Hypoxia-inducible Expression of Tumor-associated Carbonic Anhydrases

Tumor Biology

Hypoxia-inducible Expression of Tumor-associated Carbonic Anhydrases¹

Charles C. Wykoff, Nigel J. P. Beasley, Peter H. Watson, Kevin J. Turner, Jaromir Pastorek, Amen Sibtain, George D. Wilson, Helen Turley, Kate L. Talks, Patrick H. Maxwell, Christopher W. Pugh, Peter J. Ratcliffe² and Adrian L. Harris

Institute of Molecular Medicine [C. C. W., N. J. P. B., K. J. T., A. L. H.] and the Nuffield Department of Clinical Laboratory Sciences [H. T., K. L. T.], John Radcliffe Hospital, Oxford OX3 9DS, United Kingdom; Department of Pathology, University of Manitoba, Winnipeg, Manitoba, R3E OW3 Canada [P. H. W.]; Institute of Virology, Slovak Academy of Sciences, 84246 Bratislava, Slovak Republic [J. P.]; Gray Laboratory Cancer Research Trust, Mount Vernon Hospital, Middlesex HA6 2JR, United Kingdom [A. S., G. D. W.]; Wellcome Trust Centre for Human Genetics, Oxford OX3 7BN, United Kingdom [P. H. M., C. W. P., P. J. R.]

The transcriptional complex hypoxia-inducible factor-1 (HIF-1)has emerged as an important mediator of gene expression patternsin tumors, although the range of responding genes is still incompletelydefined. Here we show that the tumor-associated carbonic anhydrases(CAs) are tightly regulated by this system. Both CA9 and CA12were strongly induced by hypoxia in a range of tumor cell lines.In renal carcinoma cells that are defective for the von Hippel-Lindau(VHL) tumor suppressor, up-regulation of these CAs is associatedwith loss of regulation by hypoxia, consistent with the criticalfunction of pVHL in the regulation of HIF-1. Further studies ofCA9 defined a HIF-1-dependent hypoxia response element in theminimal promoter and demonstrated that tight regulation by theHIF/pVHL system was reflected in the pattern of CA IX expression withintumors. Generalized up-regulation of CA IX in VHL-associated renalcell carcinoma contrasted with focal perinecrotic expressionin a variety of non-VHL-associated tumors. In comparison withvascular endothelial growth factor mRNA, expression of CA IXdemonstrated a similar, although more tightly circumscribed,pattern of expression around regions of necrosis and showedsubstantial although incomplete overlap with activation of thehypoxia marker pimonidazole. These studies define a new classof HIF-1-responsive gene, the activation of which has implicationsfor the understanding of hypoxic tumor metabolism and whichmay provide endogenous markers for tumor hypoxia.

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M. H. T. Bui, D. Seligson, K.-r. Han, A. J. Pantuck, F. J. Dorey, Y. Huang, S. Horvath, B. C. Leibovich, S. Chopra, S.-Y. Liao, et al.
Carbonic Anhydrase IX Is an Independent Predictor of Survival in Advanced Renal Clear Cell Carcinoma: Implications for Prognosis and Therapy
Clin. Cancer Res., February 1, 2003; 9(2): 802 - 811.
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J. H. A. M. Kaanders, K. I. E. M. Wijffels, H. A. M. Marres, A. S. E. Ljungkvist, L. A. M. Pop, F. J. A. van den Hoogen, P. C. M. de Wilde, J. Bussink, J. A. Raleigh, and A. J. van der Kogel
Pimonidazole Binding and Tumor Vascularity Predict for Treatment Outcome in Head and Neck Cancer
Cancer Res., December 1, 2002; 62(23): 7066 - 7074.
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M. Yao, M. Yoshida, T. Kishida, N. Nakaigawa, M. Baba, K. Kobayashi, T. Miura, M. Moriyama, Y. Nagashima, Y. Nakatani, et al.
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J Natl Cancer Inst, October 16, 2002; 94(20): 1569 - 1575.
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C. Willam, N. Masson, Y.-M. Tian, S. A. Mahmood, M. I. Wilson, R. Bicknell, K.-U. Eckardt, P. H. Maxwell, P. J. Ratcliffe, and C. W. Pugh
Peptide blockade of HIFalpha degradation modulates cellular metabolism and angiogenesis
PNAS, August 6, 2002; 99(16): 10423 - 10428.
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S. Kaluz, M. Kaluzova, A. Chrastina, P. L. Olive, S. Pastorekova, J. Pastorek, M. I. Lerman, and E. J. Stanbridge
Lowered Oxygen Tension Induces Expression of the Hypoxia Marker MN/Carbonic Anhydrase IX in the Absence of Hypoxia-inducible Factor 1{alpha} Stabilization: A Role for Phosphatidylinositol 3'-Kinase
Cancer Res., August 1, 2002; 62(15): 4469 - 4477.
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R. H. WENGER
Cellular adaptation to hypoxia: O2-sensing protein hydroxylases, hypoxia-inducible transcription factors, and O2-regulated gene expression
FASEB J, August 1, 2002; 16(10): 1151 - 1162.
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E. P. Hui, A. T. C. Chan, F. Pezzella, H. Turley, K.-F. To, T. C. W. Poon, B. Zee, F. Mo, P. M. L. Teo, D. P. Huang, et al.
Coexpression of Hypoxia-inducible Factors 1{alpha} and 2{alpha}, Carbonic Anhydrase IX, and Vascular Endothelial Growth Factor in Nasopharyngeal Carcinoma and Relationship to Survival
Clin. Cancer Res., August 1, 2002; 8(8): 2595 - 2604.
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M. Leppilampi, P. Koistinen, E.-R. Savolainen, J. Hannuksela, A.-K. Parkkila, O. Niemela, S. Pastorekova, J. Pastorek, A. Waheed, W. S. Sly, et al.
The Expression of Carbonic Anhydrase II in Hematological Malignancies
Clin. Cancer Res., July 1, 2002; 8(7): 2240 - 2245.
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M. S. Wiesener, M. Seyfarth, C. Warnecke, J. S. Jurgensen, C. Rosenberger, N. V. Morgan, E. R. Maher, U. Frei, and K.-U. Eckardt
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Blood, May 15, 2002; 99(10): 3562 - 3565.
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C. N. Coleman, J. B. Mitchell, and K. Camphausen
Tumor Hypoxia: Chicken, Egg, or a Piece of the Farm?
J. Clin. Oncol., February 1, 2002; 20(3): 610 - 615.
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P. L. Olive, C. Aquino-Parsons, S. H. MacPhail, S.-Y. Liao, J. A. Raleigh, M. I. Lerman, and E. J. Stanbridge
Carbonic Anhydrase 9 as an Endogenous Marker for Hypoxic Cells in Cervical Cancer
Cancer Res., December 1, 2001; 61(24): 8924 - 8929.
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A. Giatromanolaki, M. I. Koukourakis, E. Sivridis, J. Pastorek, C. C. Wykoff, K. C. Gatter, and A. L. Harris
Expression of Hypoxia-inducible Carbonic Anhydrase-9 Relates to Angiogenic Pathways and Independently to Poor Outcome in Non-Small Cell Lung Cancer
Cancer Res., November 1, 2001; 61(21): 7992 - 7998.
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M. I. Koukourakis, A. Giatromanolaki, E. Sivridis, K. Simopoulos, J. Pastorek, C. C. Wykoff, K. C. Gatter, and A. L. Harris
Hypoxia-regulated Carbonic Anhydrase-9 (CA9) Relates to Poor Vascularization and Resistance of Squamous Cell Head and Neck Cancer to Chemoradiotherapy
Clin. Cancer Res., November 1, 2001; 7(11): 3399 - 3403.
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A. Lal, H. Peters, B. St. Croix, Z. A. Haroon, M. W. Dewhirst, R. L. Strausberg, J. H. A. M. Kaanders, A. J. van der Kogel, and G. J. Riggins
Transcriptional Response to Hypoxia in Human Tumors
J Natl Cancer Inst, September 5, 2001; 93(17): 1337 - 1343.
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J. A. Loncaster, A. L. Harris, S. E. Davidson, J. P. Logue, R. D. Hunter, C. C. Wycoff, J. Pastorek, P. J. Ratcliffe, I. J. Stratford, and C. M. L. West
Carbonic Anhydrase (CA IX) Expression, a Potential New Intrinsic Marker of Hypoxia: Correlations with Tumor Oxygen Measurements and Prognosis in Locally Advanced Carcinoma of the Cervix
Cancer Res., September 1, 2001; 61(17): 6394 - 6399.
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S. K. Chia, C. C. Wykoff, P. H. Watson, C. Han, R. D. Leek, J. Pastorek, K. C. Gatter, P. Ratcliffe, and A. L. Harris
Prognostic Significance of a Novel Hypoxia-Regulated Marker, Carbonic Anhydrase IX, in Invasive Breast Carcinoma
J. Clin. Oncol., August 15, 2001; 19(16): 3660 - 3668.
[Abstract] [Full Text] [PDF]

N. J. P. Beasley, C. C. Wykoff, P. H. Watson, R. Leek, H. Turley, K. Gatter, J. Pastorek, G. J. Cox, P. Ratcliffe, and A. L. Harris
Carbonic Anhydrase IX, an Endogenous Hypoxia Marker, Expression in Head and Neck Squamous Cell Carcinoma and its Relationship to Hypoxia, Necrosis, and Microvessel Density
Cancer Res., July 1, 2001; 61(13): 5262 - 5267.
[Abstract] [Full Text] [PDF]

C. C. Wykoff, N. Beasley, P. H. Watson, L. Campo, S. K. Chia, R. English, J. Pastorek, W. S. Sly, P. Ratcliffe, and A. L. Harris
Expression of the Hypoxia-Inducible and Tumor-Associated Carbonic Anhydrases in Ductal Carcinoma in Situ of the Breast
Am. J. Pathol., March 1, 2001; 158(3): 1011 - 1019.
[Abstract] [Full Text] [PDF]