Mechanical stimulations can prevent bone loss, but their effects on the tumor‐invaded bone or solid tumors are elusive. Here, we evaluated the effect of knee loading, dynamic loads applied to the knee, on metastasized bone and mammary tumors. In a mouse model, tumor cells were inoculated to the mammary fat pad or the proximal tibia. Daily knee loading was then applied and metabolic changes were monitored mainly through urine. Urine samples were also collected from human subjects before and after step aerobics. The result showed that knee loading inhibited tumor progression in the loaded tibia. Notably, it also reduced remotely the growth of mammary tumors. In the urine, an altered level of cholesterol was observed with an increase in calcitriol, which is synthesized from a cholesterol derivative. In urinary proteins, knee loading in mice and step aerobics in humans markedly reduced WNT1‐inducible signaling pathway protein 1, WISP1, which leads to poor survival among patients with breast cancer. In the ex vivo breast cancer tissue assay, WISP1 promoted the growth of cancer fragments and upregulated tumor‐promoting genes, such as Runx2, MMP9, and Snail. Collectively, the present preclinical and human study demonstrated that mechanical stimulations, such as knee loading and step aerobics, altered urinary metabolism and downregulated WISP1. The study supports the benefit of mechanical stimulations for locally and remotely suppressing tumor progression. It also indicated the role of WISP1 downregulation as a potential mechanism of loading‐driven tumor suppression.

中文翻译：

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机械刺激可通过下调 WISP1 抑制局部和远程肿瘤进展

机械刺激可以防止骨质流失，但它们对肿瘤侵入的骨或实体瘤的影响是难以捉摸的。在这里，我们评估了膝关节负荷、施加于膝关节的动态负荷、对转移的骨和乳腺肿瘤的影响。在小鼠模型中，将肿瘤细胞接种到乳腺脂肪垫或胫骨近端。然后每天施加膝关节负荷，主要通过尿液监测代谢变化。还从有氧运动前后的人类受试者收集尿液样本。结果表明，膝关节负荷抑制了负荷胫骨的肿瘤进展。值得注意的是，它还远程减少了乳腺肿瘤的生长。在尿液中，随着骨化三醇的增加，观察到胆固醇水平的改变，骨化三醇是由胆固醇衍生物合成的。在尿蛋白中，小鼠的膝关节负荷和人类的踏步有氧运动显着降低了 WNT1 诱导的信号通路蛋白 1，WISP1，这导致乳腺癌患者的生存率降低。在体外乳腺癌组织试验中，WISP1 促进了癌症片段的生长并上调了促癌基因，如 Runx2、MMP9 和 Snail。总的来说，目前的临床前和人体研究表明，机械刺激，如膝关节负荷和有氧运动，改变了尿液代谢并下调了 WISP1。该研究支持机械刺激对局部和远程抑制肿瘤进展的好处。它还表明 WISP1 下调作为负载驱动的肿瘤抑制的潜在机制的作用。这导致乳腺癌患者的生存率很低。在体外乳腺癌组织试验中，WISP1 促进了癌症片段的生长并上调了促癌基因，如 Runx2、MMP9 和 Snail。总的来说，目前的临床前和人体研究表明，机械刺激，如膝关节负荷和有氧运动，改变了尿液代谢并下调了 WISP1。该研究支持机械刺激对局部和远程抑制肿瘤进展的好处。它还表明 WISP1 下调作为负载驱动的肿瘤抑制的潜在机制的作用。这导致乳腺癌患者的生存率很低。在体外乳腺癌组织试验中，WISP1 促进了癌症片段的生长并上调了促癌基因，如 Runx2、MMP9 和 Snail。总的来说，目前的临床前和人体研究表明，机械刺激，如膝关节负荷和有氧运动，改变了尿液代谢并下调了 WISP1。该研究支持机械刺激对局部和远程抑制肿瘤进展的好处。它还表明 WISP1 下调作为负载驱动的肿瘤抑制的潜在机制的作用。目前的临床前和人体研究表明，机械刺激，如膝关节负荷和有氧运动，改变了尿液代谢并下调了 WISP1。该研究支持机械刺激对局部和远程抑制肿瘤进展的好处。它还表明 WISP1 下调作为负载驱动的肿瘤抑制的潜在机制的作用。目前的临床前和人体研究表明，机械刺激，如膝关节负荷和有氧运动，改变了尿液代谢并下调了 WISP1。该研究支持机械刺激对局部和远程抑制肿瘤进展的好处。它还表明 WISP1 下调作为负载驱动的肿瘤抑制的潜在机制的作用。