Journal of Cancer Research and Treatment
ISSN (Print): 2374-1996 ISSN (Online): 2374-2003 Website: Editor-in-chief: Jean Rommelaere
Open Access
Journal Browser
Journal of Cancer Research and Treatment. 2018, 6(2), 34-38
DOI: 10.12691/jcrt-6-2-2
Open AccessArticle

Biomarkers for Bladder Cancer: Present Challenges and Recent Developments

Barnali Deb1, 2 and Prashant Kumar1, 2,

1Institute of Bioinformatics, International Technology Park, Bangalore, India

2Manipal Academy of Higher Education, Madhav Nagar, Manipal, India

Pub. Date: May 08, 2018

Cite this paper:
Barnali Deb and Prashant Kumar. Biomarkers for Bladder Cancer: Present Challenges and Recent Developments. Journal of Cancer Research and Treatment. 2018; 6(2):34-38. doi: 10.12691/jcrt-6-2-2


Bladder cancer is the most common carcinoma of the urinary system. Early detection and diagnosis of bladder cancer is a major challenge. Urine cytology has low sensitivity and specificity, especially for low-grade tumors. Cystoscopy is the gold standard for the detection and follow-up of bladder tumors. However, it is an expensive and invasive procedure and can fail to detect many bladder lesions such as carcinoma in situ (CIS). It is thus an unmet need to identify a robust set of biomarkers, which can improve the current diagnostic practice. During the last one decade, several bladder tumor markers have been identified for diagnosis, however, none of these diagnostic markers offer sufficient sensitivity and specificity to be routinely used in the clinics. Recent advancement in mass spectrometry (MS)-based quantitative proteomics has emerged as a powerful method to discover wide range of proteins in complex biological samples. In this review, we summarize the status of biomarkers currently identified and used for bladder cancer diagnosis.

bladder cancer biomarker diagnosis non-invasive mass spectrometry

Creative CommonsThis work is licensed under a Creative Commons Attribution 4.0 International License. To view a copy of this license, visit


[1]  L.A. Torre, F. Bray, R.L. Siegel, J. Ferlay, J. Lortet-Tieulent, A. Jemal, Global cancer statistics, 2012, CA: a cancer journal for clinicians, 65 (2015) 87-108.
[2]  R.L. Siegel, K.D. Miller, A. Jemal, Cancer Statistics, 2017, CA: a cancer journal for clinicians, 67 (2017) 7-30.
[3]  F. Zhao, Y.Z. Ge, L.H. Zhou, L.W. Xu, Z. Xu, W.W. Ping, M. Wang, C.C. Zhou, R. Wu, R.P. Jia, Identification of hub miRNA biomarkers for bladder cancer by weighted gene coexpression network analysis, OncoTargets and therapy, 10 (2017) 5551-5559.
[4]  D.H. Tang, S.S. Chang, Management of carcinoma in situ of the bladder: best practice and recent developments, Therapeutic advances in urology, 7 (2015) 351-364.
[5]  J.A. Witjes, Bladder carcinoma in situ in 2003: state of the art, European urology, 45 (2004) 142-146.
[6]  M. Babjuk, A. Bohle, M. Burger, O. Capoun, D. Cohen, E.M. Comperat, V. Hernandez, E. Kaasinen, J. Palou, M. Roupret, B.W. van Rhijn, S.F. Shariat, V. Soukup, R.J. Sylvester, R. Zigeuner, EAU Guidelines on Non-Muscle-invasive Urothelial Carcinoma of the Bladder: Update 2016, European urology, 71 (2017) 447-461.
[7]  B.S. Tae, C.W. Jeong, C. Kwak, H.H. Kim, K.C. Moon, J.H. Ku, Pathology in repeated transurethral resection of a bladder tumor as a risk factor for prognosis of high-risk non-muscle-invasive bladder cancer, PloS one, 12 (2017) e0189354.
[8]  F.A. Yafi, W. Kassouf, Radical cystectomy is the treatment of choice for invasive bladder cancer, Canadian Urological Association journal. Journal de l'Association des urologues du Canada, 3 (2009) 409-412.
[9]  P.U. Malmstrom, S. Agrawal, M. Blackberg, P.J. Bostrom, B. Malavaud, D. Zaak, G.G. Hermann, Non-muscle-invasive bladder cancer: a vision for the future, Scandinavian journal of urology, 51 (2017) 87-94.
[10]  A. Salama, A.M. Abdelmaksoud, A. Shawki, A. Abdelbary, H. Aboulkassem, Outcome of Muscle-Invasive Urothelial Bladder Cancer After Radical Cystectomy, Clinical genitourinary cancer, 14 (2016) e43-47.
[11]  J. Bellmunt, A. Orsola, J.J. Leow, T. Wiegel, M. De Santis, A. Horwich, Bladder cancer: ESMO Practice Guidelines for diagnosis, treatment and follow-up, Annals of oncology : official journal of the European Society for Medical Oncology, 25 Suppl 3 (2014) iii40-48.
[12]  S.J. Maclennan, M. Imamura, M.I. Omar, L. Vale, T. Lam, P. Royle, J. Royle, S. Swami, R. Pickard, S. McClinton, T.R. Griffiths, P. Dahm, J. N'Dow, Urological cancer care pathways: development and use in the context of systematic reviews and clinical practice guidelines, World journal of urology, 29 (2011) 291-301.
[13]  C.J. Rosser, V. Urquidi, S. Goodison, Urinary biomarkers of bladder cancer: an update and future perspectives, Biomarkers in medicine, 7 (2013) 779-790.
[14]  V. Thongboonkerd, K.R. McLeish, J.M. Arthur, J.B. Klein, Proteomic analysis of normal human urinary proteins isolated by acetone precipitation or ultracentrifugation, Kidney international, 62 (2002) 1461-1469.
[15]  M. Frantzi, K.E. van Kessel, E.C. Zwarthoff, M. Marquez, M. Rava, N. Malats, A.S. Merseburger, I. Katafigiotis, K. Stravodimos, W. Mullen, J. Zoidakis, M. Makridakis, M. Pejchinovski, E. Critselis, R. Lichtinghagen, K. Brand, M. Dakna, M.G. Roubelakis, D. Theodorescu, A. Vlahou, H. Mischak, N.P. Anagnou, Development and Validation of Urine-based Peptide Biomarker Panels for Detecting Bladder Cancer in a Multi-center Study, Clinical cancer research : an official journal of the American Association for Cancer Research, 22 (2016) 4077-4086.
[16]  J. Zoidakis, M. Makridakis, P.G. Zerefos, V. Bitsika, S. Esteban, M. Frantzi, K. Stravodimos, N.P. Anagnou, M.G. Roubelakis, M. Sanchez-Carbayo, A. Vlahou, Profilin 1 is a potential biomarker for bladder cancer aggressiveness, Molecular & cellular proteomics : MCP, 11 (2012) M111 009449.
[17]  M. Frantzi, J. Zoidakis, T. Papadopoulos, P. Zurbig, I. Katafigiotis, K. Stravodimos, A. Lazaris, I. Giannopoulou, A. Ploumidis, H. Mischak, W. Mullen, A. Vlahou, IMAC fractionation in combination with LC-MS reveals H2B and NIF-1 peptides as potential bladder cancer biomarkers, Journal of proteome research, 12 (2013) 3969-3979.
[18]  J.P. Tolson, T. Flad, V. Gnau, H. Dihazi, J. Hennenlotter, A. Beck, G.A. Mueller, M. Kuczyk, C.A. Mueller, Differential detection of S100A8 in transitional cell carcinoma of the bladder by pair wise tissue proteomic and immunohistochemical analysis, Proteomics, 6 (2006) 697-708.
[19]  C.L. Chen, Y.F. Lai, P. Tang, K.Y. Chien, J.S. Yu, C.H. Tsai, H.W. Chen, C.C. Wu, T. Chung, C.W. Hsu, C.D. Chen, Y.S. Chang, P.L. Chang, Y.T. Chen, Comparative and targeted proteomic analyses of urinary microparticles from bladder cancer and hernia patients, Journal of proteome research, 11 (2012) 5611-5629.
[20]  N. Bansal, A.K. Gupta, A. Gupta, S.N. Sankhwar, A.A. Mahdi, Serum-based protein biomarkers of bladder cancer: A pre- and post-operative evaluation, Journal of pharmaceutical and biomedical analysis, 124 (2016) 22-25.
[21]  J. Bi, X. Chen, Y. Zhang, B. Li, J. Sun, H. Shen, C. Kong, Fascin is a predictor for invasiveness and recurrence of urothelial carcinoma of bladder, Urologic oncology, 30 (2012) 688-694.
[22]  S.F. Shariat, R. Ashfaq, P.I. Karakiewicz, O. Saeedi, A.I. Sagalowsky, Y. Lotan, Survivin expression is associated with bladder cancer presence, stage, progression, and mortality, Cancer, 109 (2007) 1106-1113.
[23]  J.W. Choi, Y. Kim, J.H. Lee, Y.S. Kim, Prognostic significance of lactate/proton symporters MCT1, MCT4, and their chaperone CD147 expressions in urothelial carcinoma of the bladder, Urology, 84 (2014) 245 e249-215.
[24]  H. Li, Y. Xu, CD147 as a novel biomarker for predicting the prognosis and clinicopathological features of bladder cancer: a meta-analysis, Oncotarget, 8 (2017) 62573-62588.
[25]  B.V. Offersen, M.M. Knap, M.R. Horsman, J. Verheijen, R. Hanemaaijer, J. Overgaard, Matrix metalloproteinase-9 measured in urine from bladder cancer patients is an independent prognostic marker of poor survival, Acta Oncol, 49 (2010) 1283-1287.
[26]  V. Pozzi, G. Di Ruscio, D. Sartini, R. Campagna, R. Seta, P. Fulvi, A. Vici, G. Milanese, G. Brandoni, A.B. Galosi, R. Montironi, M. Cecati, M. Emanuelli, Clinical performance and utility of a NNMT-based urine test for bladder cancer, The International journal of biological markers, (2017) 0.
[27]  N. Yang, S. Feng, K. Shedden, X. Xie, Y. Liu, C.J. Rosser, D.M. Lubman, S. Goodison, Urinary glycoprotein biomarker discovery for bladder cancer detection using LC/MS-MS and label-free quantification, Clinical cancer research : an official journal of the American Association for Cancer Research, 17 (2011) 3349-3359.
[28]  M. Miyake, S. Ross, A. Lawton, M. Chang, Y. Dai, L. Mengual, A. Alcaraz, E.G. Giacoia, S. Goodison, C.J. Rosser, Investigation of CCL18 and A1AT as potential urinary biomarkers for bladder cancer detection, BMC urology, 13 (2013) 42.
[29]  Y.T. Chen, C.L. Chen, H.W. Chen, T. Chung, C.C. Wu, C.D. Chen, C.W. Hsu, M.C. Chen, K.H. Tsui, P.L. Chang, Y.S. Chang, J.S. Yu, Discovery of novel bladder cancer biomarkers by comparative urine proteomics using iTRAQ technology, Journal of proteome research, 9 (2010) 5803-5815.
[30]  D. Bhagirath, N. Abrol, R. Khan, M. Sharma, A. Seth, A. Sharma, Expression of CD147, BIGH3 and Stathmin and their potential role as diagnostic marker in patients with urothelial carcinoma of the bladder, Clinica chimica acta; international journal of clinical chemistry, 413 (2012) 1641-1646.
[31]  B. Nisman, V. Barak, A. Shapiro, D. Golijanin, T. Peretz, D. Pode, Evaluation of urine CYFRA 21-1 for the detection of primary and recurrent bladder carcinoma, Cancer, 94 (2002) 2914-2922.
[32]  M. Sanchez-Carbayo, A. Espasa, V. Chinchilla, E. Herrero, J. Megias, A. Mira, F. Soria, New electrochemiluminescent immunoassay for the determination of CYFRA 21-1: analytical evaluation and clinical diagnostic performance in urine samples of patients with bladder cancer, Clinical chemistry, 45 (1999) 1944-1953.
[33]  S. Eissa, R.A. Labib, M.S. Mourad, K. Kamel, O. El-Ahmady, Comparison of telomerase activity and matrix metalloproteinase-9 in voided urine and bladder wash samples as a useful diagnostic tool for bladder cancer, European urology, 44 (2003) 687-694.
[34]  H. Liu, MicroRNAs in breast cancer initiation and progression, Cellular and molecular life sciences : CMLS, 69 (2012). 3587-3599.
[35]  S.P. Nana-Sinkam, C.M. Croce, MicroRNA regulation of tumorigenesis, cancer progression and interpatient heterogeneity: towards clinical use, Genome biology, 15 (2014) 445.
[36]  Z. Chen, L. Wu, Q. Lin, J. Shi, X. Lin, L. Shi, Evaluation of miR-182/miR-100 Ratio for Diagnosis and Survival Prediction in Bladder Cancer, Archives of Iranian medicine, 19 (2016) 645-651.
[37]  X. Jiang, L. Du, L. Wang, J. Li, Y. Liu, G. Zheng, A. Qu, X. Zhang, H. Pan, Y. Yang, C. Wang, Serum microRNA expression signatures identified from genome-wide microRNA profiling serve as novel noninvasive biomarkers for diagnosis and recurrence of bladder cancer, International journal of cancer, 136 (2015) 854-862.
[38]  M. Hanke, K. Hoefig, H. Merz, A.C. Feller, I. Kausch, D. Jocham, J.M. Warnecke, G. Sczakiel, A robust methodology to study urine microRNA as tumor marker: microRNA-126 and microRNA-182 are related to urinary bladder cancer, Urologic oncology, 28 (2010) 655-661.
[39]  Y. Yamada, H. Enokida, S. Kojima, K. Kawakami, T. Chiyomaru, S. Tatarano, H. Yoshino, K. Kawahara, K. Nishiyama, N. Seki, M. Nakagawa, MiR-96 and miR-183 detection in urine serve as potential tumor markers of urothelial carcinoma: correlation with stage and grade, and comparison with urinary cytology, Cancer science, 102 (2011). 522-529.
[40]  M.F. Sarosdy, The use of the BTA Test in the detection of persistent or recurrent transitional-cell cancer of the bladder, World journal of urology, 15 (1997) 103-106.
[41]  D. Pode, A. Shapiro, M. Wald, O. Nativ, M. Laufer, I. Kaver, Noninvasive detection of bladder cancer with the BTA stat test, The Journal of urology, 161 (1999) 443-446.
[42]  V. Poulakis, U. Witzsch, R. De Vries, H.M. Altmannsberger, M.J. Manyak, E. Becht, A comparison of urinary nuclear matrix protein-22 and bladder tumour antigen tests with voided urinary cytology in detecting and following bladder cancer: the prognostic value of false-positive results, BJU international, 88 (2001). 692-701.
[43]  R. Pichler, G. Tulchiner, J. Fritz, G. Schaefer, W. Horninger, I. Heidegger, Urinary UBC Rapid and NMP22 Test for Bladder Cancer Surveillance in Comparison to Urinary Cytology: Results from a Prospective Single-Center Study, International journal of medical sciences, 14 (2017) 811-819.
[44]  P. Kumar, S. Nandi, T.Z. Tan, S.G. Ler, K.S. Chia, W.Y. Lim, Z. Butow, D. Vordos, A. De la Taille, M. Al-Haddawi, M. Raida, B. Beyer, E. Ricci, M. Colombel, T.W. Chong, E. Chiong, R. Soo, M.K. Park, H.K. Ha, J. Gunaratne, J.P. Thiery, Highly sensitive and specific novel biomarkers for the diagnosis of transitional bladder carcinoma, Oncotarget, 6 (2015) 13539-13549.