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

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.

Targeting Cyclooxygenase-2 in Hematological Malignancies: Rationale and Promise

“…PGE 2 can modulate VEGF synthesis through the EP3 receptor [73]. Cox-2 expression is positively correlated with high VEGF levels in patients with multiple types of cancer and is associated with increased angiogenesis and metastasis [74,75]. Therefore, use of Cox-2 selective inhibitors could potentially reduce growth factor levels, thereby reducing angiogenesis.…”

Cyclooxygenase-2 and the inflammogenesis of breast cancer

“…Molecular investigations of breast cancer tissues provide strong evidence that COX-2-derived PGE-2 stimulates the synthesis and release of VEGF resulting in angiogenesis and ingrowth of new blood vessels that are immature and highly permeable thereby facilitating metastatic spread of tumor cells [7,28,154] . Tumor secretion of VEGF (and other growth factors) may further amplify COX-2 expression in a positive feedback loop to produce lymphangiogenesis [155,156] . Notably, inhibition of this vicious cycle by COX-2 inhibiting agents such as celecoxib has been found to limit angiogenesis and halt the progression and metastatic spread of tumors in animals [157] .…”

Targeting COX-2 and EP4 to control tumor growth, angiogenesis, lymphangiogenesis and metastasis to the lungs and lymph nodes in a breast cancer model

“…[18][19][20] However, recent evidence clearly reveals that expression of VEGF-C 9,17,21 or VEGF-D 22 in human breast cancer in situ is strongly correlated with lymphangiogenesis, lympho-vascular invasion and lymphatic metastasis. In addition to its role in promoting lymphangiogenesis, we found that VEGF-C production by breast cancer cells served as an autocrine stimulus for their motility by binding to a diverse group of VEGF-C receptors.…”