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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...

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Autores principales: Kitamura, Takanori, Qian, Bin-Zhi, Soong, Daniel, Cassetta, Luca, Noy, Roy, Sugano, Gaël, Kato, Yu, Li, Jiufeng, Pollard, Jeffrey W.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2015
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.
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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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