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

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 TGF? 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.

SUBMITTER: Fan Y

PROVIDER: S-EPMC7021802 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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