JCHOR
Journal of Current Hematology & Oncology Research

The Journal of Current Hematology & Oncology Research regularly publishes internationally qualified research in hematology and oncology within the current scholarly knowledge.

ISSN: Active
eISSN: 2980-0854
Creative Commons CC BY-NC-ND 4.0 International License.
EndNote Style

Online Manuscript System

Index
Original Article
The importance of acidic microenvironment in urothelial carcinomas of the bladder: relationship with carbonic anhydrase IX expression and prognostic factors
Abstract
Aims: Bladder urothelial carcinoma (BUC) is a prevalent malignancy worldwide, ranking 13th in terms of mortality. Several prognostic factors affecting survival have been identified, including histologic grade, invasion of the muscularis propria, tumor diameter, and lymphovascular invasion. However, new markers that will be helpful in diagnosis, treatment and prognosis are still needed. Carbonic anhydrase IX (CA IX) is a tumor-associated cell surface glycoprotein that aids in adaptation to acidosis induced by hypoxia and plays a role in cancer progression.There are few studies on the prognostic impact of CA IX on BUCs. This study aimed to investigate whether CA IX is a promising diagnostic and prognostic biomarker in BUC.
Methods: A retrospective analysis was conducted on 117 cases diagnosed with BUC whithout muscularis propria invasion between September 1995 and January 2023. Transurethral resection specimens were examined histological grade, lymphovascular invasion, tumor diameter by a single pathologist. CAIX was performed by immunohistochemical method.
Results: Among the 117 patients included in the study, 61 had low-grade tumors, while the remaining 56 had high-grade tumors. CA IX expression exhibited a significant positive correlation with histological grade (p < 0.01), lymphovascular invasion (p < 0.01). and tumor diameter (p < 0.01). Low CA IX staining was observed in three normal tissues and ıt was found to be a biomarker in the distinction between malignant and benign cases.
Conclusion: CA IX expression is associated with poor prognosis in BUCs as in some other tumors. Evaluation of CA IX staining may be important for patient follow-up and treatment strategies. Adding carbonic anhydrase enzyme inhibitors to chemotherapy regimens could potentially create new treatment options.

Keywords : Bladder, carcinoma, CAIX, prognostic factor

Download Article


1. Ahdoot M, Theodorescu D. Immunotherapy of high risk non-muscle invasive bladder cancer. Expert Rev Clin Pharmacol. 2021;14(11):1345-1352. doi:10.1080/17512433.2021.1950531
2. Ferlay J, Ervik M, Lam F, et al. Global cancer observatory: cancer today. Lyon, France: International Agency for Research on Cancer. 2024 Available from: https://gco.iarc.who.int/today,accessed
3. Saginala K, Barsouk A, Aluru JS, Rawla P, Padala SA, Barsouk A. Epidemiology of bladder cancer. Med Sci (Basel). 2020;8(1):15. doi:10.3390/medsci8010015
4. Aibara N, Miyata Y, Araki K, et al. Detection of novel urine markers using immune complexome analysis in bladder cancer patients: a preliminary study. In Vivo. 2021;35(4):2073-2080. doi:10.21873/invivo.12476
5. Han JH, Jeong S, Yuk HD, Jeong CW, Kwak C, Ku JH. Acidic urine is associated with poor prognosis in patients with bladder cancer undergoing radical cystectomy. Front Oncol [Internet]. 2022. doi:10.3389/fonc.2022.964571
6. Moch H, Cubilla AL, Humphrey PA, Reuter VE, Ulbright TM. The 2016 WHO classification of tumours of the urinary system and male genital organs-part a: renal, penile, and testicular tumours. Eur Urol. 2016;70(1): 93-105. doi:10.1016/j.eururo.2016.02.029
7. Comp&eacute;rat EM, Burger M, Gontero P, et al. Grading of urothelial carcinoma and the new &ldquo;World Health Organisation classification of tumours of the urinary system and male genital organs 2016&rdquo;. Eur Urol Focus. 2019;5(3): 457-466. doi:10.1016/j.euf.2018.01.003
8. Xiang AP, Chen XN, Xu PF, Shao SH, Shen YF. Expression and prognostic value of carbonic anhydrase IX (CA-IX) in bladder urothelial carcinoma. BMC Urol. 2022;22(1):120. doi:10.1186/s12894-022-01074-9
9. Sylvester RJ, van der Meijden AP, Oosterlinck W, et al. Predicting recurrence and progression in individual patients with stage Ta T1 bladder cancer using EORTC risk tables: a combined analysis of 2596 patients from seven EORTC trials. Eur Urol. 2006;49(3):466-5;475-477. doi:10.1016/j.eururo.2005.12.031
10. Lemke EA, Shah AY. Management of advanced bladder cancer: an update. J Adv Pract Oncol. 2018;9(4):410-416.
11. Carroll CP, Bolland H, Vancauwenberghe E, et al. Targeting hypoxia regulated sodium driven bicarbonate transporters reduces triple negative breast cancer metastasis. Neoplasia. 2022;25:41-52. doi:10.1016/j.neo.2022. 01.003
12. Lee P, Chandel NS, Simon MC. Cellular adaptation to hypoxia through hypoxia inducible factors and beyond. Nat Rev Mol Cell Biol. 2020;21(5): 268-283. doi:10.1038/s41580-020-0227-y
13. Godet I, Doctorman S, Wu F, Gilkes DM. Detection of hypoxia in cancer models: significance, challenges, and advances. Cells. 2022;11(4):686. doi: 10.3390/cells11040686
14. Gillies RJ, Brown JS, Anderson ARA, Gatenby RA. Eco-evolutionary causes and consequences of temporal changes in intratumoural blood flow. Nat Rev Cancer. 2018;18(9):576-585. doi:10.1038/s41568-018-0030-7
15. Wu Q, You L, Nepovimova E, et al. Hypoxia-inducible factors: master regulators of hypoxic tumor immune escape. J Hematol Oncol. 2022;15(1): 77. doi:10.1186/s13045-022-01292-6
16. Swietach P. What is pH regulation, and why do cancer cells need it? Cancer Metastasis Rev. 2019;38(1-2):5-15. doi:10.1007/s10555-018-09778-x
17. Riemann A, Rauschner M, Gie&szlig;elmann M, Reime S, Haupt V, Thews O. Extracellular acidosis modulates the expression of epithelial-mesenchymal transition (EMT) markers and adhesion of epithelial and tumor cells. Neoplasia. 2019;21(5):450-458. doi:10.1016/j.neo.2019.03.004
18. Pastorekova S, Gillies RJ. The role of carbonic anhydrase IX in cancer development: links to hypoxia, acidosis, and beyond. Cancer Metastasis Rev. 2019;38(1-2):65-77. doi:10.1007/s10555-019-09799-0
19. Chahal V, Nirwan S, Pathak M, Kakkar R. Identification of potent human carbonic anhydrase IX inhibitors: a combination of pharmacophore modeling, 3D-QSAR, virtual screening and molecular dynamics simulations. J Biomol Struct Dyn. 2022;40(10):4516-4531. doi:10.1080/07391102.2020.1860132
20. Hsin MC, Hsieh YH, Hsiao YH, Chen PN, Wang PH, Yang SF. Carbonic anhydrase IX promotes human cervical cancer cell motility by regulating PFKFB4 expression. Cancers (Basel). 2021;13(5):1174. doi:10.3390/cancers 13051174
21. Bin Riaz I, Khan AM, Catto JW, Hussain SA. Bladder cancer: shedding light on the most promising investigational drugs in clinical trials. Expert Opin Investig Drugs. 2021;30(8):837-855. doi:10.1080/13543784.2021.1948999
22. Zhu Y, Zhou XY, Yao XD, et al. Prognostic value of carbonic anhydrase IX expression in penile squamous cell carcinoma: a pilot study. Urol Oncol. 2013;31(5):706-11. doi:10.1016/j.urolonc.2011.04.011
23. Tafreshi NK, Lloyd MC, Bui MM, Gillies RJ, Morse DL. Carbonic anhydrase IX as an imaging and therapeutic target for tumors and metastases. Subcell Biochem. 2014;75:221-54. doi:10.1007/978-94-007-7359-2_12
24. van Kuijk SJ, Yaromina A, Houben R, Niemans R, Lambin P, Dubois LJ. Prognostic significance of carbonic anhydrase IX expression in cancer patients: a meta-analysis. Front Oncol. 2016;6:69. doi:10.3389/fonc.2016. 00069
25. Rezuchova I, Bartosova M, Belvoncikova P, et al. Carbonic anhydrase IX in tumor tissue and plasma of breast cancer patients: reliable biomarker of hypoxia and prognosis. Int J Mol Sci. 2023;24(5):4325. doi:10.3390/ijms 24054325
26. Hoskin PJ, Sibtain A, Daley FM, Wilson GD. GLUT1 and CAIX as intrinsic markers of hypoxia in bladder cancer: relationship with vascularity and proliferation as predictors of outcome of ARCON. Br J Cancer. 2003;89(7): 1290-1297. doi:10.1038/sj.bjc.6601260
27. Klatte T, Belldegrun AS, Pantuck AJ. The role of carbonic anhydrase IX as a molecular marker for transitional cell carcinoma of the bladder. BJU Int. 2008;101(Suppl 4):45-48. doi:10.1111/j.1464-410X.2008.07650.x
28. Todenh&ouml;fer T, Gibb EA, Seiler R, et al. Evaluation of carbonic anhydrase IX as a potential therapeutic target in urothelial carcinoma. Urol Oncol. 2021; 39(8):498.e1. doi:10.1016/j.urolonc.2021.04.011
29. Singh S, Lomelino CL, Mboge MY, Frost SC, McKenna R. Cancer drug development of carbonic anhydrase inhibitors beyond the active site. Molecules. 2018;23(5):1045. doi:10.3390/molecules23051045
30. Chen HY, Lin CE, Wu SC, et al. Para-toluenesulfonamide, a novel potent carbonic anhydrase inhibitor, improves hypoxia-induced metastatic breast cancer cell viability and prevents resistance to &alpha;PD-1 therapy in triple-negative breast cancer. Biomed Pharmacother. 2023;167:115533. doi:10. 1016/j.biopha.2023.115533
31. Peixoto A, Fernandes E, Gaiteiro C, et al. Hypoxia enhances the malignant nature of bladder cancer cells and concomitantly antagonizes protein O-glycosylation extension. Oncotarget. 2016;7(39):63138-63157. doi:10. 18632/oncotarget.11257
32. Mussi S, Rezzola S, Chiodelli P, Nocentini A, Supuran CT, Ronca R. Antiproliferative effects of sulphonamide carbonic anhydrase inhibitors C18, SLC-0111 and acetazolamide on bladder, glioblastoma and pancreatic cancer cell lines. J Enzyme Inhib Med Chem. 2022;37(1):280-286. doi:10. 1080/14756366.2021.2004592
Article available in :
Volume 3, Issue 1, 2025
Page : 6-10
https://doi.org/10.51271/JCHOR-0052
Article Information
Received : 16 Eki 2024
Accepted : 13 Ara 2024
Published : 04 Şub 2025
Corresponding Author :

Özgen Arslan Solmaz: Department of Pathology, Fethi Sekin City Hospital, Elazığ, Turkiye

[email protected]
Citation : Solmaz ÖA, Ayyıldız H, Oğraş MS. The importance of acidic microenvironment in urothelial carcinomas of the bladder: relationship with carbonic anhydrase IX expression and prognostic factors. J Curr Hematol Oncol Res. 2025;3(1):6-10.

Read: 21
Cited: 0
Download : 19
_Footer