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[Cancer Research 61, 6394-6399, September 1, 2001]
© 2001 American Association for Cancer Research

Clinical Investigations

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 Cervix1

Juliette A. Loncaster, Adrian L. Harris, Susan E. Davidson, John P. Logue, Robert D. Hunter, Charles C. Wycoff, Jaromir Pastorek, Peter J. Ratcliffe, Ian J. Stratford and Catharine M. L. West2

CRC Experimental Radiation Oncology Group, Paterson Institute [J. A. L., C. M. L. W.] and Department of Clinical Oncology [S. E. D., J. P. L., R. D. H.], Christie Hospital NHS Trust, Manchester M20 4BX, United Kingdom; Institute of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DS, United Kingdom [A. L. H., C. C. W.]; School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester M13 9PL, United Kingdom [I. J. S.]; Wellcome Trust Centre for Human Genetics, Oxford OX3 7BN, United Kingdom [P. J. R.]; and Institute of Virology, Slovak Academy of Sciences, 84246 Bratislava, Slovak Republic [J. P.]

There is increasing evidence that hypoxia-regulated gene expression influences tumor aggressiveness, contributing to the poorer outcome of patients with hypoxic tumors. The role of the transcriptional complex hypoxia-inducible factor-1 as an important mediator of hypoxia-regulated gene expression is one of the best documented pathways. Recently, it has emerged that certain tumor-associated carbonic anhydrases (CAs) can be added to the list of known hypoxia-inducible factor-responsive genes. Here we show that the immunohistochemical expression of the tumor-associated CA IX is correlated with the level of hypoxia in human cervical tumors. We performed a prospective study in 68 patients where needle electrodes were used to make direct measurements of tumor oxygenation levels. CA IX expression was evaluated immunohistochemically in pretreatment tumor biopsies. There was a significant positive correlation between the level of tumor hypoxia (HP5) and the extent of CA IX expression. A retrospective study of 130 squamous cell cervical carcinomas demonstrated that a semiquantitative immunohistochemical analysis of CA IX expression in tumor biopsies is a significant and independent prognostic indicator of overall survival and metastasis-free survival after radiation therapy. These studies provide clinical evidence that CA IX expression is up-regulated in hypoxic human cervical tumors and is associated with a poor prognosis. CA IX may act as an intrinsic marker of tumor hypoxia and poor outcome after radiation therapy. The level of CA IX expression may be used to aid in the selection of patients who would benefit most from hypoxia-modification therapies or bio-reductive drugs.




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