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

Molecular Cancer

Research

Xiping Xin¹  Mousumi Majumder¹  Elena Tutunea-Fatan¹  Peeyush K Lala² 

[1] Department of Anatomy & Cell Biology, Schulich School of Medicine and Dentistry, Western University, 1151 Richmond St, N6A 5C1, London, ON, Canada;Department of Anatomy & Cell Biology, Schulich School of Medicine and Dentistry, Western University, 1151 Richmond St, N6A 5C1, London, ON, Canada;Department of Oncology, Schulich School of Medicine and Dentistry, Western University, 790 Commissioners Rd. E, N6A 4L6, London, ON, Canada;Children’s Health Research Institute, 800 Commissioners Rd. E, N6C 2V5, London, ON, Canada;

关键词: CCL21 chemokine;    CCR7 chemokine receptor;    Vascular endothelial growth factor-C;    Protein kinase B;    Lymphangiogenesis;    Breast cancer;   

DOI  :  10.1186/s12943-015-0306-4

 received in 2014-07-17, accepted in 2015-01-27,  发布年份 2015

来源: Springer

【 摘 要 】

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.

【 授权许可】

Unknown   
© Tutunea-Fatan et al.; licensee Biomed Central. 2015. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.