CCL5 derived from tumor-associated macrophages promotes prostate cancer stem cells and metastasis via activating β-catenin/STAT3 signaling

TLDR

Prostate cancer stem cells drive disease progression and metastasis, while tumor‑associated macrophages are the predominant immune cells in the tumor microenvironment. The study sought to identify critical targets within the PCSC–TAM interaction, focusing on CCL5, to suppress PCSC self‑renewal and metastatic spread. TAM‑secreted CCL5 enhances prostate cancer cell migration, invasion, EMT, and PCSC self‑renewal by activating β‑catenin/STAT3 signaling, and its knockdown reduces tumor growth, bone metastasis, and PCSC tumorigenicity, with high CCL5 expression correlating with aggressive disease.

Abstract

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.