Mechanical stimulations can inhibit local and remote tumor progression by downregulating WISP1

Shengzhi Liu, Di Wu, Xun Sun, Yao Fan, Rongrong Zha, Aydin Jalali, Meghana Teli, Tomohiko Sano, Amanda Siegel, Akihiro Sudo, Mangilal Agarwal, Alexander Robling, Bai Yan Li, Hiroki Yokota

Research output: Contribution to journalArticle


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.

Original languageEnglish (US)
Pages (from-to)12847-12859
Number of pages13
JournalFASEB Journal
Issue number9
StatePublished - Sep 1 2020


  • TGFβ calcitriol
  • WISP1
  • bone metastasis
  • breast cancer
  • cholesterol
  • urine
  • vitamin D

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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  • Cite this

    Liu, S., Wu, D., Sun, X., Fan, Y., Zha, R., Jalali, A., Teli, M., Sano, T., Siegel, A., Sudo, A., Agarwal, M., Robling, A., Li, B. Y., & Yokota, H. (2020). Mechanical stimulations can inhibit local and remote tumor progression by downregulating WISP1. FASEB Journal, 34(9), 12847-12859.