Abstract
Purpose
The aims of this study were to investigate the expression levels of proteins involved in cell cycle regulation in specimens of bladder cancer and to correlate them with the clinicopathological characteristics, proliferative activity and survival.
Methods
Eighty-two specimens obtained from patients affected by muscle-invasive bladder cancer were evaluated immunohistochemically for p53, p21 and cyclin D1 expression, as well as for the tumour proliferation index, Ki-67. The statistical analysis included Kaplan–Meier curves with log-rank test and Cox proportional hazards models.
Results
In univariate analyses, low Ki-67 proliferation index (P = 0.045) and negative p21 immunoreactivity (P = 0.04) were associated to patient’s overall survival (OS), but in multivariate models p21 did not reach statistical significance. When the combinations of the variables were assessed in two separate multivariate models that included tumour stage, grading, lymph node status, vascular invasion and perineural invasion, the combined variables p21/Ki-67 or p21/cyclin D1 expression were independent predictors for OS; in particular, patients with positive p21/high Ki-67 (P = 0.015) or positive p21/negative cyclin D1 (P = 0.04) showed the worst survival outcome.
Conclusions
Important alterations in the cell cycle regulatory pathways occur in muscle-invasive bladder cancer and the combined use of cell cycle regulators appears to provide significant prognostic information that could be used to select the patients most suitable for multimodal therapeutic approaches.
Similar content being viewed by others
References
Ather MH, Fatima S, Sinanoglu O (2005) Extent of lymphadenectomy in radical cystectomy for bladder cancer. World J Surg Oncol 3:43
Baretton GB, Klenk U, Diebold J, Schmeller N, Löhrs U (1999) Proliferation- and apoptosis-associated factors in advanced prostatic carcinomas before and after androgen deprivation therapy: prognostic significance of p21/WAF1/CIP1 expression. Br J Cancer 80:546–555
Clasen S, Schulz WA, Gerharz CD, Grimm MO, Christoph F, Schmitz-Drager BJ (1998) Frequent and heterogeneous expression of cyclin-dependent kinase inhibitor WAF1/p21 protein and mRNA in urothelial carcinoma. Br J Cancer 77:515–521
Cox DR (1972) Regression models and life tables. J R Stat Soc Ser B 34:187–220
Donnellan R, Chetty R (1998) Cyclin D1 and human neoplasia. J Clin Pathol: Mol Pathol 51:1–7
Epstein JI, Armin Mb, Reuter VR, Mostofi FK (1998) The bladder consensus conference committee: the World Health Organization/International Society of Urological Pathology consensus classification of urothelial (transitional cell) neoplasm of the urinary bladder. Am J Surg Pathol 22:1435–1448
Esrig D, Elmajian D, Groshen S, Freeman JA, Stein JP, Chen SC, et al (1994) Accumulation of nuclear p53 and tumor progression in bladder cancer. N Engl J Med 331:1259–1264
Garcia del Muro X, Condom E, Vigués F, Castellsagué X, Figueras A, Munoz J, et al (2004) p53 and p21 expression levels predict organ preservation and survival in invasive bladder carcinoma treated with a combined-modality approach. Cancer 100:1859–1867
Harrington EA, Bruce JL, Harlow E, Dyson N (1998) pRB plays an essential role in cell cycle arrest induced by DNA damage. Proc Natl Acad Sci USA 95:11945–11950
Jahnson S, Karlsson MG (2000) Tumor mapping of regional immunostaining for p21, p53 and mdm2 in locally advanced bladder carcinoma. Cancer 89:619–629
Kaplan EL, Meier P (1958) Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457–481
Knowles MA (2006) Molecular subtypes of bladder cancer: Jekyll and Hyde or chalk and cheese? Carcinogenesis 27:361–373
Malats N, Bustos A, Nascimento CM, Fernandez F, Rivas M, Puente D, et al (2005) p53 as a prognostic marker for bladder cancer: a meta-analysis and review. Lancet Oncol 6:678–686
Nemes JA, Nemes Z, Márton IJ (2005) p21WAF1/CIP1 expression is a marker of poor prognosis in oral squamous cell carcinoma. J Oral Pathol Med 34:274–279
Niehans GA, Kratzke RA, Froberg MK, Aeppli DM, Nguyen PL, Geradts J (1999) G1 checkpoint protein and p53 abnormalities occur in most invasive transitional cell carcinomas of the urinary bladder. Br J Cancer 80:1175–1184
Osen I, Fossa SD, Majak B, Rotterud R, Berner A (1998) Prognostic factors in muscle-invasive bladder cancer treated with radiotherapy: an immunohistochemical study. Br J Urol 81:862–869
Peto R, Pike MC, Armitage P, Breslow NE, Cox DR, Howard SV, et al (1977) Design and analysis of randomised clinical trials requiring prolonged observation of each patient: II. Analysis and examples. Br J Cancer 35:1–39
Popov Z, Hoznek A, Colombel M, Bastuji-Garin S, Lefrere-Belda MA, Bellot J, et al (1997) The prognostic value of p53 nuclear over-expression and MIB-1 as a proliferative marker in transitional cell carcinoma of the bladder. Cancer 80:1472–1481
Primdahl H, von der Maase H, Sørensen FB, Wolf H, Ørntoft TF (2002) Immunohistochemical study of the expression of cell cycle regulating proteins at different stages of bladder cancer. J Cancer Res Clin Oncol 128:295–301
Qureshi KN, Griffiths TRL, Robinson MC, Marsh C, Roberts JT, et al (2001) Combined p21WAF1/CIP1 and p53 over-expression predict improved survival in muscle-invasive bladder cancer treated by radical radiotherapy. Int J Radiat Oncol Biol Phys 51:1234–1240
Roedel C, Grabenbauer GG, Roedel F, Birkenhake S, Kuehn R, Martus P, et al (2000) Apoptosis, p53, Bcl-2, and Ki-67 in invasive bladder carcinoma: possible predictors for response to radiochemotherapy and successful bladder preservation. Int J Radiat Oncol Biol Phys 46:1213–1221
Ruggeri EM, Giannarelli D, Bria E, Carlini P, Felici A, Nelli F, et al (2006) Adjuvant chemotherapy in muscle-invasive bladder carcinoma: a pooled analysis from phase III studies. Cancer 106:783–788
Shariat SF, Kim J, Raptidis G, Ayala GE, Lerner SP (2003) Association of p53 and p21 expression with clinical outcome in patients with carcinoma in situ of the urinary bladder. Urology 61:1140–1145
Shariat SF, Tokunaga H, Zhou J, Kim J, Ayala GE, Benedict WF, Lerner SP (2004) p53, p21, pRB, and p16 expression predict clinical outcome in cystectomy with bladder cancer. J Clin Oncol 22:1014–1024
Sherr CJ, Roberts JM (1999) CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev 13:1501–1512
Stein JP, Ginsberg DA, Grossfeld GD, Chatterjee SJ, Esrig D, Dickinson MG, et al (1998) Effect of p21WAF1/CIP1 expression on tumour progression in bladder cancer. J Natl Cancer Inst 90:1072–1079
Stein JP, Lieskovsky G, Cote R, Groshen S, Feng AC, Boyd S, et al (2001) Radical cystectomy in the treatment of invasive bladder cancer: long term results in 1054 patients. J Clin Oncol 19:666–675
Tut VM, Braithwaite KL, Angus B, Neal DE, Lunec J, Mellon JK (2001) Cyclin D1 expression in transitional cell carcinoma of the bladder: correlation with p53, waf1, pRb and Ki67. Br J Cancer 84:270–275
Vale C for the Advanced Bladder Cancer (ABC) Overview Collaboration (2003) Neoadjuvant chemotherapy in invasive bladder cancer: a systematic review and meta-analysis. Lancet 361:1927–1934
Acknowledgement
We thank Simona Barozzi for her assistance with this manuscript.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Galmozzi, F., Rubagotti, A., Romagnoli, A. et al. Prognostic value of cell cycle regulatory proteins in muscle-infiltrating bladder cancer. J Cancer Res Clin Oncol 132, 757–764 (2006). https://doi.org/10.1007/s00432-006-0123-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00432-006-0123-7