title: CCL2-induced chemokine cascade promotes breast cancer metastasis by enhancing retention of metastasis-associated macrophages.
abstract: 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.
authors.affiliation: MRC Centre for Reproductive Health, Queen's Medical Research Institute, the University of Edinburgh, Edinburgh EH16 4TJ, Scotland, UK.
authors.forename: Takanori
authors.initials: T
authors.lastname: Kitamura
authors.affiliation: MRC Centre for Reproductive Health, Queen's Medical Research Institute, the University of Edinburgh, Edinburgh EH16 4TJ, Scotland, UK.
authors.forename: Bin-Zhi
authors.initials: BZ
authors.lastname: Qian
authors.affiliation: MRC Centre for Reproductive Health, Queen's Medical Research Institute, the University of Edinburgh, Edinburgh EH16 4TJ, Scotland, UK.
authors.forename: Daniel
authors.initials: D
authors.lastname: Soong
authors.affiliation: MRC Centre for Reproductive Health, Queen's Medical Research Institute, the University of Edinburgh, Edinburgh EH16 4TJ, Scotland, UK.
authors.forename: Luca
authors.initials: L
authors.lastname: Cassetta
authors.affiliation: Department of Developmental and Molecular Biology, Center for the Study of Reproductive Biology and Women's Health, Albert Einstein College of Medicine, New York, NY 10461.
authors.forename: Roy
authors.initials: R
authors.lastname: Noy
authors.affiliation: MRC Centre for Reproductive Health, Queen's Medical Research Institute, the University of Edinburgh, Edinburgh EH16 4TJ, Scotland, UK.
authors.forename: Gaël
authors.initials: G
authors.lastname: Sugano
authors.affiliation: Department of Developmental and Molecular Biology, Center for the Study of Reproductive Biology and Women's Health, Albert Einstein College of Medicine, New York, NY 10461.
authors.forename: Yu
authors.initials: Y
authors.lastname: Kato
authors.affiliation: Department of Developmental and Molecular Biology, Center for the Study of Reproductive Biology and Women's Health, Albert Einstein College of Medicine, New York, NY 10461.
authors.forename: Jiufeng
authors.initials: J
authors.lastname: Li
authors.affiliation: MRC Centre for Reproductive Health, Queen's Medical Research Institute, the University of Edinburgh, Edinburgh EH16 4TJ, Scotland, UK Department of Developmental and Molecular Biology, Center for the Study of Reproductive Biology and Women's Health, Albert Einstein College of Medicine, New York, NY 10461 Jeff.Pollard@ed.ac.uk.
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Pollard
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D001943:Breast Neoplasms / Q000503:physiopathology*; D018932:Chemokine CCL2 / Q000378:metabolism*; D054405:Chemokine CCL3 / Q000235:genetics / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D008163:Luminescent Measurements; D008175:Lung Neoplasms / Q000556:secondary*; D008264:Macrophages / Q000166:cytology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046228:Microarray Analysis; D009362:Neoplasm Metastasis / Q000503:physiopathology*; D060888:Real-Time Polymerase Chain Reaction; D054389:Receptors, CCR1 / Q000172:deficiency / Q000378:metabolism; D054390:Receptors, CCR2 / Q000235:genetics; D019713:Receptors, CCR5 / Q000235:genetics
chemical_list: C000592874:CCR5 protein, mouse; C496534:Ccl3 protein, mouse; C515301:Ccr1 protein, mouse; C515335:Ccr2 protein, mouse; D018932:Chemokine CCL2; D054405:Chemokine CCL3; D017931:DNA Primers; D054389:Receptors, CCR1; D054390:Receptors, CCR2; D019713:Receptors, CCR5