title: Induction of Monocyte Chemoattractant Proteins in Macrophages via the Production of Granulocyte/Macrophage Colony-Stimulating Factor by Breast Cancer Cells.
abstract: Monocyte chemoattractant protein-1 (MCP-1)/CCL2 plays an important role in the initiation and progression of cancer. We previously reported that in 4T1 murine breast cancer, non-tumor stromal cells, including macrophages, were the major source of MCP-1. In the present study, we analyzed the potential mechanisms by which MCP-1 is upregulated in macrophages infiltrating 4T1 tumors. We found that cell-free culture supernatants of 4T1 cells (4T1-sup) markedly upregulated MCP-1 production by peritoneal inflammatory macrophages. 4T1-sup also upregulated other MCPs, such as MCP-3/CCL7 and MCP-5/CCL12, but modestly upregulated neutrophil chemotactic chemokines, such as KC/CXCL1 or MIP-2/CXCL2. Physicochemical analysis indicated that an approximately 20-30 kDa 4T1 cell product was responsible for the capacity of 4T1-sup to upregulate MCP-1 expression by macrophages. A neutralizing antibody against granulocyte/macrophage colony-stimulating factor (GM-CSF), but not macrophage CSF, almost completely abrogated MCP-1-inducing activity of 4T1-sup, and recombinant GM-CSF potently upregulated MCP-1 production by macrophages. The expression levels of GM-CSF in 4T1 tumors in vivo were higher than other tumors, such as Lewis lung carcinoma. Treatment of mice with anti-GM-CSF antibody significantly reduced the growth of 4T1 tumors at the injection sites but did not reduce MCP-1 production or lung metastasis in tumor-bearing mice. These results indicate that 4T1 cells have the capacity to directly upregulate MCP-1 production by macrophages by releasing GM-CSF; however, other mechanisms are also involved in increased MCP-1 levels in the 4T1 tumor microenvironment.
authors.affiliation: Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD, USA; Department of Pathology and Experimental Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan.
authors.forename: Teizo
authors.initials: T
authors.lastname: Yoshimura
authors.affiliation: Laboratory of Human Retrovirology and Immunoinformatics, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research , Frederick, MD , USA.
authors.forename: Tomozumi
authors.initials: T
authors.lastname: Imamichi
authors.affiliation: Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute , Frederick, MD , USA.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Weiss
authors.affiliation: Department of Pathology and Experimental Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University , Okayama , Japan.
authors.forename: Miwa
authors.initials: M
authors.lastname: Sato
authors.affiliation: Engineering Research Center for Cell and Therapeutic Antibody of Ministry of Education, School of Pharmacy, Shanghai Jiaotong University , Shanghai , China.
authors.forename: Liangzhu
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Pathology and Experimental Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University , Okayama , Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Matsukawa
authors.affiliation: Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute , Frederick, MD , USA.
authors.forename: Ji Ming
authors.initials: JM
authors.lastname: Wang
keywords: breast cancer; chemokines; inflammation; monocytes/macrophages; tumor microenvironment
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