Tumor-associated carbonic anhydrases are linked to metastases in primary cervical cancer

Purpose: Carbonic anhydrase IX (CA9) has emerged as an important surrogate marker for hypoxia in solid tumors. CA12 shares a role with CA9 in acidification of micromilieu but it is less strictly regulated by hypoxia than CA9. In this study, we investigated expression of CA9 and CA12 mRNA in primary cervical cancer. We also examined whether CA9 expression can be an indicator of reoxygenation of tumor by measuring its mRNA expression during fractionated radiotherapy. Methods: Tumor tissues were obtained from 59 patients with uterine cervical cancer who underwent radiotherapy, and a second biopsy was taken after patients had received either 10 or 20 Gy of radiation. The follow-up period ranged from 2.4 to 75 months (median = 23 months). The ratio of CA9 and β-actin mRNA expression was determined both pre- and during radiation treatment by RT-PCR. Results: CA9 and CA12 mRNA expression was detected in 62.7 and 88.1% of tumors (i.e. patients), respectively, and co-expression was observed in 61% of patients. Multivariate analysis revealed that CA9 expression was the most significant factor associated with metastasis-free survival (P = 0.008, hazard ratio 34.8), whereas CA12 mRNA expression was linked to a lower risk of metastasis (P = 0.007, hazard ratio of 0.07). Tumor CA9 expression was not altered following either 10 or 20 Gy of radiotherapy. Conclusion: The strong correlation between CA9 expression and metastasis suggests that CA9 expression might be an important indicator for identifying patients who require more aggressive systemic therapy.