title: Overexpression of cyclooxygenase-2 in urothelial carcinoma in conjunction with tumor-associated-macrophage infiltration, hypoxia-inducible factor-1alpha expression, and tumor angiogenesis.
abstract: This study examines whether the expression of cyclooxgenase-2 (COX-2) in urothelial carcinoma (UC) is associated with macrophage infiltration, hypoxia-inducible factor-1alpha (HIF-1alpha) expression and angiogenesis. We investigated the expression of COX-2 associated with HIF-1alpha 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-1alpha expression in UC (p<0.0001, p=0.003, p<0.0001, 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 (p<0.0001). Adjacent to the principal of COX-2 expression areas, MVD value and TAM density were significantly increased in HIF-1alpha high-expression specimens compared with HIF-1alpha low-expression ones (p<0.0001). Interestingly, our data revealed that high COX-2 expression (p=0.002), high HIF-1alpha expression (p<0.0001) and TAM density (p<0.0001) 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-1alpha regulation by hypoxia.
authors.affiliation: Department of Pathology, Kaohsiung Medical University, Chung-Ho Memorial Hospital, No. 100 Tzyou 1st Road, Kaohsiung City, Taiwan.
authors.forename: Wan-Tzu
authors.initials: WT
authors.lastname: Chen
authors.forename: Wen-Chun
authors.initials: WC
authors.lastname: Hung
authors.forename: Wan-Yi
authors.initials: WY
authors.lastname: Kang
authors.forename: Ya-Chun
authors.initials: YC
authors.lastname: Huang
authors.forename: Yue-Chiu
authors.initials: YC
authors.lastname: Su
authors.forename: Ching-Hsiu
authors.initials: CH
authors.lastname: Yang
authors.forename: Chee-Yin
authors.initials: CY
authors.lastname: Chai
mesh_terms: D000368:Aged; D002277:Carcinoma / Q000098:blood supply* / Q000201:enzymology / Q000473:pathology; D051546:Cyclooxygenase 2 / Q000096:biosynthesis*; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007150:Immunohistochemistry; D007680:Kidney Neoplasms / Q000201:enzymology / Q000473:pathology; D008264:Macrophages / Q000473:pathology; D008297:Male; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic / Q000201:enzymology*; D014516:Ureteral Neoplasms / Q000473:pathology; D001749:Urinary Bladder Neoplasms / Q000201:enzymology / Q000473:pathology; D014571:Urologic Neoplasms / Q000098:blood supply* / Q000201:enzymology / Q000473:pathology; D019459:Urothelium / Q000201:enzymology / Q000473:pathology*
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051546:Cyclooxygenase 2