Cyclooxygenase‐2 promotes angiogenesis in pTa/T1 urothelial bladder carcinoma but does not predict recurrence

Abstract

OBJECTIVE To investigate the effect of cyclooxygenase‐2 (COX‐2) on microvessel density (MVD) and on the clinical prognosis in patients with non‐muscle invasive urothelial carcinoma of the bladder, as COX‐2 expression is significantly greater in epithelial tumours and there is increasing evidence that COX‐2 might contribute to tumour neovascularization. PATIENTS AND METHODS We assessed tumour samples from 110 patients undergoing transurethral resection for primary pTa/pT1 bladder carcinoma (pTa, 84; pT1, 26; grade 1, 22; grade 2, 81; grade 3, seven). Paraffin sections were assessed immunohistochemically using antibodies against COX‐2, CD34 (endothelial cells) and CD105 (proliferating vessels). COX‐2 expression was quantified by the number of stained cells (negative, +, ++) and the MVD calculated as vessels per field. RESULTS Of the 110 tumours, 45 (41%) had no immunostaining for COX‐2, 40 had faint staining with at least isolated positive cells (+) and 25 stained ++. COX‐2 positive tumours had significantly greater vascularization for proliferating vessels. In COX‐2 negative tumours the MVD was 22.1, identified by CD34 immunostaining, and 3.4 for proliferating vessels (CD105), whereas COX‐2 positive tumours had a MVD of 18.3 (CD34), and of 5.8, respectively (CD105). Complete follow‐up data were available in 91 patients; after a mean follow‐up of 25 months, 18 (20%) had tumour recurrences. There was no significant difference in the recurrence rates or disease‐free survival between COX‐2‐positive (19%, 25.6 months) or ‐negative patients (21%, 25.2 months). CONCLUSION These results confirm the involvement of COX‐2 in angiogenesis in bladder cancer, as COX‐2 promoted blood vessel proliferation in the tumour zone, and indicate the usefulness of COX‐2‐inhibiting drugs in preventing and treating superficial bladder cancer.

Cyclooxygenase-2 Expression in Bladder Cancer and Patient Prognosis: Results from a Large Clinical Cohort and Meta-Analysis

“…Other groups have reported frequencies ranging from 53–88%; however, these studies used different COX2 antibodies and expression evaluation techniques and had smaller sample sizes [16], [28], [29], [45], [46]. In accordance with reported results [11], [18], [45] we observed significantly higher COX2 expression in MIBCs (58%) than in NMIBCs.…”

Heme oxygenase-1 promotes angiogenesis in urothelial carcinoma of the urinary bladder

“…The threshold percentages that were used to distinguish between low and high expression levels were established prior to statistical analysis of the data. Specifically, these percentages were defined as 10% for VEGF (35), 10% for HIF-1· (24), 50% for HIF-2· (24), and 10% for COX-2 (27). IHC evaluations were performed independently by two investigators in this study (M.M.…”

“…HIF-2·, originally called endothelial PAS protein-1 (EPAS1), shares close amino acid sequence homology and similar pharmacological and regulatory properties with HIF-1· (24,25). In addition, there is increasing evidence that cyclooxygenase-2 (COX-2) promotes tumor angiogenesis by regulating HIF-1· and VEGF, even in cases of gastric cancer (25)(26)(27). Furthermore, prostaglandin E2, a product of COX-2, is directly involved in the formation of new blood vessels (11).…”

Lower cyclooxygenase-2 expression is associated with recurrence of solitary non-muscle invasive bladder carcinoma

“…There is no doubt that COX-2 expression is sequentially up-regulated from normal to chronic cystitis and to malignant changes [30]. Also there are evidence that COX-2 is involved in angiogenesis in BC, as described in the paper where COX-2 promoted vessel proliferation in the tumor zone of pTa/pT1 NMIBC [31]. Moreover, COX-2 is probably up-regulated during tumor progression, as mentioned above, but we believe its role in initial stage is very complex.…”