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The role of CCL21/CCR7 chemokine axis in breast cancer-induced lymphangiogenesis
BACKGROUND: Tumor-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/...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4339430/ https://www.ncbi.nlm.nih.gov/pubmed/25744065 http://dx.doi.org/10.1186/s12943-015-0306-4 |
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author | Tutunea-Fatan, Elena Majumder, Mousumi Xin, Xiping Lala, Peeyush K |
author_facet | Tutunea-Fatan, Elena Majumder, Mousumi Xin, Xiping Lala, Peeyush K |
author_sort | Tutunea-Fatan, Elena |
collection | PubMed |
description | BACKGROUND: Tumor-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. METHODS: The 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. RESULTS: We 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. CONCLUSIONS: These 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 MATERIAL: The online version of this article (doi:10.1186/s12943-015-0306-4) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-4339430 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-43394302015-02-26 The role of CCL21/CCR7 chemokine axis in breast cancer-induced lymphangiogenesis Tutunea-Fatan, Elena Majumder, Mousumi Xin, Xiping Lala, Peeyush K Mol Cancer Research BACKGROUND: Tumor-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. METHODS: The 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. RESULTS: We 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. CONCLUSIONS: These 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 MATERIAL: The online version of this article (doi:10.1186/s12943-015-0306-4) contains supplementary material, which is available to authorized users. BioMed Central 2015-02-10 /pmc/articles/PMC4339430/ /pubmed/25744065 http://dx.doi.org/10.1186/s12943-015-0306-4 Text en © 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. |
spellingShingle | Research Tutunea-Fatan, Elena Majumder, Mousumi Xin, Xiping Lala, Peeyush K The role of CCL21/CCR7 chemokine axis in breast cancer-induced lymphangiogenesis |
title | The role of CCL21/CCR7 chemokine axis in breast cancer-induced lymphangiogenesis |
title_full | The role of CCL21/CCR7 chemokine axis in breast cancer-induced lymphangiogenesis |
title_fullStr | The role of CCL21/CCR7 chemokine axis in breast cancer-induced lymphangiogenesis |
title_full_unstemmed | The role of CCL21/CCR7 chemokine axis in breast cancer-induced lymphangiogenesis |
title_short | The role of CCL21/CCR7 chemokine axis in breast cancer-induced lymphangiogenesis |
title_sort | role of ccl21/ccr7 chemokine axis in breast cancer-induced lymphangiogenesis |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4339430/ https://www.ncbi.nlm.nih.gov/pubmed/25744065 http://dx.doi.org/10.1186/s12943-015-0306-4 |
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