title: Crosstalk between Tumor Cells and Macrophages in Stroma Renders Tumor Cells as the Primary Source of MCP-1/CCL2 in Lewis Lung Carcinoma.
abstract: The chemokine MCP-1/CCL2 is produced by a variety of tumors and plays an important role in cancer progression. We and others previously demonstrated that the primary source of MCP-1 in several mouse tumors, including 4T1 breast cancer, M5076 sarcoma, and B16 melanoma, was stromal cells. In the present study, we identified that tumor cells were the primary source of MCP-1 in Lewis lung carcinoma (LLC), because MCP-1 mRNA was highly expressed in tumors grown in both wild type (WT) and MCP-1(-/-) mice with elevated serum MCP-1 levels. Since LLC cells isolated from tumors expressed low levels of MCP-1 in vitro, it appeared that the tumor-stromal cell interaction in a tumor microenvironment increased MCP-1 expression in LLC cells. In fact, co-culture of LLC cells with normal mouse peritoneal macrophages or normal lung cells containing macrophages increased MCP-1 expression by LLC cells. Macrophages from TNFα(-/-) mice failed to activate LLC cells and anti-TNFα neutralizing antibody abolished the effect of WT macrophages on LLC cells. When LLC cells were transplanted into TNFα(-/-) mice, the levels of MCP-1 mRNA in tumors and serum MCP-1 levels were markedly lower as compared to WT mice, and importantly, tumors grew more slowly. Taken together, our results indicate that TNFα released by tumor cell-activated macrophages is critical for increased MCP-1 production by tumors cells. Thus, disruption of tumor-stromal cell interaction may inhibit tumor progression by reducing the production of tumor-promoting proinflammatory mediators, such as MCP-1.
authors.affiliation: Laboratory of Molecular Immunoregulation, Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute , Frederick, MD , USA.
authors.forename: Teizo
authors.initials: T
authors.lastname: Yoshimura
authors.affiliation: Laboratory of Molecular Immunoregulation, Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute , Frederick, MD , USA ; Department of Spine Surgery, Daping Hospital, Third Military Medical University , Chongqing , China.
authors.forename: Mingyong
authors.initials: M
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau , Macao , China ; Basic Science Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc. , Frederick, MD , USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Chen
authors.affiliation: Laboratory of Molecular Immunoregulation, Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute , Frederick, MD , USA ; 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: Laboratory of Molecular Immunoregulation, 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: chemokines; inflammation; lung cancer; monocytes/macrophages; tumor microenvironment