Prognostic Significance of Carbonic Anhydrase IX Expression in Cancer Patients: A Meta-Analysis

Abstract

Hypoxia is a characteristic of many solid tumors and an adverse prognostic factor for treatment outcome. Hypoxia increases the expression of carbonic anhydrase IX (CAIX), an enzyme that is predominantly found on tumor cells and is involved in maintaining the cellular pH balance. Many clinical studies investigated the prognostic value of CAIX expression, but most have been inconclusive, partly due to small numbers of patients included. The present meta-analysis was therefore performed utilizing the results of all clinical studies to determine the prognostic value of CAIX expression in solid tumors. Renal cell carcinoma was excluded from this meta-analysis due to an alternative mechanism of upregulation. 958 papers were identified from a literature search performed in PubMed and Embase. These papers were independently evaluated by two reviewers and 147 studies were included in the analysis. The meta-analysis revealed strong significant associations between CAIX expression and all endpoints: overall survival [hazard ratio (HR) = 1.76, 95% confidence interval (95%CI) 1.58–1.98], disease-free survival (HR = 1.87, 95%CI 1.62–2.16), locoregional control (HR = 1.54, 95%CI 1.22–1.93), disease-specific survival (HR = 1.78, 95%CI 1.41–2.25), metastasis-free survival (HR = 1.82, 95%CI 1.33–2.50), and progression-free survival (HR = 1.58, 95%CI 1.27–1.96). Subgroup analyses revealed similar associations in the majority of tumor sites and types. In conclusion, these results show that patients having tumors with high CAIX expression have higher risk of locoregional failure, disease progression, and higher risk to develop metastases, independent of tumor type or site. The results of this meta-analysis further support the development of a clinical test to determine patient prognosis based on CAIX expression and may have important implications for the development of new treatment strategies.

Downregulation of carbonic anhydrase IV contributes to promotion of cell proliferation and is associated with poor prognosis in non-small cell lung cancer

“…The diagnostic and prognostic value of carbonic anhydrases were proved in many solid tumors. It is generally acknowledged that overexpression of CAs can predict poor survival of patients, containing those with NSCLC (14,24). However, clinical properties and prognostic significance of CA IV in NSCLC remain unclear.…”

Breast cancer intratumour heterogeneity: current status and clinical implications

“…Interestingly, on TMA assessment, the majority of discordant cases were shown to be false‐negative, representing sampling from negative areas in otherwise positive cases . Similarly, another biomarker, carbonic anhydrase IX (CAIX), whose expression is greatly induced by hypoxia (tumour heterogeneity resulting from the epigenetic alteration) also showed discrepant results between a TMA platform and full‐face tissue sections . These findings raised the issue of significant heterogeneous expression of the above markers.…”

Activation of carbonic anhydrase IX by alternatively spliced tissue factor under late-stage tumor conditions

“…Through the same process, CAIX leads to an accumulation of protons extracellularly, which makes the extra-cellular environment more acidic. In various types of cancers, patients having tumors with high CAIX expression have a higher risk of locoregional failure, disease progression, and higher risk to develop metastases 29 . CAIX is a downstream mediator of HIF-1α, which is activated by hypoxia.…”