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Cancer Cell-Derived Granulocyte-Macrophage Colony-Stimulating Factor Is Dispensable for the Progression of 4T1 Murine Breast Cancer

1
Department of Pathology and Experimental Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata, Kita-ku, Okayama 700-8558, Japan
2
Division of Molecular Bioregulation, Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2019, 20(24), 6342; https://doi.org/10.3390/ijms20246342
Received: 7 November 2019 / Revised: 9 December 2019 / Accepted: 10 December 2019 / Published: 16 December 2019
(This article belongs to the Special Issue Tumor Microenvironment 3.0)
We previously reported that 4T1 murine breast cancer cells produce GM-CSF that up-regulates macrophage expression of several cancer promoting genes, including Mcp-1/Ccl2, Ccl17 and Rankl, suggesting a critical role of cancer cell-derived GM-CSF in cancer progression. Here, we attempted to define whether 4T1 cell-derived GM-CSF contributes to the expression of these genes by 4T1tumors, and their subsequent progression. Intraperitoneal injection of anti-GM-CSF neutralizing antibody did not decrease the expression of Mcp-1, Ccl17 or Rankl mRNA by 4T1 tumors. To further examine the role of cancer cell-derived GM-CSF, we generated GM-CSF-deficient 4T1 cells by using the Crisper-Cas9 system. As previously demonstrated, 4T1 cells are a mixture of cells and cloning of cells by itself significantly reduced tumor growth and lung metastasis. By contrast, GM-CSF-deficiency did not affect tumor growth, lung metastasis or the expression of these chemokine and cytokine genes in tumor tissues. By in-situ hybridization, the expression of Mcp-1 mRNA was detected in both F4/80-expressing and non-expressing cells in tumors of GM-CSF-deficient cells. These results indicate that cancer cell-derived GM-CSF is dispensable for the tuning of the 4T1 tumor microenvironment and the production of MCP-1, CCL17 or RANKL in the 4T1 tumor microenvironment is likely regulated by redundant mechanisms. View Full-Text
Keywords: macrophages; chemokines; cytokines; inflammation; tumor microenvironment; breast cancer macrophages; chemokines; cytokines; inflammation; tumor microenvironment; breast cancer
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Yoshimura, T.; Nakamura, K.; Li, C.; Fujisawa, M.; Shiina, T.; Imamura, M.; Li, T.; Mukaida, N.; Matsukawa, A. Cancer Cell-Derived Granulocyte-Macrophage Colony-Stimulating Factor Is Dispensable for the Progression of 4T1 Murine Breast Cancer. Int. J. Mol. Sci. 2019, 20, 6342.

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