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Carbonic Anhydrase IX: a Regulator of Ph and Participant in Carcinogenesis Alessandro Pietro Aldera ‍ ‍ ,1,2 Dhirendra Govender ‍ ‍ 1,3

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Carbonic Anhydrase IX: a Regulator of Ph and Participant in Carcinogenesis Alessandro Pietro Aldera ‍ ‍ ,1,2 Dhirendra Govender ‍ ‍ 1,3 Molecules in pathogenesis J Clin Pathol: first published as 10.1136/jclinpath-2020-207073 on 22 February 2021. Downloaded from Carbonic anhydrase IX: a regulator of pH and participant in carcinogenesis Alessandro Pietro Aldera ,1,2 Dhirendra Govender 1,3 1Division of Anatomical ABSTRACT CAIX STRUCTURE, FUNCTION AND NORMAL Pathology, University of Cape Carbonic anhydrase IX (CAIX) is a transmembrane STATE Town, Cape Town, South Africa 2JDW Pathology Inc, Cape Town, metalloenzyme which is upregulated in tumour cells Carbonic anhydrases are a family of 16 distinct, South Africa under hypoxic conditions. CAIX expression is induced highly conserved and ubiquitous zinc metalloen- 3Anatomical Pathology, Pathcare by the accumulation of hypoxia-inducible factor-1α and zymes involved in the reversible hydration of carbon Cape Town, Cape Town, South has several downstream effects, including acidification dioxide to bicarbonate and a proton. CAIX belongs Africa of the extracellular pH, loss of cellular adhesion and to the alpha class of carbonic anhydrases, together increased tumour cell migration. CAIX is upregulated with CAXII.5 CAIX is an integral transmembrane Correspondence to Dr Alessandro Pietro Aldera, in a variety of solid organ tumours and has prognostic glycoprotein with an extracellular- facing catalytic JDW Pathology, 19 Upper Camp implications. High CAIX protein expression is a marker site and shows the highest hydrogen ion transfer Road, Maitland 7405, South of poor prognosis in breast, lung, ovarian and bladder rate among the carbonic anhydrases.6 The protein Africa; aldera@ jdwpathology. carcinomas. Conversely, low expression is an indicator of comprises 459 amino acids with the following struc- co. za poor prognosis in clear cell renal cell carcinoma (CCRCC). ture: N-terminal single peptide extracellular region, Received 30 August 2020 CAIX immunohistochemistry is useful diagnostically to transmembrane region and intracellular C-terminal Revised 31 October 2020 identify metastatic CCRCC, and the recently recognised region (figure 1). There is a proteoglycan (PG)- Accepted 24 January 2021 clear cell papillary renal cell carcinoma. There is much like domain adjacent to the extracellular catalytic Published Online First interest in targeting CAIX with monoclonal antibodies domain which permits the enzyme to remain active 22 February 2021 7 8 and small molecule inhibitors. There are several at more acidic pH values. The intracellular tail 443 small molecule inhibitors under development which contains three potential phosphorylation sites, T, 448 449 have shown promising results in clinical trials. In this S and Y. Activation of protein kinase A leads to 443 paper, we provide an overview of the role of CAIX in phosphorylation on T of CAIX, which results in 9 tumourigenesis and outline its use as a prognostic, increased catalytic activity. Interestingly, dephos- 448 diagnostic and therapeutic biomarker. phorylation of S seems to be required for full activation of CAIX.9 The chief function of the carbonic anhydrases is the regulation of intracellular pH. The extra- cellular positioning of the active site allows CAIX INTRODUCTION to contribute to acidification of the extracellular Rapid cell division and growth in solid tumours microenvironment while shuttling bicarbonate http://jcp.bmj.com/ leads to spatial and flow- based disruption of the into the cytoplasm. The CAIX promotor contains microcirculation, and ultimately tissue hypoxia.1 a hypoxia responsive element that binds HIF-1α, This leads to activation of a series of adaptive which is the exclusive regulator of its activity.2 10 cellular responses, central to which is activation of CAIX expression is limited in normal tissues. In the transcription factor hypoxia- inducible factor-1α human tissue, expression of CAIX is restricted to (HIF-1α). The accumulation of HIF-1α causes tran- the basolateral aspect of proliferating small bowel scription of downstream effectors, which include on October 1, 2021 by guest. Protected copyright. crypt epithelium,11 efferent ducts in the testis12 and vascular endothelial growth factor, erythropoietin, occasional small foci in pancreatic acini.13 glycolytic enzymes and carbonic anhydrase IX (CAIX).2 The carbonic anhydrases are a family of metalloenzymes which are involved with the regu- ROLE OF CAIX IN TUMOUR PATHOGENESIS lation of intracellular and extracellular pH. Sixteen Maintaining a slightly alkaline intracellular pH has isoforms have been identified and show different been shown to favour tumour cell growth.14 Inhibi- subcellular localisation, catalytic activity and tissue tion of CAIX results in decreased intracellular pH 3 distribution. and negatively influences tumour cell survival.15 16 CAIX has been shown to be overexpressed in Acidification of the extracellular pH is associated a variety of solid tumours. Since the identifica- with tumour migration and invasion, extracellular tion of CAIX in 1986 (then called G250- antigen), matrix breakdown, chromosomal rearrangements several studies have emerged in the literature 15 17 © Author(s) (or their and growth factor production (figure 2). CAIX employer(s)) 2021. No exploring its utility as a diagnostic and prognostic also appears to contribute to cellular adhesion and commercial re- use. See rights biomarker, as well as a potential therapeutic migration, both of which are important for meta- and permissions. Published target.4 In this paper, we provide an overview static progression in cancer. Svastová et al18 showed by BMJ. of the role of CAIX in the pathogenesis of solid in Madin- Darby canine kidney cells that CAIX To cite: Aldera AP, tumours and an update for the practising pathol- may modulate E-cadherin- mediated cell adhe- Govender D. J Clin Pathol ogist of its current role as a diagnostic, prognostic sion by competing with E- cadherin for binding to 2021;74:350–354. and therapeutic biomarker. β-catenin. CAIX expression has also been linked 350 Aldera AP, Govender D. J Clin Pathol 2021;74:350–354. doi:10.1136/jclinpath-2020-207073 Molecules in pathogenesis J Clin Pathol: first published as 10.1136/jclinpath-2020-207073 on 22 February 2021. Downloaded from Figure 1 Carbonic anhydrase IX is a transmembrane glycoprotein which comprises an extracellular catalytic domain with attached PG- like domain, a transmembrane region, and a short intracellular tail containing phosphorylation sites. PG, proteoglycan. to tumour-associated cell migration by inactivation of rho in a Mutation of the tumour suppressor gene VHL results in stabili- group of cervical carcinoma cells.19 sation of HIF-1α and promotes hypoxia- independent expression Tumour suppressors, oncogenes and microenvironmental of the HIF-1α-regulated genes, including CAIX.20 TP53 has also conditions also appear to play a role in specific circumstances. been shown to regulate CAIX expression via HIF-1α.21 http://jcp.bmj.com/ on October 1, 2021 by guest. Protected copyright. Figure 2 Under normoxic conditions, VHL protein binds HIF-1α, which leads to degradation. Hypoxic conditions cause inactivation of VHL and accumulation of HIF-1α in the cytoplasm. This causes transcription of CAIX, which is then inserted into the plasma membrane, leading to downstream effects. CAIX, carbonic anhydrase IX; HIF-1α, hypoxia- inducible factor-1α; VHL, von Hippel-Lindau. Aldera AP, Govender D. J Clin Pathol 2021;74:350–354. doi:10.1136/jclinpath-2020-207073 351 Molecules in pathogenesis J Clin Pathol: first published as 10.1136/jclinpath-2020-207073 on 22 February 2021. Downloaded from Figure 3 Diffuse complete membranous ‘box- like’ staining with Figure 4 Basolateral ‘cup- like’ staining with carbonic anhydrase IX carbonic anhydrase IX is seen in clear cell renal cell carcinoma. immunohistochemistry is diagnostic of clear cell papillary renal cell carcinoma. ROLE OF CAIX AS A PROGNOSTIC BIOMARKER CAIX is upregulated in a variety of solid tumours, and there is of HIF pathway activation—GLUT1 and HIF-1α—are typically a relationship between CAIX protein expression and prognosis. also overexpressed in CCPRCC. These tumours do not harbour High protein expression of CAIX detected by immunohistochem- mutations of the VHL gene or the typical chromosomal aberra- istry is a marker of poor prognosis in breast,22 lung,23 ovarian24 tions seen in clear cell or papillary RCC.37 and bladder25 cancers. High stromal CAIX expression in oral Strong membranous expression of CAIX occurs in haeman- squamous cell carcinoma is associated with increased nodal gioblastoma and can aid in the recognition of this tumour but metastases and decreased survival.26 Haapasalo et al27 demon- does not distinguish it from metastatic CCRCC.38 strated that expression of CAIX predicts poor prognosis in astro- In a recent paper, Nakada et al39 showed that CAIX mean cytic tumours. Srivastava et al28 recently showed high expression protein expression intensity was significantly (p<0.05) upreg- of CAIX to be an independent predictor of poor prognosis in a ulated in ulcerative colitis-associated colorectal carcinoma cohort of 179 hepatocellular carcinoma cases. Conversely, low (1.55/3) compared with sporadic colorectal carcinoma (0.9/3). protein expression of CAIX in clear cell renal cell carcinoma CAIX may therefore become a potentially useful marker in (CCRCC) has been shown to be an independent predictor of distinguishing these. 29 30 31 poor outcome. de Martino et al examined 54 metastatic There has been interest in the use of soluble plasma CAIX CCRCCs and found the CAIX single nucleotide
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