Abstract
BackgroundBoth Ang-2 and VEGFR-3 are major regulators of angiogenesis and lymphangiogenesis, respectively, and thus may affect prognosis of OSCC. We sought to determine the associations between Ang-2 and VEGFR-3 expression and survival of OSCC.MethodsAng-2 and VEGFR-3 expression was determined immunohistochemically in tumor tissues from 112 patients with OSCC; OSCC-adjacent noncancerous oral tissue from 85 OSCC patients; and normal oral mucosa from 37 cancer-free individuals. A log-rank test and Cox proportional hazard models were used to compare survival among different groups with expression of Ang-2 and VEGFR-3.ResultsAng-2 and VEGFR-3 expression was upregulated in OSCC compared to nontumor tissue (all P<0.05). High Ang-2 expression positively correlated with microvessel density (MVD) (P<0.01), and high VEGFR-3 expression positively correlated with lymph node metastasis (P<0.01) and lymphatic vessel density (LVD) (P<0.01). The patients with high expression of Ang-2 alone or in combination with VEGFR-3 had a significantly worse survival than in patients with low expression of Ang-2 or any other co-expression status (all P<0.05), respectively. Furthermore, multivariable analysis showed that patients with high expression of Ang-2 alone or in combination with VEGFR-3 had a significantly increased risk of death compared with those with low expression of Ang-2 or any other co-expression status (HR, 2.7, 95% CI, 1.1–6.2 and 5.0, 1.3–15.4, respectively).ConclusionsThese results suggest that increased expression in tumors of Ang-2 may individually, or in combination with VEGFR-3, predict poor prognosis of OSCC.
Highlights
OSCC metastasizes primarily via the lymphatic system
Previous study reported that overexpression of angiopoietin-2 (Ang-2), which has been implicated in lymphatic vessel development [2], was closely associated with angiogenesis and lymph node metastasis in OSCC [3]
The distribution of both expression of Ang-2 and Vascular endothelial growth factor receptor-3 (VEGFR-3) had no significant differences in age, gender, lesion site, tumor differentiation, TNM stage, or smoking or alcohol use except Lymph node metastasis for VEGFR-3 (P = 0.000)
Summary
OSCC metastasizes primarily via the lymphatic system. In patients with OSCC, the presence of lymph node metastases is widely accepted as a major prognostic factor and is associated with higher recurrence rates and an approximately 50% reduction in overall survival [1].the mechanisms by which OSCC metastasizes to lymph nodes have been studied only very recently. To better understand the functional contribution of Ang-2 and VEGFR-3 to lymphangiogenesis and progress of OSCC, we used a double-labeling immunohistochemical staining of CD-34/D2-40 in blood vessels and lymphatic vessels of tumor specimens for determination of microvessel density and lymphatic vessel density among 112 cases. In these tumor specimens, we performed immunohistochemical staining of VEGFR-3, a major regulator of lymphangiogenesis [4], to investigate the correlations between Ang-2 and VEGFR-3 expression and tumor lymphangiogenesis and progress and thereby reveal the role of Ang-2 and VEGFR-3 in lymphatic metastasis and clinical survival in OSCC patients. We sought to determine the associations between Ang-2 and VEGFR-3 expression and survival of OSCC
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