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.
Highlights
Breast carcinoma is one of the most common types of cancer diagnosed among women
Seventy five patients with breast carcinoma were included in the current study and 52 (69.3%) of them showed high HIF-1α expression, and 48 (64.0%) of them showed high Vascular endothelial growth factor C (VEGF-C) expression (Fig. 1)
Normal tissue showed no immunoreactivity for HIF-1α or vascular endothelial growth factor (VEGF)-C
Summary
Metastasis primarily occurs through the lymphatic system, and the extent of lymph node involvement is a key prognostic factor for the disease. Recent studies have suggested that lymphangiogenesis, the formation of new lymphatic vessels induced by tumors, is directly correlated with the extent of lymph node metastasis. Vascular endothelial growth factor C (VEGF-C) is a major lymphangiogenic and angiogenic factor, which is commonly expressed in malignant cancers[2,3,4] It promotes lymphangiogenesis, angiogenesis, and lymph node metastasis in tumors by activating its specific receptor vascular endothelial growth factor receptor-3 (VEGFR-3). Neutralizing VEGF-C or blocking VEGFR-3 signaling was reported to suppress the development of new lymphatic vessels, lymphatic hyperplasia and tumor metastasis in experimental cancer models[5]
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