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Skeletal loading regulates breast cancer-associated osteolysis in a loading intensity-dependent fashion

Authors
  • Fan, Yao1, 2
  • Jalali, Aydin2
  • Chen, Andy2
  • Zhao, Xinyu2, 3
  • Liu, Shengzhi2
  • Teli, Meghana2
  • Guo, Yunxia1, 2
  • Li, Fangjia2
  • Li, Junrui4
  • Siegel, Amanda2
  • Yang, Lianxiang4
  • Liu, Jing2
  • Na, Sungsoo2
  • Agarwal, Mangilal2
  • Robling, Alexander G.5, 5
  • Nakshatri, Harikrishna5
  • Li, Bai-Yan1
  • Yokota, Hiroki1, 2, 4, 2, 5, 5
  • 1 Harbin Medical University, Harbin, 150081, China , Harbin (China)
  • 2 Indiana University Purdue University Indianapolis, Indianapolis, IN, 46202, USA , Indianapolis (United States)
  • 3 Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, 100730, China , Beijing (China)
  • 4 Oakland University, Rochester, MI, 48309, USA , Rochester (United States)
  • 5 Indiana University School of Medicine, Indianapolis, IN, 46202, USA , Indianapolis (United States)
Type
Published Article
Journal
Bone Research
Publisher
Nature Publishing Group UK
Publication Date
Feb 14, 2020
Volume
8
Issue
1
Identifiers
DOI: 10.1038/s41413-020-0083-6
Source
Springer Nature
License
Green

Abstract

Osteocytes are mechanosensitive bone cells, but little is known about their effects on tumor cells in response to mechanical stimulation. We treated breast cancer cells with osteocyte-derived conditioned medium (CM) and fluid flow-treated conditioned medium (FFCM) with 0.25 Pa and 1 Pa shear stress. Notably, CM and FFCM at 0.25 Pa induced the mesenchymal-to-epithelial transition (MET), but FFCM at 1 Pa induced the epithelial-to-mesenchymal transition (EMT). This suggested that the effects of fluid flow on conditioned media depend on flow intensity. Fluorescence resonance energy transfer (FRET)-based evaluation of Src activity and vinculin molecular force showed that osteopontin was involved in EMT and MET switching. A mouse model of tumor-induced osteolysis was tested using dynamic tibia loadings of 1, 2, and 5 N. The low 1 N loading suppressed tumor-induced osteolysis, but this beneficial effect was lost and reversed with loads at 2 and 5 N, respectively. Changing the loading intensities in vivo also led to changes in serum TGFβ levels and the composition of tumor-associated volatile organic compounds in the urine. Collectively, this study demonstrated the critical role of intensity-dependent mechanotransduction and osteopontin in tumor-osteocyte communication, indicating that a biophysical factor can tangibly alter the behaviors of tumor cells in the bone microenvironment.

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