. Welsh, R. Williams, L. Kirkpatrick, G. Paine-Murrieta, and G. Powis
Antitumor activity and pharmacodynamic properties of PX-478, an inhibitor of hypoxia-inducible factor-1{alpha}
Mol. Cancer Ther., March 1, 2004; 3(3): 233 - 244.
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M. Kunz, S. Moeller, D. Koczan, P. Lorenz, R. H. Wenger, M. O. Glocker, H.-J. Thiesen, G. Gross, and S. M. Ibrahim
Mechanisms of Hypoxic Gene Regulation of Angiogenesis Factor Cyr61 in Melanoma Cells
J. Biol. Chem., November 14, 2003; 278(46): 45651 - 45660.
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K. Tanimoto, K. Yoshiga, H. Eguchi, M. Kaneyasu, K. Ukon, T. Kumazaki, N. Oue, W. Yasui, K. Imai, K. Nakachi, et al.
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Carcinogenesis, November 1, 2003; 24(11): 1779 - 1783.
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S. Tomita, M. Ueno, M. Sakamoto, Y. Kitahama, M. Ueki, N. Maekawa, H. Sakamoto, M. Gassmann, R. Kageyama, N. Ueda, et al.
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Mol. Cell. Biol., October 1, 2003; 23(19): 6739 - 6749.
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H. M. Sowter, R. Raval, J. Moore, P. J. Ratcliffe, and A. L. Harris
Predominant Role of Hypoxia-Inducible Transcription Factor (Hif)-1{alpha} versus Hif-2{alpha} in Regulation of the Transcriptional Response to Hypoxia
Cancer Res., October 1, 2003; 63(19): 6130 - 6134.
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S.-k. Park, A. M. Dadak, V. H. Haase, L. Fontana, A. J. Giaccia, and R. S. Johnson
Hypoxia-Induced Gene Expression Occurs Solely through the Action of Hypoxia-Inducible Factor 1{alpha} (HIF-1{alpha}): Role of Cytoplasmic Trapping of HIF-2{alpha}
Mol. Cell. Biol., July 15, 2003; 23(14): 4959 - 4971.
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L. Rosano, F. Spinella, D. Salani, V. Di Castro, A. Venuti, M. R. Nicotra, P. G. Natali, and A. Bagnato
Therapeutic Targeting of the Endothelin A Receptor in Human Ovarian Carcinoma
Cancer Res., May 15, 2003; 63(10): 2447 - 2453.
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V. T. Mihaylova, R. S. Bindra, J. Yuan, D. Campisi, L. Narayanan, R. Jensen, F. Giordano, R. S. Johnson, S. Rockwell, and P. M. Glazer
Decreased Expression of the DNA Mismatch Repair Gene Mlh1 under Hypoxic Stress in Mammalian Cells
Mol. Cell. Biol., May 1, 2003; 23(9): 3265 - 3273.
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S. Le Jan, C. Amy, A. Cazes, C. Monnot, N. Lamande, J. Favier, J. Philippe, M. Sibony, J.-M. Gasc, P. Corvol, et al.
Angiopoietin-Like 4 Is a Proangiogenic Factor Produced during Ischemia and in Conventional Renal Cell Carcinoma
Am. J. Pathol., May 1, 2003; 162(5): 1521 - 1528.
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