title: Hypoxia-induced factor-1 alpha upregulates vascular endothelial growth factor C to promote lymphangiogenesis and angiogenesis in breast cancer patients.
abstract: Hypoxia-induced factor-1 alpha (HIF-1α) affects many effector molecules and regulates tumor lymphangiogenesis and angiogenesis during hypoxia. The aim of this study was to investigate the role of HIF-1α in the regulation of vascular endothelial growth factor C (VEGF-C) expression and its effect on lymphangiogenesis and angiogenesis in breast cancer. Lymphatic vessel density (LVD), microvessel density (MVD) and the expressions of HIF-1α and VEGF-C proteins were evaluated by immunohistochemistry in 75 breast cancer samples. There was a significant correlation between HIF-1α and VEGF-C (P = 0.014, r = 0.273, Spearman's coefficient of correlation). HIF-1α and VEGF-C overexpression was significantly correlated with higher LVD (P = 0.003 and P = 0.017, respectively), regional lymph nodal involvement (P = 0.002 and P = 0.004, respectively) and advanced tumor, node, metastasis (TNM) classification (P = 0.001 and P = 0.01, respectively). Higher MVD was observed in the group expressing higher levels of HIF-1α and VEGF-C (P = 0.033 and P = 0.037, respectively). Univariate analysis showed shorter survival time in patients expressing higher levels of HIF-1α and VEGF-C. HIF-1α was also found to be an independent prognostic factor of overall survival in multivariate analysis. The results suggest that HIF-1α may affect VEGF-C expression, thus acting as a crucial regulator of lymphangiogenesis and angiogenesis in breast cancer. This study highlights promising potential of HIF-1α as a therapeutic target against tumor lymph node metastasis.
authors.affiliation: Department of Breast Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China;
authors.forename: Xiaojian
authors.initials: X
authors.lastname: Ni
authors.forename: Yingchun
authors.initials: Y
authors.lastname: Zhao
authors.forename: Jingjing
authors.initials: J
authors.lastname: Ma
authors.forename: Tiansong
authors.initials: T
authors.lastname: Xia
authors.forename: Xiaoan
authors.initials: X
authors.lastname: Liu
authors.forename: Qiang
authors.initials: Q
authors.lastname: Ding
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Zha
authors.forename: Shui
authors.initials: S
authors.lastname: Wang
keywords: HIF-1α; VEGF-C; angiogenesis; breast cancer; lymphangiogenesis