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CCL2-induced chemokine cascade promotes breast cancer metastasis by enhancing retention of metastasis-associated macrophages
Pulmonary metastasis of breast cancer cells is promoted by a distinct population of macrophages, metastasis-associated macrophages (MAMs), which originate from inflammatory monocytes (IMs) recruited by the CC-chemokine ligand 2 (CCL2). We demonstrate here that, through activation of the CCL2 recepto...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The Rockefeller University Press
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4493415/ https://www.ncbi.nlm.nih.gov/pubmed/26056232 http://dx.doi.org/10.1084/jem.20141836 |
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author | Kitamura, Takanori Qian, Bin-Zhi Soong, Daniel Cassetta, Luca Noy, Roy Sugano, Gaël Kato, Yu Li, Jiufeng Pollard, Jeffrey W. |
author_facet | Kitamura, Takanori Qian, Bin-Zhi Soong, Daniel Cassetta, Luca Noy, Roy Sugano, Gaël Kato, Yu Li, Jiufeng Pollard, Jeffrey W. |
author_sort | Kitamura, Takanori |
collection | PubMed |
description | Pulmonary metastasis of breast cancer cells is promoted by a distinct population of macrophages, metastasis-associated macrophages (MAMs), which originate from inflammatory monocytes (IMs) recruited by the CC-chemokine ligand 2 (CCL2). We demonstrate here that, through activation of the CCL2 receptor CCR2, the recruited MAMs secrete another chemokine ligand CCL3. Genetic deletion of CCL3 or its receptor CCR1 in macrophages reduces the number of lung metastasis foci, as well as the number of MAMs accumulated in tumor-challenged lung in mice. Adoptive transfer of WT IMs increases the reduced number of lung metastasis foci in Ccl3 deficient mice. Mechanistically, Ccr1 deficiency prevents MAM retention in the lung by reducing MAM–cancer cell interactions. These findings collectively indicate that the CCL2-triggered chemokine cascade in macrophages promotes metastatic seeding of breast cancer cells thereby amplifying the pathology already extant in the system. These data suggest that inhibition of CCR1, the distal part of this signaling relay, may have a therapeutic impact in metastatic disease with lower toxicity than blocking upstream targets. |
format | Online Article Text |
id | pubmed-4493415 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | The Rockefeller University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-44934152015-12-29 CCL2-induced chemokine cascade promotes breast cancer metastasis by enhancing retention of metastasis-associated macrophages Kitamura, Takanori Qian, Bin-Zhi Soong, Daniel Cassetta, Luca Noy, Roy Sugano, Gaël Kato, Yu Li, Jiufeng Pollard, Jeffrey W. J Exp Med Article Pulmonary metastasis of breast cancer cells is promoted by a distinct population of macrophages, metastasis-associated macrophages (MAMs), which originate from inflammatory monocytes (IMs) recruited by the CC-chemokine ligand 2 (CCL2). We demonstrate here that, through activation of the CCL2 receptor CCR2, the recruited MAMs secrete another chemokine ligand CCL3. Genetic deletion of CCL3 or its receptor CCR1 in macrophages reduces the number of lung metastasis foci, as well as the number of MAMs accumulated in tumor-challenged lung in mice. Adoptive transfer of WT IMs increases the reduced number of lung metastasis foci in Ccl3 deficient mice. Mechanistically, Ccr1 deficiency prevents MAM retention in the lung by reducing MAM–cancer cell interactions. These findings collectively indicate that the CCL2-triggered chemokine cascade in macrophages promotes metastatic seeding of breast cancer cells thereby amplifying the pathology already extant in the system. These data suggest that inhibition of CCR1, the distal part of this signaling relay, may have a therapeutic impact in metastatic disease with lower toxicity than blocking upstream targets. The Rockefeller University Press 2015-06-29 /pmc/articles/PMC4493415/ /pubmed/26056232 http://dx.doi.org/10.1084/jem.20141836 Text en © 2015 Kitamura et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/). |
spellingShingle | Article Kitamura, Takanori Qian, Bin-Zhi Soong, Daniel Cassetta, Luca Noy, Roy Sugano, Gaël Kato, Yu Li, Jiufeng Pollard, Jeffrey W. CCL2-induced chemokine cascade promotes breast cancer metastasis by enhancing retention of metastasis-associated macrophages |
title | CCL2-induced chemokine cascade promotes breast cancer metastasis by enhancing retention of metastasis-associated macrophages |
title_full | CCL2-induced chemokine cascade promotes breast cancer metastasis by enhancing retention of metastasis-associated macrophages |
title_fullStr | CCL2-induced chemokine cascade promotes breast cancer metastasis by enhancing retention of metastasis-associated macrophages |
title_full_unstemmed | CCL2-induced chemokine cascade promotes breast cancer metastasis by enhancing retention of metastasis-associated macrophages |
title_short | CCL2-induced chemokine cascade promotes breast cancer metastasis by enhancing retention of metastasis-associated macrophages |
title_sort | ccl2-induced chemokine cascade promotes breast cancer metastasis by enhancing retention of metastasis-associated macrophages |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4493415/ https://www.ncbi.nlm.nih.gov/pubmed/26056232 http://dx.doi.org/10.1084/jem.20141836 |
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