Abstract
BackgroundLymphangiogenesis 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.MethodsTissue 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.ResultsA 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.ConclusionThere 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.
Highlights
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
We aimed to investigate the role of COX2 immunohistochemical expression in lymphangiogenesis, vascular endothelial growth factor-C (VEGF-C) expression and D2-40 positive lymphatic vessel invasion (LVI) as well as prognosis in a series of archival human invasive breast cancer samples
Granular staining was diffuse in cytoplasm of the cancer cells, original magnification 400×. (c) : D2-40-stained lymphatic vessel with tumor cells (T) inside was noted, original magnification 200×. (d) : Breast cancer specimen with a high peritumoral lymphatic vessel density (LVD), some of the lymphatic vessels stained for D2-40 are marked with arrows, original magnification 200×. (e-f): Double staining for D2-40 and Ki-67 of lymph vessels; Positive staining for Ki-67 is seen in nuclei of lymphatic endothelial cells, original magnification 400×
Summary
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. Lymphangiogenesis, the formation of new lymphatic vessels, has become a new research frontier in tumor metastasis since the discovery of the two major lymphatic vessel growth factors-C (VEGF-C) and -D (VEGF-D), as well as reliable lymphatic markers that have allowed observation and isolation of lymphatic endothelium[1]. Cyclooxygenase-2 (COX-2), the inducible isoform of prostaglandin H synthase, has been reported to be significantly overexpressed in a variety of human malignancies including breast cancer, and was identified to be involved in the critical steps in carcinogenesis [5,6,7]. Data is still scarce in breast cancer and it is necessary to provide more documents to increase the dataset
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