Carbonic anhydrase IX (CAIX) is a transmembrane protein that is specifically overexpressed on the surface of hypoxic tumor cells. With the function of regulating the acidity of tumor cells both inside and outside, CAIX is closely related to tumor proliferation, invasion and metastasis. Therefore, CAIX is a promising target for tumor imaging and therapy. Herein, we summarized recent advances in CAIX-based tumor imaging, therapy and theranostics, and prospected future applications of using CAIX as an anti-tumor target.
Carbonic Anhydrase IX ; Carbonic Anhydrases/metabolism* ; Cell Line, Tumor

Carbonic anhydrase IX (CA IX) is a tumor associated protein which is able to be a potent anticancer target, since it is highly expressed in a multitude of carcinomas, while it is present in a limited number of normal tissues. This review focuses on its role in tumor physiology, the most recent three dimensional structure features of this enzyme which has recently been elucidated. In addition, we present recent advances in the development of small inhibitors able to target CA IX for therapeutic applications.
Antigens, Neoplasm ; metabolism ; Antineoplastic Agents ; chemistry ; therapeutic use ; Carbonic Anhydrase IX ; Carbonic Anhydrase Inhibitors ; chemistry ; therapeutic use ; Carbonic Anhydrases ; metabolism ; Humans ; Neoplasms ; drug therapy ; enzymology

OBJECTIVETo investigate the expression of MN/CAIX in patients with renal cell carcinoma (RCC) and assess the value of MN/CAIX in the diagnosis of RCC.

METHODSRT-PCR was employed to detect MN/CAIX mRNA in the carcinoma tissue and peripheral blood of 62 patients with RCC, using normal renal tissue and peripheral blood sample from 32 patients without RCC as control. Immunohistochemistry was used to detect MN/CAIX protein in the tissue specimens of clear cell RCC (n=36), non-clear cell renal neoplasm (n=17) and normal kidney (n=16).

RESULTSThe positivity rate of MN/CAIX mRNA was 82.3% (51/62) in renal carcinoma tissues and 54.8% (34/62) in the peripheral blood from patients with RCC, significantly higher than the rates in the control cases (P<0.05). In cases of clear cell renal cell carcinoma, the positivity rate of MN/CAIX mRNA was 98% (49/50) in the carcinoma tissues and 66% (33/50) in the peripheral blood, significantly higher than the rates in cases of non-clear cell type of RCC (P<0.05). Immunohistochemistry showed a significantly higher positivity rate of MN/CAIX protein in clear cell RCC tissues [97.2% (35/36)] than in non-clear cell renal neoplasm and normal renal tissues (P<0.05).

CONCLUSIONMN/CAIX is specifically overexpressed in RCC, especially in clear cell RCC, suggesting its potential in the diagnosis and prognostic and therapeutic evaluation of RCC.

Adult ; Aged ; Antigens, Neoplasm ; genetics ; metabolism ; Biomarkers, Tumor ; Carbonic Anhydrase IX ; Carbonic Anhydrases ; genetics ; metabolism ; Carcinoma, Renal Cell ; diagnosis ; metabolism ; Female ; Humans ; Kidney Neoplasms ; diagnosis ; metabolism ; Male ; Middle Aged ; RNA, Messenger ; genetics ; metabolism ; Young Adult

OBJECTIVETo study the expression of carbonic anhydrase IX (CAIX), PAX2 and PAX8 in different types of renal epithelial tumor and their association with clinicopathologic characteristics.

METHODSImmunohistochemical study by EnVision method was performed in order to assess the expression of CAIX, PAX2 and PAX8 in 155 cases of renal cell carcinoma and 4 cases of metastatic clear cell renal cell carcinoma (CCRCC). Ninety-six cases of non-neoplastic renal parenchymal tissue adjacent to CCRCC, 8 cases of clear cell hepatocellular carcinoma and 2 cases of clear cell hidradenoma were used as controls.

RESULTSCAIX was commonly expressed in CCRCC (94.0%, 63/67), of which 77.8% (49/63) showed strong positivity. CAIX was focally positive in papillary renal cell carcinoma, collecting duct carcinoma and urothelial carcinoma of renal pelvis. It was negative in chromophobe renal cell carcinoma, oncocytoma and adjacent non-neoplastic renal tissue. CAIX was also strongly expressed in the 4 cases of metastatic CCRCC. Focal expression of CAIX was demonstrated in the 8 cases of clear cell hepatocellular carcinoma and 2 cases of clear cell hidradenoma. The expression of CAIX in CCRCC did not correlate with tumor grading, clinical staging and presence of distal metastasis. On the other hand, PAX2 showed positive expression in different types of renal epithelial tumor, clear cell hepatocellular carcinoma and clear cell hidradenoma in various degrees. In contrast, PAX8 was commonly expressed in all types of renal epithelial tumor, with the exception of urothelial carcinoma of renal pelvis. PAX8 was not expressed in clear cell hepatocellular carcinoma and clear cell hidradenoma. Regarding diagnosis of CCRCC, CAIX demonstrated high sensitivity and specificity. PAX2 showed high specificity but low sensitivity. PAX8 was sensitive and specific in the diagnosis of renal epithelial tumor.

CONCLUSIONSCAIX is a useful immunohistochemical marker with high specificity and sensitivity in distinguishing CCRCC from other types of renal epithelial tumor and clear cell tumors of non-renal origin. PAX2 is a marker with high sensitivity and low specificity for diagnosis of renal epithelial tumors. PAX8 is typically expressed in renal epithelial tumors. The combined detection of CAIX, PAX2 and PAX8 is useful in the diagnosis and differential diagnosis of renal epithelial tumors.

Adenoma, Oxyphilic ; metabolism ; pathology ; Antigens, Neoplasm ; metabolism ; Carbonic Anhydrase IX ; Carbonic Anhydrases ; metabolism ; Carcinoma, Renal Cell ; metabolism ; pathology ; Diagnosis, Differential ; Humans ; Kidney Neoplasms ; metabolism ; pathology ; Male ; PAX2 Transcription Factor ; metabolism ; PAX8 Transcription Factor ; Paired Box Transcription Factors ; metabolism

Actins ; metabolism ; Aged ; Antigens, Neoplasm ; metabolism ; Carbonic Anhydrase IX ; Carbonic Anhydrases ; metabolism ; Carcinoma, Renal Cell ; metabolism ; pathology ; surgery ; Desmin ; metabolism ; Diagnosis, Differential ; Humans ; Keratin-7 ; metabolism ; Kidney Neoplasms ; metabolism ; pathology ; surgery ; Male ; Nephrectomy ; methods ; Vimentin ; metabolism

OBJECTIVETo study the relationship between fibrotic focus (FF) and carbonic anhydrase (CA) IX in invasive ductal carcinomas (IDC) of the breast.

METHODSIn 167 cases of IDC, the FF was assessed morphologically, and expression of ER, PR and CA IX was evaluated using MaxVision immunohistochemistry.

RESULTSThe expression of CA IX in IDC with and without FF was 56.3% (45/80) and 28.7% (25/87) respectively, with significant difference (P=0.001). In IDC with FF, the CA IX expression of tumor cells in tumors with CA IX-positive fibroblasts (35/40, 87.5%) was significantly (P<0.001) higher than that in tumors with CA IX-negative fibroblasts (10/40, 25.0%). In IDC with FF, the CA IX expression of fibroblasts of FF in grade 3 IDC (23/33, 69.7%) was significantly (P=0.006) higher than that in grade 1+2 tumors (17/47, 36.2%). The ER and PR expression of tumor cells in tumors containing CA IX-negative fibroblasts was 72.5% (29/40) and 65.0% (26/40) respectively, whereas the ER and PR expression of tumor cells in tumors containing CA IX-positive fibroblasts was 50.0% (20/40) and 42.5% (17/40) respectively; the difference was statistically significant (for both ER and PR, P=0.04). The age of patients with tumors containing CA IX-negative fibroblasts was significantly (P=0.002) older than those containing CA IX-positive fibroblasts. The FF diameter/tumor diameter in tumors containing CA IX-positive fibroblasts was significantly larger than those containing CA IX-negative fibroblasts. (3) For the groups of tumor size≤2 cm and tumor size between 2 cm to 5 cm, the diameter of the fibrotic focus was significantly (P<0.01) smaller than the fibrotic focus size of tumors>5 cm in size.

CONCLUSIONSCA IX expression is correlated with FF, and that in fibroblasts of FF correlated with patients' age, tumor grade, hormone receptors and FF diameter/tumor diameter. CA IX expression in FF might be a marker for poor prognosis in patients with breast cancer.

Age Factors ; Antigens, Neoplasm ; Breast Neoplasms ; metabolism ; pathology ; Carbonic Anhydrase IX ; Carbonic Anhydrases ; Carcinoma, Ductal, Breast ; enzymology ; pathology ; Female ; Fibroblasts ; metabolism ; Humans ; Immunohistochemistry ; Neoplasm Grading ; Neoplasm Proteins ; Receptors, Estrogen ; metabolism ; Receptors, Progesterone ; metabolism

OBJECTIVETo achieve high expression of human renal cell carcinoma-associated antigen G250 in Escherichia coli.

METHODSThe gene fragments encoding the protein obtained by PCR was cloned into prokaryotic expression vector pET32a(+) and expressed in E. coli Rosseta. The immunogenicity of the recombinant protein was evaluated by Western blotting.

RESULTSThe plasmid pET32a(+)/G250 was constructed and expressed in E. coli Rosseta successfully. Western blot analysis showed that the recombinant protein could be specifically recognized by monoclonal antibody M75.

CONCLUSIONEfficient G250 expression is achieved in prokaryotic expression system, which may facilitate further functional study of the protein and its monoclonal antibody preparation.

Antibodies, Monoclonal ; immunology ; Antibody Specificity ; immunology ; Antigens, Neoplasm ; genetics ; immunology ; metabolism ; Biomarkers, Tumor ; genetics ; immunology ; metabolism ; Blotting, Western ; Carbonic Anhydrase IX ; Carbonic Anhydrases ; genetics ; immunology ; metabolism ; Cloning, Molecular ; Escherichia coli ; genetics ; Gene Expression ; Humans ; Recombinant Fusion Proteins ; genetics ; immunology ; metabolism

OBJECTIVE: To analyze the expression and relationship between hypoxia inducible factor-1alpha (HIF-1alpha) and carbonic anhydrase IX (CA IX) in nasal polyps, and to explore the role of HIF-1alpha and CA IX in the pathogenesis of nasal polyps. METHOD: Twenty-eight tissues of nasal polyps and 12 tissues of normal inferior turbinate mucosa were collected in this study. And Immunohistochemistry method was used to detect the expression of HIF-1alpha and CA IX in the two groups. RESULT: The numbers and intensity of positive stained cells of HIF-1alpha and CA IX were higher in nasal polyps. IOD of HIF-1alphaa and CA IX (10(3)/HP) in the nasal polyps were respectively 21.76 +/- 3.52, 26.87 +/- 4.60 compared with 3.37 +/- 1.65, 3.25 +/- l.20 in the control group by image analysis. There were significant differences between the two groups (P < 0.05). Spearman correlation test showed that there was a close correlation between the HIF-1alpha and CA IX expression in nasal polyps (r = 0.820, P < 0.01). CONCLUSION The results showed that HIF-1alpha and CA IX were over expressed in nasal polyps, and there was a close correlation between them. Hypoxia was found in nasal polyps and it could become more severe under infection, inflammation and energy metabolic disorder which consumed a great deal of oxygen. HIF-1alpha was over expressed in nasal polyps, which activate and promote the expression for CA IX, in order to keep the normal pH of cells for adapting the hypoxic microenvironment and sustain persistent growth and hyperblastosis of cells in the hypoxic areas. At last the internal circle was forming, which accelerate the formation of nasal polyps.
Adolescent ; Adult ; Antigens, Neoplasm ; metabolism ; Carbonic Anhydrase IX ; Carbonic Anhydrases ; metabolism ; Case-Control Studies ; Female ; Humans ; Hypoxia-Inducible Factor 1, alpha Subunit ; metabolism ; Male ; Middle Aged ; Nasal Polyps ; metabolism ; pathology ; Young Adult

OBJECTIVE: To identify the difference of CA IX and P-gp expression level between laryngeal squamous cell carcinoma (LSCC) and benign tissues, evaluate the relationship of these two proteins in LSCC, and their correlation with clinical and pathological features. METHOD: Immunohistochemical detection of CA IX and P-gp were performed in 47 cases of LSCC and 20 cases of vocal cord polyps. RESULT: Overexpression of CA IX and P-gp both in LSCC and in vocal cord polyp (P < 0.05) were confirmed, with a correlation between the two proteins in LSCC (r = 0.324, P < 0.05). The expression of CA IX was related to clinical staging and lymph node metastasis in LSCC (P < 0.05). While P-gp was related to clinical staging and histological grading in LSCC (P < 0.05). CONCLUSION The overexpression of CA IX and P-gp may play a role in LSCC progression.
ATP Binding Cassette Transporter, Subfamily B ; metabolism ; Antigens, Neoplasm ; metabolism ; Carbonic Anhydrase IX ; Carbonic Anhydrases ; metabolism ; Carcinoma, Squamous Cell ; metabolism ; pathology ; Humans ; Laryngeal Neoplasms ; metabolism ; pathology ; Lymphatic Metastasis ; Neoplasm Grading ; Neoplasm Staging ; Polyps ; metabolism ; Vocal Cords ; metabolism ; pathology

OBJECTIVETo study the expression of carbonic anhydrase (CA) IX and its significance in molecular subtyping of breast carcinomas. METHODL MaxVision immunohistochemical staining was used to examine the expression of ER, PR, HER2, CK5/6, EGFR, and CA IX in 117 cases of breast invasive ductal carcinomas.

RESULTSThe patients' age ranged from 25 to 71 years (mean 49.6 years). All the 117 cases were subclassified into five subtypes, with 66 (56.4%) luminal A, 6(5.1%) luminal B, 10 (8.6%) HER2 positive, 20 (17.1%) basal-like, and 15 (12.8%) unclassified tumors. The expression of CA IX in luminal A and basal-like breast cancers was 13.6% (9/66) and 8/20, respectively, with a significant difference (P < 0.05). Among the luminal A cancers, the expression of CA IX in tumors > 2 cm (7/27, 25.9%) was significantly (P < 0.05) higher than that of tumors ≤ 2 cm (2/39, 5.1%). The expression of CA IX in grade 3 invasive ductal carcinoma (18/50, 36.0%) was significantly higher than that in grade 1 (2/21, 9.5%) and 2 (7/46, 15.2%) tumors (both P = 0.006). In CA IX-negative of invasive ductal carcinoma, the expression of ER and PR was 61.1% (55/90) and 55.6% (50/90), respectively; whereas in CA IX-positive cancers, the expression of ER and PR was 37.0% (10/27) and 29.6% (8/27), respectively. The expression of hormone receptors in CA IX-negative tumors was significantly higher than that in CA IX-positive tumors (for both ER and PR, P < 0.05).

CONCLUSIONSThe expression of CA IX correlates not only with molecular subtypes of breast cancer, but also with the grading, hormone receptors and diameter of mammary invasive ductal carcinoma. CA IX is a relative independent marker of poor prognosis in breast cancer.

Adult ; Aged ; Antigens, Neoplasm ; metabolism ; Biomarkers, Tumor ; metabolism ; Breast Neoplasms ; classification ; metabolism ; pathology ; Carbonic Anhydrase IX ; Carbonic Anhydrases ; metabolism ; Carcinoma, Ductal, Breast ; classification ; metabolism ; pathology ; Female ; Humans ; Middle Aged ; Neoplasm Grading ; Receptor, ErbB-2 ; metabolism ; Receptors, Estrogen ; metabolism ; Receptors, Progesterone ; metabolism ; Tumor Burden