Hypoxia-inducible factor-1
Expression Correlates with Focal Macrophage Infiltration, Angiogenesis and Unfavorable Prognosis in Urothelial Carcinoma
Chee-Yin Chai 1*, Wan-Tzu Chen 2, Wen-Chun Hung 3, Wan-Yi Kang 2, Ya-Chun Huang 1, Yue-Chiu Su 2 and Ching-Hsiu Yang 2
1 Department of Pathology, College of Medicine, Kaohsiung Medical University, Taiwan
2 Department of Pathology, Kaohsiung Medical University Chung-Ho Memorial Hospital, Taiwan
3 Institute of Biomedical Sciences, National Sun Yat-Sen University, Taiwan
* To whom correspondence should be addressed. E-mail: cychai{at}kmu.edu.tw.
Accepted 6 September 2007
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Abstract |
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Background: Hypoxia inducible factor-1 alpha (HIF-1
) is a critical regulatory protein of cellular response to hypoxia and is closely related to angiogenic process.
Aims: To explore the potential role and the prognostic value of HIF-1 in urothelial carcinoma (UC).
Methods: Clinicopathological and follow up data on 99 UC cases were reviewed and immunostained for HIF-1, CD68, VEGF and CD31 antigen. Tumor-associated macrophage (TAM) counts and HIF-1 expression were compared with clinicopathologic characteristics, overall survival (OS) and disease-free survival rates (DFS).
Results: High expression of HIF-1 was detected in 55 of 99 (55.6%) tumors. HIF-1 expression was correlated with tumor size, histological grade, tumor invasiveness and recurrence. VEGF and microvessel density (MVD) demonstrated their positive correlation with HIF-1 overexpression, supporting the correlation of HIF-1 upregulation with tumor angiogenesis. Higher TAM infiltration was identified in high expression of HIF-1 cases rather than HIF-1 low expression cases (P=0.002). Kaplan-Meier analysis found that HIF-1 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 tumor size (P=0.038) to be an independently significant prognostic factors for OS, in addition, HIF-1 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 indicated that HIF-1 is a key regulator of the angiogenic cascade. We showed that HIF-1 is an independent prognostic factor for disease-free survival.
Key Words:
angiogenesis, hypoxia inducible factor-1 alpha, microvessel density, tumor associated-macrophage, urothelial carcinoma
