Infiltrating macrophages promote prostate tumorigenesis via modulating androgen receptor-mediated CCL4-STAT3 signaling.
Infiltrating macrophages promote prostate tumorigenesis via modulating androgen receptor-mediated CCL4-STAT3 signaling.
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DOI：
10.1158/0008-5472.can-12-3228
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发表时间：
2013-09-15
期刊：
影响因子：
11.2
通讯作者：
Chang C
中科院分区：
文献类型：
--
作者：
Fang LY;Izumi K;Lai KP;Liang L;Li L;Miyamoto H;Lin WJ;Chang C
浸润性巨噬细胞是肿瘤发生过程中炎症的关键组成部分，但这种联系的直接证据仍不清楚。我们在这里报告说，永久性的前列腺上皮细胞与巨噬细胞，不添加任何致癌物质，诱导前列腺肿瘤的发生，诱导涉及改变巨噬细胞雄激素受体（AR）-炎性趋化因子CCL 4-STAT 3激活以及上皮细胞间质转化（EMT）和下调p53/PTEN肿瘤抑制信号。体内研究进一步表明，缺乏巨噬细胞AR的PTEN+/−小鼠发生的前列腺上皮内瘤变（PIN）病变要少得多，这支持了巨噬细胞AR在前列腺肿瘤发生过程中的体内作用。CCL 4中和抗体有效地阻断巨噬细胞诱导的前列腺肿瘤发生信号传导，并且通过AR降解增强剂ASC-J 9 ®靶向AR，减少体内CCL 4表达和异种移植肿瘤生长。重要的是，在高级别PIN和前列腺癌中，CCL 4上调与Snail表达增加和p53/PTEN下调相关。总之，我们的研究结果确定了AR-CCL 4-STAT 3轴作为前列腺肿瘤发生过程中的关键调节因子，并强调了浸润性巨噬细胞和炎性细胞因子在前列腺肿瘤发生中的重要作用。
Infiltrating macrophages are a key component of inflammation during tumorigenesis, but the direct evidence of such linkage remains unclear. We report here that persistent co-culturing of immortalized prostate epithelial cells with macrophages, without adding any carcinogens, induces prostate tumorigenesis, and that induction involves the alteration of signaling of macrophage androgen receptor (AR)-inflammatory chemokine CCL4-STAT3 activation as well as epithelial-to-mesenchymal transition (EMT) and down-regulation of p53/PTEN tumor suppressors. In vivo studies further showed that PTEN+/− mice lacking macrophage AR developed far fewer prostatic intraepithelial neoplasia (PIN) lesions, supporting an in vivo role for macrophage AR during prostate tumorigenesis. CCL4 neutralizing antibody effectively blocked macrophage-induced prostate tumorigenic signaling, and targeting AR via an AR degradation enhancer, ASC-J9®, reduced CCL4 expression and xenografted tumor growth in vivo. Importantly, CCL4 upregulation was associated with increased Snail expression and down-regulation of p53/PTEN in high-grade PIN and prostate cancer. Together, our results identify the AR-CCL4-STAT3 axis as key regulators during prostate tumor initiation and highlight the important roles of infiltrating macrophages and inflammatory cytokines for the prostate tumorigenesis.