COX-2-mediated stimulation of the lymphangiogenic factor VEGF-C in human breast cancer

Abstract

Increased expression of COX-2 or VEGF-C has been correlated with progressive disease in certain cancers. Present study utilized several human breast cancer cell lines (MCF-7, T-47D, Hs578T and MDA-MB-231, varying in COX-2 expression) as well as 10 human breast cancer specimens to examine the roles of COX-2 and prostaglandin E (EP) receptors in VEGF-C expression or secretion, and the relationship of COX-2 or VEGF-C expression to lymphangiogenesis. We found a strong correlation between COX-2 mRNA expression and VEGF-C expression or secretion levels in breast cancer cell lines and VEGF-C expression in breast cancer tissues. Expression of LYVE-1, a selective marker for lymphatic endothelium, was also positively correlated with COX-2 or VEGF-C expression in breast cancer tissues. Inhibition of VEGF-C expression and secretion in the presence of COX-1/2 or COX-2 inhibitors or following downregulation of COX-2 with COX-2 siRNA established a stimulatory role COX-2 in VEGF-C synthesis by breast cancer cells. EP1 as well as EP4 receptor antagonists inhibited VEGF-C production indicating the roles of EP1 and EP4 in VEGF-C upregulation by endogenous PGE 2 . Finally, VEGF-C secretion by MDA-MB-231 cells was inhibited in the presence of kinase inhibitors for Her-2/neu, Src and p38 MAPK, indicating a requirement of these kinases for VEGF-C synthesis. These results, for the first time, demonstrate a regulatory role of COX-2 in VEGF-C synthesis (and thereby lymphangiogenesis) in human breast cancer, which is mediated at least in part by EP1/EP4 receptors.

A practical and sensitive method of quantitating lymphangiogenesis in vivo

“…There are many drugs that may have no direct effect on the process of lymphangiogenesis, but can block tumor-induced lymphangiogenesis by inhibiting pathways responsible for an upregulation of lymphangiogenic factors such as VEGF-C or VEGF-D produced by tumor cells. For example, expression of COX-2 was shown to upregulate VEGF-C or -D in breast cancer 25,34 and lung cancer. 35 In the case of breast cancer, this was primarily due to an activation of prostaglandin receptor EP4, so that both COX-2 inhibitor Celecoxib and the EP4 antagonist ONO-AE3-208 given orally were equally effective in blocking tumor-associated lymphangiogenesis and lymphatic metastasis in a COX-2-expressing mouse breast cancer model.…”

Induction of lymphangiogenesis through vascular endothelial growth factor-C/vascular endothelial growth factor receptor 3 axis and its correlation with lymph node metastasis in nasopharyngeal carcinoma

“…Chang, et al reported that FGF-2 stimulates the proliferation, migration and tube formation of isolated lymphatic endothelial cells, indicating a direct role in lymphatic vessel growth [38] . In addition, COX-2 demonstrates a positive regulatory role in lymphangiogenesis [39] . Interestingly, all these factors are induced by the EBV-associated oncoprotein, LMP1, in NPC [8,29,30] .…”

Role of COX-2 in lymphangiogenesis and restoration of lymphatic flow in secondary lymphedema

“…12,13 However, little is known about the direct contribution of COX-2 to lymphedema-associated lymphangiogenesis, although positive correlations between COX-2 expression in tumor tissues and lymphangiogenesis and lymph node metastasis have been reported for several human cancers, [28][29][30] as well as the effect of COX-2 inhibition on lymphangiogenesis in a tumor implantation model. 14 In a study utilizing a nonselective COX inhibitor in a mouse tail lymphedema model, ketoprofen treatment normalized the histopathology with increased TNF-a expression and VEGF-C expression.…”