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.
Highlights
Tumor tissues consist of a variety of cell types, including tumor cells, fibroblasts, endothelial cells, myocytes, and inflammatory cells, such as myeloid-derived suppressor cells, regulatory T cells, macrophages, and dendritic cells
Activated Tumor Cells are the Main Source of MCP-1 in Lewis lung carcinoma (LLC) Tumors It was previously demonstrated that the blockade of MCP-1 significantly slowed the growth of primary tumors in mouse non-small cell lung cancer (NSCLC) models, including a LLC model [16]
To evaluate the role for MCP-1 produced by non-tumor stromal cells in tumor growth in this model, we subcutaneously injected LLC cells into the flank of wild type (WT) or MCP-1−/− mice
Summary
Tumor tissues consist of a variety of cell types, including tumor cells, fibroblasts, endothelial cells, myocytes, and inflammatory cells, such as myeloid-derived suppressor cells, regulatory T cells, macrophages, and dendritic cells. These mediators include matrix metalloproteinases, growth factors, cytokines, and chemokines [1,2,3]. MCP-1/CCL2 is a chemokine with potent monocyte chemotactic activity It was initially purified from the culture supernatant of a human malignant glioma cell line [4] and a human monocytic leukemic cell line [5], and found to be identical to the previously described tumor cell-derived chemotactic factor [6]. Earlier animal studies using MCP-1-transfected tumor cells provided a combination of anti- or pro-tumor effects of MCP-1 [7,8,9,10], accumulating evidence strongly supports the notion that the production of MCP-1 by tumors promotes tumor progression. Neutralization of MCP-1 resulted in reduced growth of prostate [13,14,15] and lung cancer [16], as well as reduced metastasis of breast cancer [17, 18] in mice
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