The current basis for diagnosis and prognosis in urinary bladder cancer is based on the pathologists' assessment of a biopsy of the tumour. Urinary biomarkers are preferable as they can be non-invasively sampled. Urinary cytology is the only test with widespread use but is hampered by poor reproducibility and low sensitivity.
By studying the protein expression in bladder tumour tissue samples of proteins previously found in elevated levels in the urine of patients with bladder cancer, we have been able to show that these proteins originate from the tumour. The immunoreactivity of three of the investigated proteins increased with higher stage. Also a serine peptidase inhibitor was found to be predictive of progression from non-muscle-invasive to muscle-invasive tumours.

Objectives

To analyse the expression of five bladder cancer-associated urinary proteins and investigate if expression is related to the malignant phenotype of the tumour.
To explore the possible prognostic value of these proteins.

Patients and Methods

Urine samples, 16 from patients with bladder cancer and 26 from controls, were used in Western Blotting experiments.
Tissue microarrays with bladder tissue from 344 patients diagnosed with bladder cancer between 1984 and 2005 was used in immunohistochemistry experiments.
The proteins apolipoprotein E (APOE), fibrinogen β chain precursor (FGB), leucine-rich α2-glycoprotein (LRG1), polymerase (RNA) I polypeptide E (POLR1E), α1-antitrypsin (SERPINA1) and topoisomerase 2A (TOP2A) were probed with antibodies validated by the Human Protein Atlas.

Results

Increased expressions of APOE, FGB and POLR1E were correlated with increased tumour stage (P < 0.001).
Expression of SERPINA1 in Ta and T1 tumours was found to increase the risk of tumour progression (hazard ratio 2.57, 95% confidence interval 1.13–5.87; P = 0.025)

Conclusions

All proteins previously detected in urine from patients with bladder cancer were also expressed in bladder cancer tissue.
The expression of APOE, FGB and POLR1E increased with stage and they are potential diagnostic markers.
SERPINA1 was identified as a prognostic marker candidate.

References

1 Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 2010; 127: 2893–2917
10.1002/ijc.25516
CASPubMedWeb of Science®Google Scholar
2 Linden M, Lind SB, Mayrhofer C et al. Proteomic analysis of urinary biomarker candidates for nonmuscle invasive bladder cancer. Proteomics 2012; 12: 135–144
10.1002/pmic.201000810
CASPubMedWeb of Science®Google Scholar
3 Major AS, Joyce S, Van Kaer L. Lipid metabolism, atherogenesis and CD1-restricted antigen presentation. Trends Mol Med 2006; 12: 270–278
10.1016/j.molmed.2006.04.004
CASPubMedWeb of Science®Google Scholar
4 Videira PA, Calais FM, Correia M et al. Efficacy of bacille Calmette-Guerin immunotherapy predicted by expression of antigen-presenting molecules and chemokines. Urology 2009; 74: 944–950
10.1016/j.urology.2009.02.053
PubMedWeb of Science®Google Scholar
5 Petrache I, Fijalkowska I, Medler TR et al. alpha-1 antitrypsin inhibits caspase-3 activity, preventing lung endothelial cell apoptosis. Am J Pathol 2006; 169: 1155–1166
10.2353/ajpath.2006.060058
CASPubMedWeb of Science®Google Scholar
6 Palumbo JS, Kombrinck KW, Drew AF et al. Fibrinogen is an important determinant of the metastatic potential of circulating tumor cells. Blood 2000; 96: 3302–3309
10.1182/blood.V96.10.3302
CASPubMedWeb of Science®Google Scholar
7 Sahni A, Simpson-Haidaris PJ, Sahni SK, Vaday GG, Francis CW. Fibrinogen synthesized by cancer cells augments the proliferative effect of fibroblast growth factor-2 (FGF-2). J Thromb Haemost 2008; 6: 176–183
10.1111/j.1538-7836.2007.02808.x
CASPubMedWeb of Science®Google Scholar
8 Drygin D, Rice WG, Grummt I. The RNA polymerase I transcription machinery: an emerging target for the treatment of cancer. Annu Rev Pharmacol Toxicol 2010; 50: 131–156
10.1146/annurev.pharmtox.010909.105844
CASPubMedWeb of Science®Google Scholar
9 Lynch J, Fay J, Meehan M et al. MiRNA-335 suppresses neuroblastoma cell invasiveness by direct targeting of multiple genes from the non-canonical TGF-beta signalling pathway. Carcinogenesis 2012; 33: 976–985
10.1093/carcin/bgs114
CASPubMedWeb of Science®Google Scholar
10 Kim EJ, Lee YS, Kim YJ et al. Clinical implications and prognostic values of topoisomerase-II alpha expression in primary non-muscle-invasive bladder cancer. Urology 2010; 75: 1516 e9–13
10.1016/j.urology.2009.08.055
Web of Science®Google Scholar
11 Koren R, Kugel V, Dekel Y, Weissman Y, Livne PM, Gal R. Human DNA topoisomerase-IIalpha expression as a prognostic factor for transitional cell carcinoma of the urinary bladder. BJU Int 2003; 91: 489–492
10.1046/j.1464-410X.2003.04118.x
CASPubMedWeb of Science®Google Scholar
12 Simon R, Atefy R, Wagner U et al. HER-2 and TOP2A coamplification in urinary bladder cancer. Int J Cancer 2003; 107: 764–772
10.1002/ijc.11477
CASPubMedWeb of Science®Google Scholar
13 Kononen J, Bubendorf L, Kallioniemi A et al. Tissue microarrays for high-throughput molecular profiling of tumor specimens. Nat Med 1998; 4: 844–847
10.1038/nm0798-844
CASPubMedWeb of Science®Google Scholar
14 Sauter G, Algaba F, Amin M et al. Non invasive Urothelial Neoplasias; WHO Classification of Non invasive Papillary Urothelial Tumours, 1st edn. JN Eble, G Sauter, J Epstein, I Sesterhenn eds, Lyon: WHO, 2004
Google Scholar
15 Segersten MU, Edlund EK, Micke P et al. A novel strategy based on histological protein profiling in-silico for identifying potential biomarkers in urinary bladder cancer. BJU Int 2009; 104: 1780–1785
10.1111/j.1464-410X.2009.08674.x
CASPubMedWeb of Science®Google Scholar
16 Busch C, Malmstrom PU, Norlen BJ, Sallstrom J, Brodin T, Lundblad A. A grading system for the immunostaining of A, B and H blood group isoantigens in bladder carcinoma. Anticancer Res 1988; 8: 81–87
CASPubMedWeb of Science®Google Scholar
17 Chen YC, Pohl G, Wang TL et al. Apolipoprotein E is required for cell proliferation and survival in ovarian cancer. Cancer Res 2005; 65: 331–337
10.1158/0008-5472.331.65.1
CASPubMedWeb of Science®Google Scholar
18 Martinez-Pineiro JA, Pertusa C, Maganto E et al. Urinary fibrinogen degradation products (FDP) in bladder cancer. Eur Urol 1978; 4: 348–350
CASPubMedWeb of Science®Google Scholar
19 Mizutani Y, Nio Y, Fukumoto M, Yoshida O. Enhanced antitumor effect of Bacillus Calmette-Guerin in combination with fibrinogen on urinary bladder tumor. J Urol 1994; 151: 1420–1426
10.1016/S0022-5347(17)35272-2
CASPubMedWeb of Science®Google Scholar
20 Lynch J, Fay J, Meehan M et al. MiRNA-335 suppresses neuroblastoma cell invasiveness by direct targeting of multiple genes from the non-canonical TGF-β signalling pathway. Carcinogenesis 2012; 33: 976–985
10.1093/carcin/bgs114
CASPubMedWeb of Science®Google Scholar
21 Sun D, Kar S, Carr BI. Differentially expressed genes in TGF-beta 1 sensitive and resistant human hepatoma cells. Cancer Lett 1995; 89: 73–79
10.1016/0304-3835(94)03652-Y
CASPubMedWeb of Science®Google Scholar
22 The Protein Atlas [database on the Internet]. The Protein Atlas Project 2012; Available at: http://www.proteinatlas.org Accessed September 2012
Google Scholar
23 Hannan KM, Kennedy BK, Cavanaugh AH et al. RNA polymerase I transcription in confluent cells: Rb downregulates rDNA transcription during confluence-induced cell cycle arrest. Oncogene 2000; 19: 3487–3497
10.1038/sj.onc.1203690
CASPubMedWeb of Science®Google Scholar
24 Hanada K, Song CZ, Yamamoto K et al. RNA polymerase I associated factor 53 binds to the nucleolar transcription factor UBF and functions in specific rDNA transcription. EMBO J 1996; 15: 2217–2226
10.1002/j.1460-2075.1996.tb00575.x
CASPubMedWeb of Science®Google Scholar
25 Seither P, Zatsepina O, Hoffmann M, Grummt I. Constitutive and strong association of PAF53 with RNA polymerase I. Chromosoma 1997; 106: 216–225
10.1007/s004120050242
CASPubMedWeb of Science®Google Scholar
26 Farshchian M, Kivisaari A, Ala-Aho R et al. Serpin peptidase inhibitor clade A member 1 (SerpinA1) is a novel biomarker for progression of cutaneous squamous cell carcinoma. Am J Pathol 2011; 179: 1110–1119
10.1016/j.ajpath.2011.05.012
CASPubMedWeb of Science®Google Scholar
27 Normandin K, Peant B, Le Page C et al. Protease inhibitor SERPINA1 expression in epithelial ovarian cancer. Clin Exp Metastasis 2010; 27: 55–69
10.1007/s10585-009-9303-6
CASPubMedWeb of Science®Google Scholar
28 Fristrup N, Ulhoi BP, Birkenkamp-Demtroder K et al. Cathepsin e, maspin, plk1, and survivin are promising prognostic protein markers for progression in non-muscle invasive bladder cancer. Am J Pathol 2012; 180: 1824–1834
10.1016/j.ajpath.2012.01.023
CASPubMedWeb of Science®Google Scholar

Citing Literature

Volume112, Issue3

August 2013

Pages 407-415

Tumour expression of bladder cancer-associated urinary proteins

Abstract

What's known on the subject? and What does the study add?

Objectives

Patients and Methods

Results

Conclusions

References

Citing Literature

References

Information

About Wiley Online Library

Help & Support

Opportunities

Connect with Wiley

Tumour expression of bladder cancer-associated urinary proteins

Abstract

What's known on the subject? and What does the study add?

Objectives

Patients and Methods

Results

Conclusions

References

Citing Literature

References

Related

Information