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.

Highlights

  • Hypoxia is a characteristic of many different types of solid tumors and is caused by an inadequate vascular supply

  • Include only limited numbers of patients and remain inconclusive. This current meta-analysis is the first complete overview of all reported clinical studies investigating the impact of pretreatment carbonic anhydrase IX (CAIX) expression in solid tumors on prognosis

  • A strong association between high CAIX expression and poor prognosis was found in the majority of different tumor sites, supporting an important role of CAIX in disease progression and treatment resistance in many cancer types

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Summary

Introduction

Hypoxia is a characteristic of many different types of solid tumors and is caused by an inadequate vascular supply. Tumor cells have adopted several mechanisms to survive the hostile conditions during hypoxia, of which one is the hypoxiainducible factor (HIF) pathway [9, 10]. CAIX is important in maintaining the cellular pH regulation and is located on the cell membrane where it hydrolyzes carbon dioxide, produced as a waste product during glycolysis, to bicarbonate and a proton. Hypoxia-induced CAIX expression, tumor-specific expression of CAIX, and its important role in maintaining the pH balance make CAIX a promising endogenous marker of tumor hypoxia and an attractive target for anti-cancer therapies with newly designed inhibitors [6, 11, 12]

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