Rationale: Osteosarcoma (OS), a common malignant bone tumor, calls for the investigation of novel treatment strategies. Low-intensity vibration (LIV) presents itself as a promising option, given its potential to enhance bone health and decrease cancer susceptibility. This research delves into the effects of LIV on OS cells and mesenchymal stem cells (MSCs), with a primary focus on generating induced tumor-suppressing cells (iTSCs) and tumor-suppressive conditioned medium (CM)./nMethods: To ascertain the influence of vibration frequency, we employed numerical simulations and conducted experiments to determine the most effective LIV conditions. Subsequently, we generated iTSCs and CM through LIV exposure and assessed the impact of CM on OS cells. We also explored the underlying mechanisms of the tumor-suppressive effects of LIV-treated MSC CM, with a specific focus on vinculin (VCL). We employed cytokine array, RNA sequencing, and Western blot techniques to investigate alterations in cytokine profiles, transcriptomes, and tumor suppressor proteins./nResults: Numerical simulations validated LIV frequencies within the 10-100 Hz range. LIV induced notable morphological changes in OS cells and MSCs, confirming its dual role in inhibiting OS cell progression and promoting MSC conversion into iTSCs. Upregulated VCL expression enhanced MSC responsiveness to LIV, significantly bolstering CM's efficacy. Notably, we identified tumor suppressor proteins in LIV-treated CM, including procollagen C endopeptidase enhancer (PCOLCE), histone H4 (H4), peptidylprolyl isomerase B (PPIB), and aldolase A (ALDOA). Consistently, cytokine levels decreased significantly in LIV-treated mouse femurs, and oncogenic transcript levels were downregulated in LIV-treated OS cells. Moreover, our study demonstrated that combining LIV-treated MSC CM with chemotherapy drugs yielded additive anti-tumor effects./nConclusions: LIV effectively impeded the progression of OS cells and facilitated the transformation of MSCs into iTSCs. Notably, iTSC-derived CM demonstrated robust anti-tumor properties and the augmentation of MSC responsiveness to LIV via VCL. Furthermore, the enrichment of tumor suppressor proteins within LIV-treated MSC CM and the reduction of cytokines within LIV-treated isolated bone underscore the pivotal tumor-suppressive role of LIV within the bone tumor microenvironment.

中文翻译：

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增强抗肿瘤潜力：低强度振动抑制骨肉瘤进展并增强间充质干细胞的肿瘤抑制能力

理由：骨肉瘤（OS）是一种常见的恶性骨肿瘤，需要研究新的治疗策略。低强度振动 (LIV) 是一种很有前景的选择，因为它具有增强骨骼健康和降低癌症易感性的潜力。本研究深入探讨 LIV 对 OS 细胞和间充质干细胞 (MSC) 的影响，主要关注生成诱导肿瘤抑制细胞 (iTSC) 和肿瘤抑制条件培养基 (CM)。/n 方法：确定为了克服振动频率的影响，我们采用数值模拟并进行实验来确定最有效的LIV条件。随后，我们通过 LIV 暴露生成 iTSC 和 CM，并评估 CM 对 OS 细胞的影响。我们还探讨了 LIV 治疗的 MSC CM 肿瘤抑制作用的潜在机制，特别关注纽蛋白 (VCL)。我们采用细胞因子阵列、RNA 测序和蛋白质印迹技术来研究细胞因子谱、转录组和肿瘤抑制蛋白的变化。/n结果：数值模拟验证了 10-100 Hz 范围内的 LIV 频率。LIV 诱导 OS 细胞和 MSC 发生显着的形态变化，证实了其抑制 OS 细胞进展和促进 MSC 转化为 iTSC 的双重作用。VCL 表达上调增强了 MSC 对 LIV 的反应，显着增强了 CM 的功效。值得注意的是，我们在 LIV 治疗的 CM 中发现了肿瘤抑制蛋白，包括原胶原 C 内肽酶增强子 (PCOLCE)、组蛋白 H4 (H4)、肽基脯氨酰异构酶 B (PPIB) 和醛缩酶 A (ALDOA)。一致的是，LIV 处理的小鼠股骨中的细胞因子水平显着下降，并且 LIV 处理的 OS 细胞中的致癌转录物水平下调。此外，我们的研究表明，将 LIV 处理的 MSC CM 与化疗药物相结合可产生额外的抗肿瘤作用。/n结论： LIV 有效阻止 OS 细胞的进展，并促进 MSC 向 iTSC 的转化。值得注意的是，iTSC 衍生的 CM 表现出强大的抗肿瘤特性，并通过 VCL 增强 MSC 对 LIV 的反应性。此外，LIV 处理的 MSC CM 中肿瘤抑制蛋白的富集以及 LIV 处理的离体骨中细胞因子的减少强调了 LIV 在骨肿瘤微环境中的关键肿瘤抑制作用。