Hypoxia inducible factor-alpha expression correlates with vascular endothelial growth factor-C expression and lymphangiogenesis/angiogenesis in oral squamous cell carcinoma.
BACKGROUND
The number of blood vessels correlates with metastasis in solid tumors, including oral squamous cell carcinoma (OSCC). Hypoxia inducible factor-1alpha (HIF-1alpha) could play a role in tumor lymphangiogenesis by regulating the lymphatic expression of vascular endothelial growth factor-C (VEGF-C). HIF-1alpha protein expression, VEGF-C protein expression, lymphatic vessel density (LVD) and blood vessel density (BVD) in OSCC were investigated.


METHODS
HIF-1alpha 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-1alpha expression and the clinicopathological parameters was evaluated.


RESULTS
HIF-1alpha 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-1alpha and high VEGF-C expression cases. HIF-1alpha overexpression was significantly correlated with VEGF-C overexpression (p = .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-1alpha and VEGF-C expression groups (p < 0.001, Mann-Whitney U-test).


CONCLUSIONS
HIF-1alpha 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-1alpha might be a particularly promising target for controlling regional lymph node metastases by a combination of antiangiogenic and anti-lymphangiogenic effects in OSCC.
Liang
Xinhua
X
Department of Oral and Maxillofacial Surgery, West China College of Stomatology, Sichuan University, Chengdu Sichuan, People's Republic of China. Liang.xinhua@Mayo.edu
Yang
Dajiang
D
Hu
Jing
J
Hao
Xiaoming
X
Gao
Jiarang
J
Mao
Zuyi
Z
D000328:Adult; D000368:Aged; D002294:Carcinoma, Squamous Cell / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis*; D007150:Immunohistochemistry; D042583:Lymphangiogenesis; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D009062:Mouth Neoplasms / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis*
C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A