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The carbonic anhydrases (CAs; EC 18.104.22.168) are a family of metalloenzymes that catalyze the reversible hydration of carbon dioxide and bicarbonate. Among those identified, there are eight cytosolic proteins (CA I, CA II, CA III, CA VII, CA VIII, CA X, CA XI, CA XIII), two mitochondrial matrix proteins (CA VA, CA VB), one secreted protein (CA VI), two glycosylphosphatidylinositol (GPI)-anchored proteins (CA IV and CA XV), and three transmembrane proteins (CA IX, CA XII, CA XIV).
Carbonic anhydrase IX (CA IX) is the gene most widely expressed in response to hypoxia. Its crucial role in intracellular pH maintenance represents the means by which cancer cells adapt to the toxic conditions of the extracellular milieu. CA IX expression in many types of tumor indicates its relevance as a general marker of tumor hypoxia. Moreover, its expression is closely related to prognosis of the clinical outcome in several tumor types. All of the above-mentioned facts support the strong position of CA IX as a potential drug therapy target.
The CA IX protein is mainly involved in the following three aspects:
In 1986, using monoclonal antibody G250, a novel marker specific for renal cell carcinoma (RCC) was discovered. Among different RCC subtypes, clear cell renal cell carcinoma (CCRCC) is associated with the highest CA IX expression. The protein is expressed in 97% of CCRCC cases with apparently no expression in normal renal tissue. Therefore, CA IX bears the potential of being a diagnostic marker for renal malignancies. However, its expression is not only connected with numerous RCC subtypes, but with a whole spectrum of solid tumors. Large-scale studies of tumor-derived cell line and tissue specimens revealed CA IX expression in specific carcinomas of the cervix uteri and uterine corpus, ovary, gastrointestinal tract, liver, pancreas, lung, head/neck, salivary gland, body cavity, and skin. CA IX is thus a general marker of tumor hypoxia in many solid tumors rather than a specific marker for distinct types/subtypes of malignancies (1).
The importance of detecting CA IX ectopic expression in human tumors lies not only in its diagnostic nature. Interestingly, the level of CA IX expression is also associated with staging and survival prognosis in several types of human tumor. Higher levels of CA IX expression are associated with poor clinical outcome in cervical, rectal, breast, lung, and brain tumors (2).
CA IX is generally localized on the cell membrane but may also be found to a lesser degree in the cytoplasm. The extracellular domain of CA IX, including the PG and CA domains, can be released into the culture medium of CCRCC cells or in the body ﬂuids (blood, urine) of patients with CCRCC. This release is most likely a result of proteolytic cleavage. The soluble 50/54 kDa form is termed s-CA IX and is cleared from the blood within a few days after nephrectomy. The concentration of s-CA IX is very low in healthy subjects. Therefore, it can be assayed by ELISA in serum, plasma, and tissue for clinical detection and prognostic evaluation of patients with different types of cancers. ELISA could be a potential quantitative method for non-invasive diagnosis of renal tumors. Serum CA IX levels were significantly higher in CCRCC than in non-CCRCC and increased in conjunction with increased stage of tumor progression (3). Serum levels of CA IX in metastatic breast cancer and vulvar cancer were correlated with poor prognosis. In non-small cell lung cancer, high plasma levels of s-CA IX were determined to be an independent prognostic biomarker, particularly for early stage I or II carcinomas and were associated with signiﬁcantly worse survival. Also, detection of s-CA IX protein by ELISA and immunocytochemistry have been used to detect malignant pleural effusions. The potential use of serum s-CA IX as a biomarker for therapy response was tested in patients with primary epithelial ovarian cancer, yet were not signiﬁcantly altered during ﬁrst-line therapy (4).
|CA I||13198-2-AP||ELISA, WB|
|CA II||16961-1-AP||ELISA, WB|
|CA III||15197-1-AP||ELISA, WB, IHC|
|CA IV||13931-1-AP||ELISA, WB|
|CA VB||13342-1-AP||ELISA, WB|
|CA VII||13670-1-AP||ELISA, WB, IHC|
|CA VIII||12391-1-AP||ELISA, WB, IHC|
|CA IX||11071-1-AP||ELISA, WB, IHC, FC, IP|
|CA X||12953-1-AP||ELISA, WB,|
|CA XI||15435-1-AP||ELISA, WB, IHC|
|CA XII||15180-1-AP||ELISA, WB, IHC, FC|
|CA XIII||16696-1-AP||ELISA, WB, IHC|
|CA XIV||13736-1-AP||ELISA, WB|
1. Genega EM, Ghebremichael M, et al. Carbonic anhydrase IX expression in renal neoplasms: correlation with tumor type and grade. Am J Clin Pathol (2010)134(6):873–879.
2. Ziru L, Zhulin Y, et al. Paxillin and carbonic anhydrase IX are prognostic markers in gallbladder squamous cell/adenosquamous carcinomas and adenocarcinomas. Histopathology 2014, 921-934. DOI: 10.1111/his.12341.
3. Li G, Feng G, Gentil-Perret A, Genin C, Tostain J. Serum carbonic anhydrase 9 level is associated with postoperative recurrence of conventional renal cell cancer. J Urol (2008)180:510–513.
4. Kock L, Mahner S, et al. Serum carbonic anhydrase IX and its prognostic relevance in vulvar cancer. Int J Gynecol Cancer (2011) 21:141–148.