Department of Urology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China.
Department of Urology, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, 530021, China.
Stem Cell Res Ther. 2018 Sep 26;9(1):242. doi: 10.1186/s13287-018-0989-8.
Androgen deprivation (AD) as the first-line treatment for advanced prostate cancer (PCa) is insufficient for a long-term effect. Castration resistance remains the greatest obstacle in PCa clinical therapy. Mesenchymal stem cells (MSCs) can migrate into PCa tissues contributing to tumor progression, therefore, in this study we explored the effect of AD on MSC migration to PCa and elicited its importance for the emergence of castration resistance.
MSC migration assay was performed in several PCa cells (LNCaP, VCaP, and 22Rv1) using in-vivo and in-vitro approaches. Reactive oxygen species generation was evaluated by fluorescence assay. IL-1β was analyzed by immunohistochemistry, and neutralization experiments were conducted using neutralization antibody. Stem markers (CD133, CD44, and SOX2) were quantified by real-time PCR analysis. The concentration of chemokine ligand 5 was measured by enzyme-linked immunosorbent assay and small hairpin RNA was used for functional analyses.
AD could significantly contribute to PCa recruitment of MSCs in vivo and in vitro. AD-induced oxidative stress could promote the inflammatory response mediated by IL-1β secretion via activating the NF-κB signaling pathway. Moreover, N-acetylcysteine could significantly inhibit MSC recruitment to PCa sites when AD is performed. Furthermore, we found MSCs could increase stemness of PCa cells via promoting chemokine ligand 5 secretion in the AD condition, and consequently accelerate emergence of castration resistance.
Our results suggest that castration in clinical PCa therapy may elicit oxidative stress in tumor sites, resulting in increased MSC migration and in tumor cell growth in an androgen-independent manner. Blocking MSC migration to the tumor may provide a new potential target to suppress castration-resistant PCa emergence.
雄激素剥夺（AD）作为晚期前列腺癌（PCa）的一线治疗方法，长期效果不足。去势抵抗仍然是 PCa 临床治疗的最大障碍。间充质干细胞（MSCs）可以迁移到 PCa 组织中，促进肿瘤进展，因此，在这项研究中，我们探讨了 AD 对 MSC 迁移到 PCa 的影响，并揭示了其对去势抵抗出现的重要性。
采用体内和体外方法研究 AD 对几种 PCa 细胞（LNCaP、VCaP 和 22Rv1）中 MSC 迁移的影响。通过荧光测定法评估活性氧（ROS）的产生。采用免疫组织化学分析白细胞介素-1β（IL-1β），并用中和抗体进行中和实验。通过实时 PCR 分析定量干细胞标志物（CD133、CD44 和 SOX2）。用酶联免疫吸附试验测量趋化因子配体 5 的浓度，并使用小发夹 RNA 进行功能分析。
AD 可显著促进 MSC 在体内和体外向 PCa 的募集。AD 诱导的氧化应激可通过激活 NF-κB 信号通路促进由 IL-1β 分泌介导的炎症反应。此外，在进行 AD 时，N-乙酰半胱氨酸可显著抑制 MSC 向 PCa 部位的募集。此外，我们发现，在 AD 条件下，MSCs 可通过促进趋化因子配体 5 的分泌来增加 PCa 细胞的干性，从而加速去势抵抗的出现。
我们的研究结果表明，在临床 PCa 治疗中去势可能会在肿瘤部位引起氧化应激，导致 MSC 迁移增加和雄激素非依赖性肿瘤细胞生长。阻断 MSC 向肿瘤的迁移可能为抑制去势抵抗性 PCa 出现提供新的潜在靶点。
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