Prognostic significance of apoptotic cell death in bladder cancer: a tissue microarray study on 179 urothelial carcinomas from cystectomy specimens

Aims: To assess the prognostic significance of apoptosis related markers in bladder cancer. Methods: A tissue microarray containing 179 bladder carcinomas from cystectomy specimens was analysed immunohistochemically for active caspase‐3, single‐stranded DNA (ssDNA), p53, Bcl‐2, Bax, and COX‐2, in correlation to clinicopathological factors. Results: Active caspase‐3, ssDNA, p53, Bax and COX‐2 were more frequently observed among high grade and higher stage (≥T2) carcinomas compared with low grade and lower stage (T1) tumours. On the contrary, Bcl‐2 was more frequently detected in T1 than in ≥T2 carcinomas. Active caspase‐3 correlated with a better survival of the patients. Conclusions: The decreased detection of active caspase‐3 and ssDNA and the increased presence of Bcl‐2 in T1 carcinomas suggest that alterations in interrelated apoptosis markers may play an important role in the progression of urothelial carcinoma from a superficially infiltrating to a muscle invading tumour and would help to better characterise a subpopulation of T1 carcinomas that could profit from early cystectomy or more aggressive adjuvant chemotherapy. Active caspase‐3 might be an important prognostic factor in bladder cancer.

[1]  C. Roehrborn,et al.  Use of combined apoptosis biomarkers for prediction of bladder cancer recurrence and mortality after radical cystectomy. , 2007, The Lancet. Oncology.

[2]  B. Tharakan,et al.  Current concepts in apoptosis: The physiological suicide program revisited , 2006, Cellular & Molecular Biology Letters.

[3]  E. Messing,et al.  Prognostic markers for bladder cancer: International Consensus Panel on bladder tumor markers. , 2005, Urology.

[4]  Anirban P. Mitra,et al.  Molecular staging of bladder cancer , 2005, BJU international.

[5]  K. Williamson,et al.  Apoptosis and chemotherapy for bladder cancer. , 2005, The Journal of urology.

[6]  I. Sesterhenn,et al.  World health organization classifications of tumours. pathology and genetics of tumours of the urinary system and male genital organs , 2005 .

[7]  Fatima S. Khwaja,et al.  The p75NTR tumor suppressor induces caspase‐mediated apoptosis in bladder tumor cells , 2003, International journal of cancer.

[8]  E. Blomme,et al.  Comparison of immunohistochemistry for activated caspase‐3 and cleaved cytokeratin 18 with the TUNEL method for quantification of apoptosis in histological sections of PC‐3 subcutaneous xenografts , 2003, The Journal of pathology.

[9]  S. Korsmeyer,et al.  c-Myc Functionally Cooperates with Bax To Induce Apoptosis , 2002, Molecular and Cellular Biology.

[10]  H. Moch,et al.  Tissue microarrays for rapid linking of molecular changes to clinical endpoints. , 2001, The American journal of pathology.

[11]  S. Akiba,et al.  Relation between cyclooxygenase‐2 expression and tumor invasiveness and patient survival in transitional cell carcinoma of the urinary bladder , 2001, Cancer.

[12]  G. Evan,et al.  Proliferation, cell cycle and apoptosis in cancer , 2001, Nature.

[13]  Colin Adrain,et al.  Executioner Caspase-3, -6, and -7 Perform Distinct, Non-redundant Roles during the Demolition Phase of Apoptosis* , 2001, The Journal of Biological Chemistry.

[14]  S. Diaz-Cano,et al.  Molecular and kinetic features of transitional cell carcinomas of the bladder: biological and clinical implications , 2001, Virchows Archiv.

[15]  T. Ebert,et al.  p53 Immunohistochemistry as a Prognostic Marker in Bladder Cancer , 2000, European Urology.

[16]  C. Anderson,et al.  Caspase 3 and p27 as predictors of invasive bladder cancer. , 2000, The New England journal of medicine.

[17]  J C Reed,et al.  Mechanisms of apoptosis. , 2000, The American journal of pathology.

[18]  P. Korkolopoulou,et al.  Apoptosis in bladder carcinomas detected with monoclonal antibody to single-stranded DNA: relation to cell cycle regulators and survival. , 2000, Urology.

[19]  Y. Lazebnik,et al.  Caspases: enemies within. , 1998, Science.

[20]  V. Cryns,et al.  Proteases to die for. , 1998, Genes & development.

[21]  S. Nagata,et al.  A caspase-activated DNase that degrades DNA during apoptosis, and its inhibitor ICAD , 1998, Nature.

[22]  L. Howell,et al.  Relationship of p53 and bcl-2 to prognosis in muscle-invasive transitional cell carcinoma of the bladder. , 1996, The Journal of urology.

[23]  F. Waldman,et al.  p53 but not erbB-2 expression is associated with rapid tumor proliferation in urinary bladder cancer. , 1994, Human pathology.

[24]  S C Chen,et al.  Accumulation of nuclear p53 and tumor progression in bladder cancer. , 1994, The New England journal of medicine.

[25]  P. Lipponen,et al.  Apoptosis in bladder cancer as related to standard prognostic factors and prognosis , 1994, The Journal of pathology.

[26]  L. Marnett,et al.  Prostaglandin and thromboxane biosynthesis. , 1991, Pharmacology & therapeutics.