Expression of cyclooxygenase-2 in normal urothelium, and superficial and advanced transitional cell carcinoma of bladder.
OBJECTIVE
We compared the differential expression of cyclooxygenase-2 in normal bladder tissue, primary bladder transitional cell carcinoma and transitional cell carcinoma metastases to lymph nodes, and determined whether cyclooxygenase-2 expression is associated with molecular alterations commonly found in bladder transitional cell carcinoma and clinical outcomes after radical cystectomy.


METHODS
Immunohistochemical staining for cyclooxygenase-2, survivin (Novus Biologicals, Littleton, Colorado), p21, p27, pRB, p53, MIB-1, Bax, Bcl-2, cyclin D(1) (Dakotrade mark), cyclin E (Oncogene, Cambridge, Massachusetts) and caspase-3 (Cell Signaling, Beverley, Massachusetts) was performed on archival bladder specimens from 9 subjects who underwent cystectomy for benign causes, 21 patients who underwent transurethral resection and 157 consecutive patients after radical cystectomy, and on 41 positive lymph nodes.


RESULTS
Cyclooxygenase-2 was expressed in none of the 9 normal bladder specimens (0%), 52% of transurethral resection specimens, 62% of cystectomy specimens and 80% of lymph nodes involved with transitional cell carcinoma. Cyclooxygenase-2 expression was associated with higher pathological stage, lymphovascular invasion and metastases to lymph nodes (p=0.001, 0.045 and 0.002, respectively). Cyclooxygenase-2 expression was associated with altered expression of p53 (p=0.039), pRB (p=0.025), cyclin D1 (p=0.034) and caspase-3 (p=0.014). On univariate analysis cyclooxygenase-2 expression was associated with an increased risk of disease recurrence and bladder cancer specific mortality (p=0.0189 and 0.0472, respectively). However, on multivariate analysis only pathological stage and metastases to lymph nodes were associated with disease recurrence (p<0.001 and <0.001) and survival (p<0.001 and 0.015, respectively).


CONCLUSIONS
Cyclooxygenase-2 is not expressed in normal bladder urothelium. Cyclooxygenase-2 over expression is associated with pathological and molecular features of biologically aggressive disease, suggesting a role for cyclooxygenase-2 in bladder cancer development and invasion.
Margulis
Vitaly
V
Department of Urology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-9110, USA.
Shariat
Shahrokh F
SF
Ashfaq
Raheela
R
Thompson
Melissa
M
Sagalowsky
Arthur I
AI
Hsieh
Jer-Tsong
JT
Lotan
Yair
Y
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D002295:Carcinoma, Transitional Cell / Q000201:enzymology* / Q000556:secondary; D016022:Case-Control Studies; D018797:Cell Cycle Proteins / Q000378:metabolism; D015331:Cohort Studies; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D001749:Urinary Bladder Neoplasms / Q000201:enzymology* / Q000473:pathology; D019459:Urothelium / Q000201:enzymology*
D051017:Apoptosis Regulatory Proteins; D018797:Cell Cycle Proteins; D051546:Cyclooxygenase 2