The role of CCL21/CCR7 chemokine axis in breast cancer-induced lymphangiogenesis

Abstract

BackgroundTumor-induced lymphangiogenesis facilitates breast cancer progression by generating new lymphatic vessels that serve as conduits for tumor dissemination to lymph nodes and beyond. Given the recent evidence suggesting the implication of C-C chemokine ligand 21/chemokine receptor 7 (CCL21/CCR7) in lymph node metastasis, the aim of our study was to define the role of this chemokine pair in breast cancer-associated lymphangiogenesis.MethodsThe expression analysis of CCL21/CCR7 pair and lymphatic endothelial cell (LEC) markers in breast cancer specimens was performed by means of quantitative real-time PCR. By utilizing CCR7 and CCL21 gene manipulated breast cancer cell implants into orthotopic sites of nude mice, lymphatic vessel formation was assessed through quantitative real-time PCR, immunohistochemistry and immunofluorescence assays. Finally, the lymphangiogenic potential of CCL21/CCR7 was assessed in vitro with primary LECs through separate functional assays, each attempting to mimic different stages of the lymphangiogenic process.ResultsWe found that CCR7 mRNA expression in human breast cancer tissues positively correlates with the expression of lymphatic endothelial markers LYVE-1, podoplanin, Prox-1, and vascular endothelial growth factor-C (VEGF-C). We demonstrated that the expression of CCL21/CCR7 by breast cancer cells has the ability to promote tumor-induced lymph-vascular recruitment in vivo. In vitro, CCL21/CCR7 chemokine axis regulates the expression and secretion of lymphangiogenic factor VEGF-C and thereby promotes proliferation, migration, as well as tube formation of the primary human LECs. Finally, we showed that protein kinase B (AKT) signaling pathway is the intracellular mechanism of CCR7-mediated VEGF-C secretion by human breast cancer cells.ConclusionsThese results reveal that CCR7 and VEGF-C display a significant crosstalk and suggest a novel role of the CCL21/CCR7 chemokine axis in the promotion of breast cancer-induced lymphangiogenesis.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-015-0306-4) contains supplementary material, which is available to authorized users.

miR-199a-5p suppresses human bladder cancer cell metastasis by targeting CCR7

“…Previous studies have demonstrated CCR7 overexpression correlates with lymphatic metastasis and poor prognosis in breast cancer, colon cancer, prostate cancer and gastric cancer [9–12]. In our previous study, we also have found that CCR7 and its ligand CCL21 promote T24 cell proliferation and enhance its migration and invasion via upregulation MMP-2 and MMP-9 [13].…”

CCL5 promotes VEGF-C production and induces lymphangiogenesis by suppressing miR-507 in human chondrosarcoma cells

“…CXC chemokine ligand 12 (SDF-1) has been indicated to directly promote lymphangiogenesis in human LECs through the chemokine receptor CXCR4 [29]. Addtionally, CCL21/CCR7 chemokine axis regulates the expression and secretion of VEGF-C in human breast cancer cells, and contributes to LECs lymphangiogenesis and breast cancer-induced lymphangiogenesis [30]. Herein, we point out that CCL5/CCR5 axis induces VEGF-C-dependent lymphangiogenesis in human chondrosarcoma.…”

The dual role of tumor lymphatic vessels in dissemination of metastases and immune response development

“…The anti-CCR7 antibody as well as knockdown of CCR7 in COX-2-overexpressing MDAMB-231 cells significantly attenuates the effect of migration and invasion of breast cancer cells 36 . Additionally, COX-2 enhances secretion of VEGF-C, that in turn increases expression of CCR7 ligand, and CCL21 by LECs as well as development of new lymphatic vessels 38 . Tumor cells also secrete CCR7 ligands to generate autologous gradients of CCL19/21 chemokines that promote their migration toward functional lymphatics 39 .…”