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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.

Type

Journal article

Journal

Cancer research

Publication Date

09/2001

Volume

61

Pages

6394 - 6399

Addresses

CRC Experimental Radiation Oncology Group, Paterson Institute, Manchester M20 4BX, United Kingdom.

Keywords

Humans, Carcinoma, Squamous Cell, Oxygen, Carbonic Anhydrases, Neoplasm Proteins, Antigens, Neoplasm, Prognosis, Treatment Outcome, Immunohistochemistry, Multivariate Analysis, Retrospective Studies, Prospective Studies, Reproducibility of Results, Electrodes, Cell Hypoxia, Middle Aged, Uterine Cervical Neoplasms, Female, Biomarkers, Tumor, Carbonic Anhydrase IX