Hypoxia Inducible Factor-1alpha Expression Correlates with Vascular Endothelial Growth Factor-C Expression and Lymphangiogenesis/Angiogenesis in Oral Squamous Cell Carcinoma

Abstract

Background: The number of blood vessels correlates with metastasis in solid tumors, including oral squamous cell carcinoma (OSCC). Hypoxia inducible factor-1alpha (HIF-1α) could play a role in tumor lymphangiogenesis by regulating the lymphatic expression of vascular endothelial growth factor-C (VEGF-C). HIF-1α protein expression, VEGF-C protein expression, lymphatic vessel density (LVD) and blood vessel density (BVD) in OSCC were investigated. Materials and Methods: HIF-1α and VEGF-C protein expression were investigated by means of immunohistochemistry in samples from 65 cases of OSCC. The density of the lymphatic microvessels and blood microvessels immunohistochemically stained by LYVE-1 and CD34 antibody, respectively, was calculated. The association between the HIF-1α expression and the clinicopathological parameters was evaluated. Results: HIF-1α overexpression occurred in 43 out of the 65 tumor samples (66.2%), while VEGF-C overexpression was observed in 34 out of the 65 tumor samples (52.3%). Higher LVD was found in both high HIF-1α and high VEGF-C expression cases. HIF-1α overexpression was significantly correlated with VEGF-C overexpression (p=0.018, Chi-square test), higher LVD (p<0.001, Mann-Whitney U-test), and regional lymph nodal involvement (p=0.004, Chi-square test) as well as UICC TMN classification (p=0.043, Chi-square test), respectively. In addition, higher BVD existed in the high HIF-1α and VEGF-C expression groups (p<0.001, Mann-Whitney U-test). Conclusion: HIF-1α might play a crucial role in regional lymph node metastasis as a regulator of lymphangiogenesis and angiogenesis in OSCC with a possible novel pathway involving VEGF-C. Therefore, HIF-1α might be a particularly promising target for controlling regional lymph node metastases by a combination of anti-angiogenic and anti-lymphangiogenic effects in OSCC.