Overexpression of cyclooxygenase‐2 in urothelial carcinoma in conjunction with tumor‐associated‐macrophage infiltration, hypoxia‐inducible factor‐1α expression, and tumor angiogenesis

Abstract

Overexpression of Cyclooxygenase-2 in Urothelial Carcinoma: in conjunction with tumor-associated-macrophage infiltration, hypoxia-inducible factor-1a expression, and tumor angiogenesis. APMIS 2009; 117:176-84. This study examines whether the expression of cyclooxgenase-2 (COX-2) in urothelial carcinoma (UC) is associated with macrophage infiltration, hypoxia-inducible factor-1a (HIF-1a) expression and angiogenesis. We investigated the expression of COX-2 associated with HIF-1a and performed double immunohistochemical analysis of 216 UCs for COX-2 expression and the correlation with tumor-associated-macrophage (TAM) density and microvessel density (MVD) in situ. A high expression of COX-2 was positively correlated with tumor invasiveness, histologic grade and HIF-1a expression in UC (po0.0001, p = 0.003, po0.0001, respectively). Quantification of double staining of COX-2/CD34 and COX-2/CD68 showed that a higher MVD and TAM density was found in COX-2 high-expression than in COX-2 low-expression tumor fields (po0.0001). Adjacent to the principal of COX-2 expression areas, MVD value and TAM density were significantly increased in HIF-1a high-expression specimens compared with HIF-1a low-expression ones (po0.0001). Interestingly, our data revealed that high COX-2 expression (p = 0.002), high HIF-1a expression (po0.0001) and TAM density (po0.0001) were all associated with high MVD value. Our results suggest that COX-2 may produce a cooperative effect in promoting tumor progression and may be involved in the process of angiogenesis through increasing TAM infiltration or HIF-1a regulation by hypoxia.

Investigating associations of cyclooxygenase-2 expression with angiogenesis, proliferation, macrophage and T-lymphocyte infiltration in canine melanocytic tumours

“…This interdependence was confirmed in the present results, where COX-2 intensity, but not the extension grade, was associated with macrophage infiltration in malignant melanomas (P = 0.015), specifically of cutaneous localization (P =0.033). Similar relationships were described in humans for urothelial carcinoma [48], colorectal carcinomas [49], hepatocellular carcinoma [50] and prostate carcinoma [51]. Several mechanisms underlying COX-2 and macrophage correlation have been proposed.…”

Role of tumor‐associated macrophages in human malignancies: friend or foe?

“…Another study also reported a significant correlation between TAM density and microvessel density as well as poor prognosis. 83 With regard to bacille de Calmette et Guérin (BCG) therapy, which is the gold standard of bladder cancer treatment, a high infiltration of CD68 + TAMs was related to an increased risk of recurrence in patients with non-muscleinvasive urothelial cancer before BCG immunotherapy. 84 Analysis of patients with bladder carcinoma in situ who received BCG therapy indicated frequent recurrences in patients with a high density of CD68 + TAMs.…”

“…[82][83][84][85][86] Recurrence after BCG therapy occurred frequently in patients with a high density of TAMs. 84,85 Endometrial caner Poor prognosis High TAM density correlated with tumor progression with or without link to poor prognosis.…”

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

“…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).…”