前列腺癌
癌症研究
CCL5
转移
癌症干细胞
上皮-间质转换
癌症
肿瘤微环境
前列腺
基因敲除
生物
医学
肿瘤科
免疫学
内科学
免疫系统
细胞培养
T细胞
肿瘤细胞
白细胞介素2受体
遗传学
作者
Renlun Huang,Shengqi Wang,Neng Wang,Yifeng Zheng,Jianfu Zhou,Bowen Yang,Xuan Wang,Juping Zhang,Lang Guo,Shusheng Wang,Zhiqiang Chen,Zhiyu Wang,Shulin Xiang
标识
DOI:10.1038/s41419-020-2435-y
摘要
Abstract Prostate cancer stem cells (PCSCs) play a critical role in prostate cancer progression and metastasis, which remains an obstacle for successful prostate cancer treatment. Tumor-associated macrophages (TAMs) are the most abundant immune cell population within the tumor microenvironment (TME). Systematic investigation of the interaction and network signaling between PCSCs and TAMs may help in searching for the critical target to suppress PCSCs and metastasis. Herein, we demonstrated that TAMs-secreted CCL5 could significantly promote the migration, invasion, epithelial–mesenchymal transition (EMT) of prostate cancer cells as well as the self-renewal of PCSCs in vitro. QPCR screening validated STAT3 as the most significant response gene in prostate cancer cells following CCL5 treatment. RNA-sequencing and mechanistic explorations further revealed that CCL5 could promote PCSCs self-renewal and prostate cancer metastasis via activating the β-catenin/STAT3 signaling. Notably, CCL5 knockdown in TAMs not only significantly suppressed prostate cancer xenografts growth and bone metastasis but also inhibited the self-renewal and tumorigenicity of PCSCs in vivo. Finally, clinical investigations and bioinformatic analysis suggested that high CCL5 expression was significantly correlated with high Gleason grade, poor prognosis, metastasis as well as increased PCSCs activity in prostate cancer patients. Taken together, TAMs/CCL5 could promote PCSCs self-renewal and prostate cancer metastasis via activating β-catenin/STAT3 signaling. This study provides a novel rationale for developing TAMs/CCL5 as a potential molecular target for PCSCs elimination and metastatic prostate cancer prevention.
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