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

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.

The CCL5/CCR5 Axis in Cancer Progression

“…The CCL5/CCR5 axis is involved in prostate cancer progression: both molecules are expressed in human prostate cancer cell lines, primary cultures of prostatic adenocarcinoma cells and prostate cancer tissues [52]. High levels of CCL5 were found in blood samples and were associated with poor prognosis [187]. Prostate specific membrane antigen (PSMA) is a diagnostic biomarker because its expression is elevated in high-grade prostate cancer, in metastatic prostate cancer, and in androgen-insensitive prostate carcinoma [188].…”

CC Chemokines in a Tumor: A Review of Pro-Cancer and Anti-Cancer Properties of Receptors CCR5, CCR6, CCR7, CCR8, CCR9, and CCR10 Ligands

“…Its expression is elevated in breast cancer [ 60 ], glioblastoma multiforme [ 61 ], and hepatocellular carcinoma [ 62 ]. In a tumor, CCL5 expression is found in cancer cells [ 63 , 64 ], cancer-associated fibroblasts (CAF) [ 65 ], mesenchymal stem cells (MSC) [ 66 ], MDSC [ 67 ], TAM [ 68 , 69 , 70 , 71 ], and TIL [ 72 ]. CCL5 expression also occurs in lymphatic endothelial cells, which is crucial for the formation of the metastatic niche [ 73 ].…”

“…CCL5 acts on cancer cells by increasing their proliferation [ 62 , 64 , 74 , 75 ]. By activating the Wnt/β-catenin→signal transducer and activator of transcription 3 (STAT3) signaling pathways, it induces the self-renewal of prostate cancer stem cells [ 70 ]. Similar to other chemokines, CCL5 causes migration, invasion, and epithelial-to-mesenchymal transition (EMT) of cancer cells via its receptor [ 62 , 64 , 76 , 77 ], which is related to the activation of hedgehog [ 78 ], Wnt/β-catenin [ 70 , 79 ], and the Akt/PKB→nuclear factor κB (NF-κB) pathways [ 80 , 81 , 82 ].…”

“…However, little is known about the interactions between cells in a tumor, particularly the direct or indirect influence of cancer cells on non-cancer cells and the interactions between non-cancer cells. Especially interesting are cancer-cell-induced changes in the expression of chemokines produced by cancer-associated cells, e.g., by TAM [ 68 , 69 , 70 , 71 , 257 , 258 ], MDSC [ 67 ], and CAF [ 65 ]. In a tumor, cancer cells are not isolated but interact with cancer-associated cells, and that is why these cells (e.g., TAM, TIL, MDSC, CAF) should be investigated more often to discover new mechanisms in a tumor.…”

Hypoxia Alters the Expression of CC Chemokines and CC Chemokine Receptors in a Tumor–A Literature Review

“…In macrophages, results vary depending on the research model: chronic hypoxia may decrease [157,205], have no influence [158,177], or increase [201] CCL5/RANTES expression. Nevertheless, in cancer, CCL5/RANTES expression does occur, among others, in TAM [102,[206][207][208], and for this reason, the mechanism of the effect of hypoxia on the expression of CCL5/RANTES in these cells requires further research.…”