CCL5 derived from tumor-associated macrophages promotes prostate cancer stem cells and metastasis via activating β-catenin/STAT3 signaling
CCL5 derived from tumor-associated macrophages promotes prostate cancer stem cells and metastasis via activating β-catenin/STAT3 signaling
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源自肿瘤相关巨噬细胞的 CCL5 通过激活 β-catenin/STAT3 信号传导促进前列腺癌干细胞和转移
DOI：
10.1038/s41419-020-2435-y
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发表时间：
2020-04-16
影响因子：
9
通讯作者：
Xiang, Songtao
中科院分区：
文献类型：
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作者：
Huang, Renlun;Wang, Shengqi;Xiang, Songtao
前列腺癌干细胞（PCSCs）在前列腺癌的进展和转移中起着至关重要的作用，这仍然是成功治疗前列腺癌的障碍。肿瘤相关巨噬细胞（tumor -associated macrophages, tam）是肿瘤微环境中最丰富的免疫细胞群。系统研究PCSCs与tam之间的相互作用和网络信号传导，有助于寻找抑制PCSCs和转移的关键靶点。本研究表明，tam分泌的CCL5可以显著促进前列腺癌细胞的迁移、侵袭、上皮-间质转化（EMT）以及PCSCs的体外自我更新。QPCR筛选证实STAT3是CCL5治疗后前列腺癌细胞中最显著的应答基因。rna测序和机制探索进一步揭示CCL5可通过激活β -catenin/STAT3信号通路促进PCSCs自我更新和前列腺癌转移。值得注意的是，TAMs中CCL5的下调不仅能显著抑制前列腺癌异种移植物的生长和骨转移，还能抑制PCSCs的体内自我更新和致瘤性。最后，临床研究和生物信息学分析表明，CCL5高表达与前列腺癌患者的高Gleason分级、预后差、转移及PCSCs活性升高显著相关。综上所述，tam /CCL5可通过激活β -catenin/STAT3信号通路促进PCSCs自我更新和前列腺癌转移。该研究为开发TAMs/CCL5作为PCSCs消除和转移性前列腺癌预防的潜在分子靶点提供了新的理论基础。
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 beta-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 beta-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.