Cancer Cell-Derived Granulocyte-Macrophage Colony-Stimulating Factor Is Dispensable for the Progression of 4T1 Murine Breast Cancer
Cancer Cell-Derived Granulocyte-Macrophage Colony-Stimulating Factor Is Dispensable for the Progression of 4T1 Murine Breast Cancer
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DOI：
10.3390/ijms20246342
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发表时间：
2019-12
影响因子：
5.6
通讯作者：
T. Yoshimura;Kaoru Nakamura;Chunning Li;M. Fujisawa;Tsuyoshi Shiina;Mayu Imamura;Tiantian Li;N. Mukaida;A. Matsukawa
中科院分区：
文献类型：
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作者：
T. Yoshimura;Kaoru Nakamura;Chunning Li;M. Fujisawa;Tsuyoshi Shiina;Mayu Imamura;Tiantian Li;N. Mukaida;A. Matsukawa
我们之前报道了4T1小鼠乳腺癌细胞产生的GM-CSF上调巨噬细胞中几种促癌基因的表达，包括Mcp-1/Ccl2、Ccl17和Rankl，这表明癌细胞来源的GM-CSF在癌症进展中起关键作用。在这里，我们试图确定4T1细胞来源的GM-CSF是否有助于这些基因在4T1肿瘤中的表达，以及它们随后的进展。腹腔注射抗gm - csf中和抗体未降低4T1肿瘤Mcp-1、Ccl17和Rankl mRNA的表达。为了进一步研究癌细胞来源的GM-CSF的作用，我们使用Crisper-Cas9系统生成了缺乏GM-CSF的4T1细胞。如前所述，4T1细胞是混合细胞，克隆细胞本身可显著降低肿瘤生长和肺转移。相比之下，gm - csf缺乏不影响肿瘤生长、肺转移以及肿瘤组织中这些趋化因子和细胞因子基因的表达。原位杂交检测Mcp-1 mRNA在gm - csf缺陷细胞肿瘤中f4 /80表达细胞和非表达细胞中均有表达。这些结果表明，癌细胞来源的GM-CSF对于4T1肿瘤微环境的调节是必不可少的，并且4T1肿瘤微环境中MCP-1、CCL17或RANKL的产生可能受到冗余机制的调节。
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.