Prognostic Significance of Carbonic Anhydrase IX Expression by Cancer-associated Fibroblasts in Lung Adenocarcinoma

BACKGROUND: Cancer tissue is comprised of cancer cells and several types of stromal cells, including cancer-associated fibroblasts (CAFs). Carbonic anhydrase (CA) IX has been used as an endogenous hypoxia marker, and although its expression by cancer cells has been reported to be associated with a poor outcome in a board range of tumors, to the authors' knowledge, the biologic significance of its expression by CAFs remains unclear. METHODS: The authors investigated CA IX expression by CAFs and cancer cells immunohistochemically in 158 consecutive resected cases of lung adenocarcinoma. RESULTS: CA IX was expressed by CAFs in 39 (24.7%) of the 158 cases and by cancer cells in 40 (25.3%) cases. CA IX expression by CAFs was found to be significantly correlated with conventional prognostic factors, including pathologic tumor classification and lymph node involvement. A univariate analysis and the log-rank test demonstrated a significant association between CA IX expression by CAFs (P=.006 and P=.0052, respectively) and by cancer cells (P=.020 and P=.0179, respectively) with lower survival rate. A multivariate analysis of these 2 factors indicated a statistically significant association between CA IX expression by CAFs and a lower survival rate (hazards ratio [HR], 1.797; P=.032), but not between expression by cancer cells and lower survival rate (HR, 1.561; P=.102). CONCLUSIONS: The findings of the current study indicate that CA IX expression by CAFs was a better predictor of outcome than CA IX expression by cancer cells and provides new insights into the biologic significance of CAFs in the hypoxic microenvironment of the lung adenocarcinoma. Cancer 2009;115:2732-43. (C) 2009 American Cancer Society.