MT1-MMP in breast cancer: induction of VEGF-C correlates with metastasis and poor prognosis

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.

Matrix Metallopeptidase 14 Plays an Important Role in Regulating Tumorigenic Gene Expression and Invasion Ability of HeLa Cells

“…27,28 It has been reported that MMP14 promotes VEGF-A and VEGF-C expressions in corneal fibroblast and breast cancer, which were involved in the invasive phenotype of tumor cells. 9,11 The present study showed that reduced MMP14 expression could attenuate VEGF-B expression in both mRNA and protein levels in HeLa cells. Additionally, our results also showed that downregulated MMP14 expression significantly suppressed BSP expression, which was known as a serum bone metastasis indicator in breast cancer.…”

“…5 Evidence showed that MMP14 is involved in the secretion of vascular endothelial growth factor B (VEGF B) in the proliferation of tumor cells, 6Y8 could promote angiogenesis and vasculogenesis, and inhibits apoptosis by mediating VEGF-A in cornea, 9 glioma, 10 and breast carcinoma. 11 Many evidences also showed that transforming growth factor A 1 (TGF-A 1 ) and VEGF played crucial role in promoting cancer cell invasion, 12Y15 but the relationships among MMP14, TGF-A 1 , and VEGF in cervical carcinoma need further verification.…”

Discovery of fruquintinib, a potent and highly selective small molecule inhibitor of VEGFR 1, 2, 3 tyrosine kinases for cancer therapy

“…30,31 Clinical investigations have demonstrated that overexpression of VEGF-C/ VEGFR3 in tumors is associated with lymphangiogenesis, lymph node metastasis and poor prognosis in several types of tumor. [32][33][34][35][36] VEGF-C promotes lymphangiogenesis and lymphatic vessel-mediated metastasis to regional lymph nodes, and it could be inhibited by blocking VEGFR3 receptor. 37 Given the importance of lymphangiogenesis in tumor metastasis and overall survival for certain cancer patients, it would seem to be an attractive approach to target VEGFR3, although unlike targeting VEGFR2, there have been no successful products developed yet specifically targeting VEGFR3.…”

Expression of D2-40 in Benign and Malignant Breast Lesions and Study the Correlation between Lymphovascular Density and other Prognostic Factors of Breast Cancer

“…VEGF-C is synthesized as propeptide then activated by proteolysis to form a high-affinity ligand that binds to the extracellular domain of vascular endothelial growth factor receptor-3 (VEGFR-3), which is expressed on lymphatic endothelium (LECs), and induces tyrosine phosphorylation of VEGFR-3. Thus, VEGF-C promotes lymphangiogenesis and lymphatic metastasis in tumors [21][22][23]. Several studies [24][25] have shown that D2-40 IHC labels glandular MECs, while using it as the marker for lymphatic endothelial cells, which triggered this study to further, explore the possibility of using D2-40 as an additional MECs marker in breast pathology and in the same time using it as a prognostic marker as it is now one of the most specific and sensitive lymphatics markers.…”