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.
Highlights
Prostate cancer is the second most commonly diagnosed malignancy and the fifth leading cause of cancer death among men worldwide[1]
By conducting the clinicopathological sample analysis, RNA-sequencing, molecular biology experiment and animal experiment, we systematically demonstrated that CCL5 was mainly secreted by transformed into M2 phenotype macrophages (TAMs) and could promote Prostate cancer stem cells (PCSCs) self-renewal and metastasis via activating β-catenin/STAT3 signaling in vitro
CCL5 was mainly secreted by TAMs, and its expression was elevated in prostate cancer and associated with metastasis
Summary
Prostate cancer is the second most commonly diagnosed malignancy and the fifth leading cause of cancer death among men worldwide[1]. Development of the metastatic tumor and recapitulation of the primary tumor in a secondary site is driven by cancer stem cells (CSCs)[3]. Recent evidence has revealed the critical role of PCSCs in prostate cancer initiation and progression to metastatic disease. PCSCs can serve as prognostic markers for overall survival in both low and high Gleason grade prostate cancers[4]. The population size of PCSCs in the primary tumor or circulation could provide prognostic information capable of guiding prostate cancer treatment or predicting clinical outcomes. Several strategies have been applied for PCSCs identification, including cell surface markers (e.g., CD133, CD44, ALDH, integrin α2β1, CD117/c-kit, Trop[2], c-Met, ABCG2, and so on), functional approaches (e.g., mammosphere-forming, aldefluor staining, and side-population assays) and reporter-based lineage tracing strategies[2,5]. A better understanding of PCSCs biology as well as their interaction with microenvironment components is paramount for developing novel therapeutic strategies in the clinic
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