CAF-mediated regulation of prostate cancer stem cell stemness via the Wnt/β-catenin and SDF-1/CXCR4 pathways in castration-resistant prostate cancer
IntroductionThe role of cancer-associated fibroblasts (CAFs) in the progression, therapeutic resistance, and metastasis of castration-resistant prostate cancer (CRPC) remains incompletely understood. This study aimed to investigate how CAFs regulate the stemness of prostate cancer stem cells (PCSCs)...
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Frontiers Media S.A.
2025-07-01
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| Series: | Frontiers in Cell and Developmental Biology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fcell.2025.1617200/full |
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| author | Haoran Chen Zhen Li Yuan Yue Xudong Zhu Jiazheng Wang Yafei Chen Yilin Wang Zhanyang Luo Hao Liu |
| author_facet | Haoran Chen Zhen Li Yuan Yue Xudong Zhu Jiazheng Wang Yafei Chen Yilin Wang Zhanyang Luo Hao Liu |
| author_sort | Haoran Chen |
| collection | DOAJ |
| description | IntroductionThe role of cancer-associated fibroblasts (CAFs) in the progression, therapeutic resistance, and metastasis of castration-resistant prostate cancer (CRPC) remains incompletely understood. This study aimed to investigate how CAFs regulate the stemness of prostate cancer stem cells (PCSCs), with a focus on the Wnt/β-catenin and SDF-1/CXCR4 signaling pathways.MethodsWe assessed the expression of CAF and PCSC markers in xenograft tumor tissues from hormone-sensitive prostate cancer and CRPC mouse models using immunohistochemistry and immunofluorescence. The impact of CAFs on stemness markers, SDF-1, CXCR4, and Wnt pathway activation was evaluated both in vitro and in vivo.ResultsThe expression levels of CAF and PCSC markers were significantly elevated in CRPC tissues compared to hormone-sensitive tumors. Bioinformatics analysis indicated high expression of CXCR4 and CTNNB1 (β-catenin) in CRPC, with positive correlations to disease progression. CAFs enhanced PCSC stemness, while inhibition of Wnt3a or SDF-1 led to reduced stemness and pathway activity. In vivo, CAFs promoted CRPC tumor growth and significantly increased the expression of Wnt3a, β-catenin, TCF4, LEF1, SDF-1, and CXCR4, along with an elevated p-GSK-3β/GSK-3β ratio. Conversely, β-catenin and CXCR4 inhibitors suppressed tumor growth and downregulated Wnt signaling components.Discussionβ-Catenin and CXCR4 showed strong co-localization in xenograft tumors. These findings suggest that CAFs promote PCSC stemness and CRPC progression by activating the Wnt/β-catenin and SDF-1/CXCR4 pathways via Wnt3a and SDF-1 expression. These insights provide potential targets for managing CRPC. |
| format | Article |
| id | doaj-art-421ddc5ba5484f09b2027bd29b5b039b |
| institution | Kabale University |
| issn | 2296-634X |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cell and Developmental Biology |
| spelling | doaj-art-421ddc5ba5484f09b2027bd29b5b039b2025-08-20T03:27:22ZengFrontiers Media S.A.Frontiers in Cell and Developmental Biology2296-634X2025-07-011310.3389/fcell.2025.16172001617200CAF-mediated regulation of prostate cancer stem cell stemness via the Wnt/β-catenin and SDF-1/CXCR4 pathways in castration-resistant prostate cancerHaoran Chen0Zhen Li1Yuan Yue2Xudong Zhu3Jiazheng Wang4Yafei Chen5Yilin Wang6Zhanyang Luo7Hao Liu8Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, ChinaCollege of Traditional Chinese Medicine, Anhui University of Chinese Medicine, Hefei, Anhui, ChinaThe Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, ChinaGuang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, ChinaGuang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, ChinaGraduate School, Beijing University of Chinese Medicine, Beijing, ChinaGraduate School, Beijing University of Chinese Medicine, Beijing, ChinaShanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, ChinaGuang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, ChinaIntroductionThe role of cancer-associated fibroblasts (CAFs) in the progression, therapeutic resistance, and metastasis of castration-resistant prostate cancer (CRPC) remains incompletely understood. This study aimed to investigate how CAFs regulate the stemness of prostate cancer stem cells (PCSCs), with a focus on the Wnt/β-catenin and SDF-1/CXCR4 signaling pathways.MethodsWe assessed the expression of CAF and PCSC markers in xenograft tumor tissues from hormone-sensitive prostate cancer and CRPC mouse models using immunohistochemistry and immunofluorescence. The impact of CAFs on stemness markers, SDF-1, CXCR4, and Wnt pathway activation was evaluated both in vitro and in vivo.ResultsThe expression levels of CAF and PCSC markers were significantly elevated in CRPC tissues compared to hormone-sensitive tumors. Bioinformatics analysis indicated high expression of CXCR4 and CTNNB1 (β-catenin) in CRPC, with positive correlations to disease progression. CAFs enhanced PCSC stemness, while inhibition of Wnt3a or SDF-1 led to reduced stemness and pathway activity. In vivo, CAFs promoted CRPC tumor growth and significantly increased the expression of Wnt3a, β-catenin, TCF4, LEF1, SDF-1, and CXCR4, along with an elevated p-GSK-3β/GSK-3β ratio. Conversely, β-catenin and CXCR4 inhibitors suppressed tumor growth and downregulated Wnt signaling components.Discussionβ-Catenin and CXCR4 showed strong co-localization in xenograft tumors. These findings suggest that CAFs promote PCSC stemness and CRPC progression by activating the Wnt/β-catenin and SDF-1/CXCR4 pathways via Wnt3a and SDF-1 expression. These insights provide potential targets for managing CRPC.https://www.frontiersin.org/articles/10.3389/fcell.2025.1617200/fullcastration-resistant prostate cancercancer-associated fibroblastprostate cancer stem cellWnt/β-cateninSDF-1/CXCR4 |
| spellingShingle | Haoran Chen Zhen Li Yuan Yue Xudong Zhu Jiazheng Wang Yafei Chen Yilin Wang Zhanyang Luo Hao Liu CAF-mediated regulation of prostate cancer stem cell stemness via the Wnt/β-catenin and SDF-1/CXCR4 pathways in castration-resistant prostate cancer Frontiers in Cell and Developmental Biology castration-resistant prostate cancer cancer-associated fibroblast prostate cancer stem cell Wnt/β-catenin SDF-1/CXCR4 |
| title | CAF-mediated regulation of prostate cancer stem cell stemness via the Wnt/β-catenin and SDF-1/CXCR4 pathways in castration-resistant prostate cancer |
| title_full | CAF-mediated regulation of prostate cancer stem cell stemness via the Wnt/β-catenin and SDF-1/CXCR4 pathways in castration-resistant prostate cancer |
| title_fullStr | CAF-mediated regulation of prostate cancer stem cell stemness via the Wnt/β-catenin and SDF-1/CXCR4 pathways in castration-resistant prostate cancer |
| title_full_unstemmed | CAF-mediated regulation of prostate cancer stem cell stemness via the Wnt/β-catenin and SDF-1/CXCR4 pathways in castration-resistant prostate cancer |
| title_short | CAF-mediated regulation of prostate cancer stem cell stemness via the Wnt/β-catenin and SDF-1/CXCR4 pathways in castration-resistant prostate cancer |
| title_sort | caf mediated regulation of prostate cancer stem cell stemness via the wnt β catenin and sdf 1 cxcr4 pathways in castration resistant prostate cancer |
| topic | castration-resistant prostate cancer cancer-associated fibroblast prostate cancer stem cell Wnt/β-catenin SDF-1/CXCR4 |
| url | https://www.frontiersin.org/articles/10.3389/fcell.2025.1617200/full |
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