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URL: https://pubmed.ncbi.nlm.nih.gov/29375123/

⇱ The chemokine MCP-1 (CCL2) in the host interaction with cancer: a foe or ally? - PubMed

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Abstract

Macrophages are one of the most abundant leukocyte populations infiltrating tumor tissues and can exhibit both tumoricidal and tumor-promoting activities. In 1989, we reported the purification of monocyte chemoattractant protein-1 (MCP-1) from culture supernatants of mitogen-activated peripheral blood mononuclear cells and tumor cells. MCP-1 is a potent monocyte-attracting chemokine, identical to the previously described lymphocyte-derived chemotactic factor or tumor-derived chemotactic factor, and greatly contributes to the recruitment of blood monocytes into sites of inflammatory responses and tumors. Because in vitro-cultured tumor cells often produce significant amounts of MCP-1, tumor cells are considered to be the main source of MCP-1. However, various non-tumor cells in the tumor stroma also produce MCP-1 in response to stimuli. Studies performed in vitro and in vivo have provided evidence that MCP-1 production in tumors is a consequence of complex interactions between tumor cells and non-tumor cells and that both tumor cells and non-tumor cells contribute to the production of MCP-1. Although MCP-1 production was once considered to be a part of host defense against tumors, it is now believed to regulate the vicious cycle between tumor cells and macrophages that promotes the progression of tumors.

Keywords: chemokines; cytokines; inflammation; macrophages; tumor microenvironment.

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Conflict of interest statement

The author declares no conflict of interest.

Figures

👁 Figure 1
Figure 1
Cis-elements involved in the transcription of the human MCP-1 gene. Binding of transcription factors to multiple cis-elements in the 5′-untranslated region of the human MCP-1 gene regulates transcription of this gene. Binding of Sp1 to the GC box in the proximal region regulates basal transcription. In response to PMA, LPS, TNF-α or IL-1, NF-κB dimers, such as RelA/c-Rel heterodimers or RelA/RelA homodimers, bind to two NF-κB-binding sites (A1 and A2) in the distal region,,, whereas signal transducer and activator of transcription 1 (STAT1) homodimers bind to the IFN-γ activation site (GAS) after IFN-γ stimulation. Transcription of the MCP-1 gene in response to IFN-γ depends on a balance between a positive enhancement mechanism mediated through the GAS element and an inhibitory mechanism mediated through the IFN response-inhibitory sequence (IRIS) site. Region 1 is similar to site A in the murine MCP-1 gene and is occupied by an unknown protein before stimulation, and its function remains unclear. IFN-γ, interferon-γ; IL-1, interleukin-1; LPS, lipopolysaccharide; NF-κB, nuclear factor-κB; PMA, phorbol 12-myristate 13-acetate; TNF-α, tumor necrosis factor-α.
👁 Figure 2
Figure 2
Role of NF-κB and Sp1 in the constitutive production of MCP-1 by human glioma cell lines. U-105MG or U-373MG human malignant glioma cells were incubated in six-well culture plates for 2 days in the presence or absence of an indicated inhibitor, and then, the concentration of MCP-1 in the culture supernatant or expression of MCP-1 mRNA by glioma cells was examined by enzyme-linked immunosorbent assay or Northern blotting, respectively. (a) Constitutive production of MCP-1 by U-105MG or U-373MG cells. (b) Effect of the NF-κB inhibitor CAPE (10 μ). ***P<0.001. (c) Effect of the Sp1 inhibitor mythramycin (10−8 or 10−7 ). MCP-1, monocyte chemoattractant protein-1; NF-κB, nuclear factor-κB; Sp1, specificity protein 1.
👁 Figure 3
Figure 3
Mechanisms involved in the production of MCP-1 in LLC tumors. LLC cells harbor the activating Kras G12C mutation, which causes constitutive MCP-1 production. An unidentified product of LLC cells activates tumor-infiltrating macrophages to produce and release TNF-α. This TNF-α activates LLC cells to further upregulate MCP-1 production. The level of MCP-1 produced by LLC tumors is much higher than that in other tumors, including 4T1 and B16 tumors. We did not examine the biological significance of MCP-1 production in this model. LLC, Lewis lung carcinoma; MCP-1, monocyte chemoattractant protein-1; TNF-α, tumor necrosis factor-α.
👁 Figure 4
Figure 4
Role and mechanism of MCP-1 production in 4T1 breast cancer. Various cell types, including hematopoietic cells, fibroblasts and endothelial cells, are present in the primary tumor. Compared with LLC cells, the capacity of 4T1 cells to produce MCP-1 is significantly lower. However, 4T1 cells can activate stromal cells to produce a sufficient amount of MCP-1 for lung metastasis. For example, they produce and release GM-CSF, which upregulates the production of MCP-1 and other cytokines/chemokines by inflammatory macrophages. Activated CAFs and endothelial cells could be additional sources of MCP-1. MCP-1 production by stromal cells results in further recruitment of macrophages and angiogenesis and promotes lung metastasis. Tumor cell production of MCP-1 appears to promote the survival and seeding of tumor cells, potentially by recruiting metastasis-associated macrophages., CAF, cancer-associated fibroblast; DC, dendritic cells; EC, endothelial cells; GM-CSF, granulocyte-macrophage colony-stimulating factor; LLC, Lewis lung carcinoma; MCP-1, monocyte chemoattractant protein-1; MDSC, myeloid-derived suppressor cell; Treg, regulatory T cells; TAM, tumor-associated macrophages.
👁 Figure 5
Figure 5
Expression of MCP-1 mRNA in mouse breast cancer models. (a) Expression of MCP-1 mRNA in mammary and prostate tumors that arose in transgenic mice carrying a rat C3(1)-simian virus 40 large tumor antigen fusion gene was examined by Northern blotting. Ten micrograms of total RNA isolated from Normal mammary grand tissues, mammary tumor tissues, mammary tumor cell lines (M6, 6c, 8 and 8c), normal prostate tissue and prostate tumor cell lines (Pr-12 and 14) was used. (b) Expression of MCP-1 mRNA by 4T1 cells and 4T1-derived clones was examined by quantitative reverse transcription-PCR.

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