Tumor-Associated Macrophages Regulate Murine Breast Cancer Stem Cells Through a Novel Paracrine EGFR/Stat3/Sox-2 Signaling Pathway
Tumor-Associated Macrophages Regulate Murine Breast Cancer Stem Cells Through a Novel Paracrine EGFR/Stat3/Sox-2 Signaling Pathway
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DOI：
10.1002/stem.1281
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发表时间：
2013-02-01
期刊：
影响因子：
5.2
通讯作者：
Luo, Yunping
中科院分区：
文献类型：
--
作者：
Yang, Jian;Liao, Debbie;Luo, Yunping
肿瘤干细胞假说作为肿瘤发生的一种描述已经得到了广泛的认可。此外，已知肿瘤相关巨噬细胞（TAM）促进乳腺癌的生长和转移。然而，尚不清楚TAM是否通过调节乳腺CSC介导肿瘤发生。在这里，我们报告，TAM促进CSC样表型在小鼠乳腺癌细胞通过上调其表达的Sox-2。这些CSC样表型的特征在于增加的Sox-2、Oct-4、Nanog、AbcG 2和Sca-1基因表达，以及增加的药物外排能力、对化疗的抗性和增加的体内致瘤性。通过siRNA下调肿瘤细胞中的Sox-2阻断TAM诱导这些CSC样表型的能力并抑制体内肿瘤生长。此外，我们确定了一种新的表皮生长因子受体（EGFR）/信号转导和转录激活因子3（Stat 3）/Sox-2旁分泌信号通路之间的巨噬细胞和小鼠乳腺癌细胞，这是所需的巨噬细胞诱导的Sox-2和CSC的肿瘤细胞表型上调。我们表明，这种串扰被分别针对EGFR和Stat 3的小分子抑制剂AG 1478或CDDO-Im有效地阻断。因此，我们的报告确定了TAM在乳腺CSC调节中的新作用，并建立了靶向EGFR/Stat 3/Sox-2信号通路用于CSC治疗的基本原理。干细胞2013;31：248-258
The cancer stem cell (CSC) hypothesis has gained significant recognition as a descriptor of tumorigenesis. Additionally, tumor-associated macrophages (TAMs) are known to promote growth and metastasis of breast cancer. However, it is not known whether TAMs mediate tumorigenesis through regulation of breast CSCs. Here, we report that TAMs promote CSC-like phenotypes in murine breast cancer cells by upregulating their expression of Sox-2. These CSC-like phenotypes were characterized by increased Sox-2, Oct-4, Nanog, AbcG2, and Sca-1 gene expression, in addition to increased drug-efflux capacity, resistance to chemotherapy, and increased tumorigenicity in vivo. Downregulation of Sox-2 in tumor cells by siRNA blocked the ability of TAMs to induce these CSC-like phenotypes and inhibited tumor growth in vivo. Furthermore, we identified a novel epidermal growth factor receptor (EGFR)/signal transducers and activators of transcription 3 (Stat3)/Sox-2 paracrine signaling pathway between macrophages and mouse breast cancer cells that is required for macrophage-induced upregulation of Sox-2 and CSC phenotypes in tumor cells. We showed that this crosstalk was effectively blocked by the small molecule inhibitors AG1478 or CDDO-Im against EGFR and Stat3, respectively. Therefore, our report identifies a novel role for TAMs in breast CSC regulation and establishes a rationale for targeting the EGFR/Stat3/Sox-2 signaling pathway for CSC therapy. STEM CELLS 2013;31:248-258