Carbonic anhydrase (CA IX) expression, a potential new intrinsic marker ofhypoxia: Correlations with tumor oxygen measurements and prognosis in locally advanced carcinoma of the cervix

There is increasing evidence that hypoxia-regulated gene expression influen ces tumor aggressiveness, contributing to the poorer outcome of patients wi th hypoxic tumors. The role of the transcriptional complex hypoxia-inducibl e 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 kno wn hypoxia-inducible factor-responsive genes. Here we show that the immunoh istochemical expression of the tumor-associated CA IX is correlated with th e level of hypoxia in human cervical tumors. We performed a prospective stu dy in 68 patients where needle electrodes were used to make direct measurem ents of tumor oxygenation levels. CA IX expression was evaluated immunohist ochemically in pretreatment tumor biopsies. There was a significant positiv e correlation between the level of tumor hypoxia (HP5) and the extent of CA IX expression. A retrospective study of 130 squamous cell cervical carcino mas demonstrated that a semiquantitative immunohistochemical analysis of CA IX expression in tumor biopsies is a significant and independent prognosti c indicator of overall survival and metastasis-free survival after radiatio n therapy. These studies provide clinical evidence that CA IX expression is up-regulated in hypoxic human cervical tumors and is associated with a poo r 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-mo dification therapies or bio-reductive drugs.