Abstract
BackgroundRecent evidence suggests that vascular endothelial growth factor-C (VEGF-C)- dependent tumour production promotes lymphangiogenesis, while membrane-type matrix 1 metalloproteinase (MT1-MMP) is involved in the critical steps leading to carcinogenesis. However, the role of MT1-MMP in lymphangiogenesis and lymphatic metastasis remains poorly understood. In the present study, we investigated the relationship between MT1-MMP and VEGF-C in human breast cancer and correlated MT1-MMP and VEGF-C expression with lymphangiogenesis and prognosis.MethodsMT1-MMP and VEGF-C levels were compared in five breast carcinoma cell lines. We used a membrane invasion assay to assess the effect of MT1-MMP and VEGF-C expression, as well as anti-MT1-MMP and VEGF-C antibodies, on cancer cell invasion. We further assessed MT1-MMP and VEGF-C immunoreactivity and lymph vessels in a cohort of human breast cancer specimens (n = 106) and associated MT1-MMP and VEGF-C expression with clinicopathological parameters, such as lymphatic vessel density (LVD), and patient prognosis.ResultsMT1-MMP and VEGF-C expression differed among the five breast cancer cell lines and MT1-MMP and VEGF-C expression were correlated with tumour cell invasion. VEGF-C mRNA expression levels and invasive activity of MDA-MB-231 cells was inhibited by an anti-MT1-MMP antibody in a concentration-dependent manner. A significant correlation was found between the expression of MT1-MMP and VEGF-C in breast cancer patient samples and elevated MT1-MMP and VEGF-C expression was associated with higher LVD, lymph node metastasis, cancer stage, and a decline in overall survival rates.ConclusionsOur data demonstrate that MT1-MMP expression is closely correlated with VEGF-C expression, and that MT1-MMP promotes lymphangiogenesis by up-regulating VEGF-C expression in human breast cancer. Thus, elevated MT1-MMP may serve as a significant prognostic factor in breast cancer.
Highlights
Recent evidence suggests that vascular endothelial growth factor-C (VEGF-C)- dependent tumour production promotes lymphangiogenesis, while membrane-type matrix 1 metalloproteinase (MT1-Matrix metalloproteinases (MMP)) is involved in the critical steps leading to carcinogenesis
MDAMB-231 and MCF-7ADR cell lines had higher expression levels of VEGF-C and Membrane-type matrix 1 metalloproteinase (MT1-MMP), while neither MT1MMP mRNA nor protein expression was detected in MCF-7 cells
Effects of MT1-MMP and VEGF-C on invasive phenotype of tumour cells We found a statistically significant correlation between MT1-MMP mRNA expression in five breast cancer cell lines and the number of invasive tumour cells
Summary
Recent evidence suggests that vascular endothelial growth factor-C (VEGF-C)- dependent tumour production promotes lymphangiogenesis, while membrane-type matrix 1 metalloproteinase (MT1-MMP) is involved in the critical steps leading to carcinogenesis. Matrix 1 metalloproteinase (MT1-MMP) is significant [1] as it directly degrades a number of ECM macromolecules, including collagen types I, II, III, Metastasis to regional lymph nodes via the lymphatic vessels is the predominant pattern of metastasis in breast cancer. Little is known about lymphangiogenesis due to the lack of markers with which to isolate and study lymphatic endothelium. This has been overcome after the identification of vascular endothelial growth factor C (VEGF-C) as a lymphangiogenic factor. VEGF-C promotes intratumoural lymphangiogenesis and lymphatic metastasis in tumours [7]
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