title: Hypoxia-inducible factor-1alpha expression correlates with focal macrophage infiltration, angiogenesis and unfavourable prognosis in urothelial carcinoma.
abstract: BACKGROUND
  Hypoxia inducible factor (HIF)-1alpha is a critical regulatory protein of cellular response to hypoxia and is closely related to angiogenic process.
  
  
  OBJECTIVE
  To explore the potential role and the prognostic value of HIF-1alpha in urothelial carcinoma (UC).
  
  
  METHODS
  Clinicopathological and follow-up data on 99 UC cases were reviewed and immunostained for HIF-1alpha, CD68, vascular endothelial growth factor (VEGF) and CD34 antigen. Tumour-associated macrophage (TAM) counts and HIF-1alpha expression were compared with clinicopathologic characteristics, overall survival (OS) and disease-free survival rates (DFS).
  
  
  RESULTS
  High expression of HIF-1alpha was detected in 55 of 99 (55.6%) tumours. HIF-1alpha expression was correlated with tumour size, histological grade, tumour invasiveness and recurrence. VEGF and microvessel density (MVD) demonstrated their positive correlation with HIF-1alpha overexpression, supporting the correlation of HIF-1alpha up-regulation with tumour angiogenesis. Higher TAM infiltration was identified in high expression of HIF-1alpha cases rather than HIF-1alpha low expression cases (p = 0.002). Kaplan-Meier analysis found that HIF-1alpha overexpression and high TAM count was only associated with worse DFS (p = 0.009, p = 0.023) but was not associated with OS (p = 0.696, p = 0.141). Multivariate analyses indicated only tumour size (p = 0.038) to be an independently significant prognostic factor for OS, in addition, HIF-1alpha expression (p = 0.011), as well as histological grade (p = 0.038), and MVD (p = 0.004), to be independently significant prognostic factors for DFS.
  
  
  CONCLUSIONS
  Our results indicate that HIF-1alpha is a key regulator of the angiogenic cascade. We show that HIF-1alpha is an independent prognostic factor for disease-free survival.
authors.affiliation: Department of Pathology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan. cychai@kmu.edu.tw
authors.forename: C-Y
authors.initials: CY
authors.lastname: Chai
authors.forename: W-T
authors.initials: WT
authors.lastname: Chen
authors.forename: W-C
authors.initials: WC
authors.lastname: Hung
authors.forename: W-Y
authors.initials: WY
authors.lastname: Kang
authors.forename: Y-C
authors.initials: YC
authors.lastname: Huang
authors.forename: Y-C
authors.initials: YC
authors.lastname: Su
authors.forename: C-H
authors.initials: CH
authors.lastname: Yang
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000378:metabolism*; D002295:Carcinoma, Transitional Cell / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D018450:Disease Progression; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007124:Immunoenzyme Techniques; D008264:Macrophages / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D011379:Prognosis; D016019:Survival Analysis; D001749:Urinary Bladder Neoplasms / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009363:Neoplasm Proteins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A