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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

Abstract

Background

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.

Methods

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.

Results

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.

Conclusion

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.