期刊
JOURNAL OF EXPERIMENTAL MEDICINE
卷 212, 期 7, 页码 1043-1059出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20141836
关键词
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资金
- United States Department of Defense Congressionally Directed Medical Research Programs [W81xWH-11-1-0703]
- National Institutes of Health [R01 CA172451, P01 CA100324]
- Wellcome Trust, UK [101067/Z/13/Z]
- MRC [G1002033] Funding Source: UKRI
- Medical Research Council [G1002033] Funding Source: researchfish
- Wellcome Trust [101067/Z/13/Z] Funding Source: researchfish
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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