Expression of carbonic anhydrase IX (CAIX) in malignant mesothelioma. An immunohistochemical and immunocytochemical study

Abstract

Malignant mesothelioma is an aggressive tumor with a poor prognosis. Carbonic anhydrase IX (CAIX) is a membranously located metalloenzyme involved in pH homeostasis with influence on regulation of cell proliferation, oncogenesis and tumor progression. Much attention has been paid recently to carboanhydrases and their inhibitors as they offer an opportunity for both developing novel anticancer drugs, as well as diagnostic and prognostic tools. This study was designed to assess the expression of CAIX in malignant pleural and peritoneal mesotheliomas, their benign counterparts, and in pleural effusions from patients with malignant mesothelioma, metastatic carcinoma or a benign disease. Tissue blocks from 51 malignant mesotheliomas of pleura (47 cases; 41 epithelioid, 2 biphasic, 4 sarcomatoid) and peritoneum (4 cases; all epithelioid), 14 cases with normal or reactive pleural tissue, and 19 cell blocks were analyzed. CAIX expression was determined using immunohistochemistry and its membranous immunoreactivity was semiquantitatively evaluated. Specimens were divided into five subgroups according to the staining pattern and intensity.Overall, 92.2% (47/51) of mesotheliomas expressed CAIX. All epithelioid mesotheliomas showed CAIX positivity, which was predominantly strong and diffuse (73.3%, 33/45). Sarcomatoid mesotheliomas and sarcomatoid areas in biphasic mesotheliomas were negative. A strong diffuse staining was observed in all cases of normal mesothelia. In pleural effusions, CAIX expression was observed in malignant cells as well as in benign mesothelial cells. In conclusion, CAIX is expressed virtually in all mesotheliomas except for sarcomatoid subtype, and in benign mesothelia. There are probably more mechanisms of CAIX overexpression than hypoxia-induced in malignant mesothelioma, with the influence of other tissue specific transcription or growth factors depending on the type of the cell lineage. CAIX immunoreactivity is not a reliable diagnostic marker for distinguishing malignant cells from benign mesothelia in pleural effusions. Nevertheless, our data support the potential use of therapeutics targeting CAIX in patients with advanced mesothelioma.

DNA methylation profiling of asbestos-treated MeT5A cell line reveals novel pathways implicated in asbestos response

“…Several genes resulting up-regulated after chrysotile exposure (CD68,SLC2A1,CD44,AXL,CA9,FOSL1,NRP1,THBS2,ADM,DIO2,DKK1,F3,GREM1,and TPBG), were already found deregulated in MPM cell lines, or involved in MPM development (Capkova et al 2014;Lee et al 2004;Nymark et al 2007).…”

Carbonic Anhydrases: Role in pH Control and Cancer

“…This suggests that CA IX is a more “druggable” target. Cancers associated with CA IX expression include brain, breast, bladder, cervix, colon, colorectal, head and neck, pancreas, kidney, lung, ovaries, stomach oral cavity, and T-cell lymphomas [ 52 , 68 , 136 , 139 , 208 , 209 , 210 ]. CA IX expression, especially in hypoxic tumors, is modulated by hypoxia-inducible factor 1 (HIF-1) in response to low oxygen levels and increased cell density [ 211 ].…”

Switching off malignant mesothelioma: exploiting the hypoxic microenvironment

“…CA-IX is a membrane associated isoform showing extensive diversity in tissue distributions and in subcellular localizations [ 71 ]. It is an established endogenous marker of hypoxia, and particularly overexpressed in VHL mutated clear cell renal cell carcinomas [ 113 , 114 ], mesotheliomas [ 115 , 116 ], kidney [ 15 ], as well as other hypoxic solid tumors [ 113 ]. CA-IX expression is correlated with poor patient prognosis, metastasis, and therapy resistance [ 5 , 71 , 117 ].…”

“…CA-IX expression is correlated with poor patient prognosis, metastasis, and therapy resistance [ 5 , 71 , 117 ]. This is particularly interesting as more than 90% of mesotheliomas are positive for CA-IX [ 95 , 115 , 118 ] and so one would expect its inhibition would limit pH-driven growth and metastasis. Monoclonal antibodies and small molecule inhibitors specific to CA-IX are being investigated for potential targeted therapeutics in the pre-clinical studies.…”