Plasmatic carbonic anhydrase IX as a diagnostic marker for clear cell renal cell carcinoma

Abstract

Carbonic anhydrase (CA, EC 4.2.1.1) IX is regarded as a tumour hypoxia marker and CA inhibitors have been proposed as a new class of antitumor agents, with one such agent in Phase II clinical trials. The expression of some CAs, in particular the isoforms CA IX and CA XII, has been correlated with tumour aggressiveness and progression in several cancers. The aim of this study was to evaluate the possibility that CA IX could represent a marker related to clear cell Renal Cell Carcinoma (ccRCC). Bcl-2 and Bax, and the activity of caspase-3, evaluated in tissue biopsies from patients, were congruent with resistance to apoptosis in ccRCCs with respect to healthy controls, respectively. In the same samples, the CA IX and pro-angiogenic factor VEGF expressions revealed that both these hypoxia responsive proteins were strongly increased in ccRCC with respect to controls. CA IX plasma concentration and CA activity were assessed in healthy volunteers and patients with benign kidney tumours and ccRCCs. CA IX expression levels were found strongly increased only in plasma from ccRCC subjects, whereas, CA activity was found similarly increased both in plasma from ccRCC and benign tumour patients, compared to healthy volunteers. These results show that the plasmatic level of CA IX, but not the CA total activity, can be considered a diagnostic marker of ccRCCs. Furthermore, as many reports exist relating CA IX inhibition to a better outcome to anticancer therapy in ccRCC, plasma levels of CA IX could be also predictive for response to therapy.

Advances in the discovery of exosome inhibitors in cancer

“…All these results indicated that CA IX could be a new therapeutic target to interfere exosome release in hypoxic tumours. Moreover, currently, there is already one CA IX inhibitor (SLC-0111) in Phase Ib/II clinical trials for the treatment of hypoxic, metastatic tumors 45,46,[63][64][65][66][67] . PPIs and CA IX inhibitors are both inhibiting exosome release by regulating the pH of tumour microenvironment.…”

Plasmatic exosomes from prostate cancer patients show increased carbonic anhydrase IX expression and activity and low pH

“…However, to prevent intracellular H þ accumulation cancer cells upregulates proton exchangers that extrude protons in excess contributing to acidify extracellular tumour microenvironment 9,11,12 . Among these proton exchangers, a primary role is played by CA IX, an enzyme overexpressed in many types of cancers, including prostate cancer, with the potential to represent both a promising tumour biomarker and a specific target for future cancer therapies 13,[30][31][32][33][37][38][39][40][41]44 . Under the pressure of the acidic microenvironment, CA IX expression and activity are upregulated in both tumour cells 30,44 and the exosomes released extracellularly 30 .…”

Carbonic Anhydrase IX in Renal Cell Carcinoma, Implications for Disease Management

“…Lucarini et al [ 32 ] evaluated the potential of circulating CAIX to diagnose ccRCC. The concentration of circulating CAIX was significantly higher in patients presenting ccRCC in comparison to controls (benign tumors or healthy subjects).…”