ORIGINAL RESEARCH article
Front. Cell Dev. Biol.
Sec. Cancer Cell Biology
Volume 13 - 2025 | doi: 10.3389/fcell.2025.1617200
CAF-Mediated Regulation of Prostate Cancer Stem Cell Stemness via the Wnt/β-Catenin and SDF-1/CXCR4 Pathways in Castration-Resistant Prostate Cancer
Provisionally accepted
- 1Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, Beijing Municipality, China
- 2Key Laboratory of the Chinese Ministry of Education, Anhui University of Chinese Medicine, Hefei, China
- 3The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
- 4Graduate school, Beijing University of Chinese Medicine, Beijing, China
- 5Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, China
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Introduction: The role of cancer-associated fibroblasts (CAFs) in castration-resistant prostate cancer (CRPC) progression, therapeutic resistance, and metastasis remains unclear. Therefore, we investigated this role, focusing on the regulation of prostate cancer stem cell (PCSC) stemness via the Wnt/β-catenin and SDF-1/CXCR4 pathways. Methods: We examined CAF and PCSC marker expression in xenograft tumor tissues from mice with hormone-sensitive prostate cancer and those 2 with CRPC using immunohistochemistry and immunofluorescence assays. We examined the effects of CAFs on stemness marker, SDF-1, and CXCR4 expression and Wnt pathway activation in vitro and in vivo. Results: The expression of CAF and PCSC stemness markers was significantly higher in mice with CRPC than in those with hormone-sensitive prostate cancer. Bioinformatics analysis revealed a high expression of the β-catenin genes CXCR4 and CTNNB1 in CRPC, demonstrating a positive correlation with CRPC development. CAF promoted PCSC stemness, whereas inhibition of Wnt3a and SDF-1 expression significantly decreased it, affecting downstream pathways. CAFs promoted CRPC growth in vivo; significantly upregulated Wnt3a, β-catenin, TCF4, LEF1, SDF-1, and CXCR4 expression; and increased the p-GSK-3β/GSK-3β ratio in tumor tissue. Conversely, βcatenin and CXCR4 inhibitors suppressed tumor growth and proliferation and downregulated Wnt pathway protein expression. Discussion: β-Catenin and CXCR4 exhibited strong co-localization in transplanted tumors. Thus, CAFs activate the Wnt/β-catenin and SDF-1/CXCR4 pathways in PCSCs through the expression of Wnt3a and SDF-1. These results have implications for understanding and managing CRPC.
Keywords: castration-resistant prostate cancer, Cancer-associated fibroblast, Prostate cancer stem cell, Wnt/β-catenin, SDF-1/CXCR4
Received: 24 Apr 2025; Accepted: 03 Jul 2025.
Copyright: © 2025 Chen, Li, Yue, Zhu, Wang, Chen, Wang, Luo and Liu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Zhanyang Luo, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, China
Hao Liu, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 100053, Beijing Municipality, China
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