Apoptosis in bladder carcinomas detected with monoclonal antibody to single-stranded DNA: relation to cell cycle regulators and survival.
OBJECTIVE
To investigate the incidence of baseline apoptosis in relation to p27(Kip1), p53, and p21(Cip1) expression, proliferation status, standard clinicopathologic parameters, and patient outcome. Cell cycle regulators and apoptotic cell death have been implicated in tumor aggressiveness in many human malignancies. Their interaction, however, in the prognosis of patients with transitional cell carcinoma (TCC) of the urinary bladder has not yet received intense scrutiny.


METHODS
Apoptotic fractions were quantified immunohistochemically by means of a novel monoclonal antibody recognizing single-stranded DNA regions in apoptotic nuclei in 103 paraffin-embedded primary TCC specimens. Proliferative activity was expressed as the percentage of Ki-67 positive cells (Ki-67 index). Tissue specimens were also stained for p27(Kip1), p53, and p21(Cip1) proteins. Patients were followed up until death (n = 30) or for an average of 40 months (median 36).


RESULTS
The apoptotic index increased with grade, T stage, nonpapillary status, proliferative activity, and p53 expression and was inversely related to p27(Kip1) and independently to p21(Cip1) expression. A negative correlation was found between p27(Kip1) expression and proliferation. The increased apoptotic index had an adverse impact on overall and disease-free survival (univariate analysis) and, along with T stage, was an independent predictor in muscle-invasive TCC.


CONCLUSIONS
An increased apoptotic rate, increased proliferative activity, and decreased p21(Cip1) expression are independently interrelated in TCC. More importantly, the assessment of apoptotic potential appears to be more informative than standard prognosticators in predicting overall survival in patients with muscle-invasive TCC.
Korkolopoulou
P
P
Department of Pathology, National University of Athens, Athens, Greece.
Konstantinidou
A E
AE
Christodoulou
P
P
Patsouris
E
E
Thomas-Tsangli
E
E
Kapralos
P
P
Davaris
P
P
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000704:Analysis of Variance; D000911:Antibodies, Monoclonal; D017209:Apoptosis; D002295:Carcinoma, Transitional Cell / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D018797:Cell Cycle Proteins; D002455:Cell Division; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016213:Cyclins / Q000378:metabolism*; D053938:DNA Fragmentation; D004277:DNA, Single-Stranded / Q000032:analysis*; D005260:Female; D006801:Humans; D008297:Male; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000032:analysis*; D016019:Survival Analysis; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D025521:Tumor Suppressor Proteins; D001749:Urinary Bladder Neoplasms / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*
D000911:Antibodies, Monoclonal; C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004277:DNA, Single-Stranded; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27