Open Access Highly Accessed Research article

Coexpression of VEGF-C and COX-2 and its association with lymphangiogenesis in human breast cancer

Xiao-Hua Zhang1, Du-Ping Huang1*, Gui-Long Guo1, Guo-Rong Chen2, Hu-Xiang Zhang2, Li Wan2 and Sheng-Ying Chen3

Author Affiliations

1 Department of Oncology, The First Affiliated Hospital of Wenzhou Medical College, Wenzhou, 325000, China

2 Department of Pathology, The First Affiliated Hospital of Wenzhou Medical College, Wenzhou, 325000, China

3 Department of stomatology, The First Affiliated Hospital of Wenzhou Medical College, Wenzhou, 325000, China

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BMC Cancer 2008, 8:4  doi:10.1186/1471-2407-8-4

Published: 13 January 2008



Lymphangiogenesis has become a new research frontier in tumor metastasis since the discovery of reliable lymphatic markers that have allowed observation and isolation of lymphatic endothelium. Cyclooxygenase-2 (COX-2) has been reported to be involved in the critical steps in carcinogenesis. However, possible role of COX-2 in lymphangiogenesis and lymphatic metastasis is still poorly understood. In present study, we aimed to investigate the relationship between vascular endothelial growth factor-C (VEGF-C) and COX-2 in human breast cancer, and correlations with lymphangiogenesis and prognosis.


Tissue samples of primary tumors from 70 patients undergoing intentionally curative surgical resections for breast cancer were immunohistochemically examined for VEGF-C, COX-2, and D2-40 expressions. The association between COX-2 and VEGF-C expressions and clinicopathological parameters as well as prognosis were analysised. To demonstrate the presence of proliferating lymphatic endothelial cells, 10 random cases with high LVD counts were selected for D2-40/Ki-67 double immunostaining.


A significant correlation was found between the expression of VEGF-C and COX-2 (r = 0.529, P < 0.001), and both elevated VEGF-C expression and elevated COX-2 expression were associated with higher lymph vessel density (LVD), lymph node metastasis and D2-40 positive lymphatic invasion (LVI) as well as worse disease free survival (DFS) and overall survival (OS) in a univariate analysis. In the double immunostain for the lymph vessel marker D2-40 and the proliferation marker Ki-67, the results confirmed Ki-67-positive nuclei in a proportion of lymph vessel endothelial cells.


There is indeed lymphangiogenesis in breast cancer, the most compelling evidence being the presence of proliferating lymphatic endothelial cells. VEGF-C and COX-2 are coexpressed and significantly associated with lymphangiogenesis and prognosis in invasive breast cancer. Suggesting COX-2 may up-regulate VEGF-C expression and thus promote lymph node metastasis via lymphangiogenesis pathway in human breast cancer.