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Biotechnol Bioeng. 2019 Nov;116(11):3084-3097. doi: 10.1002/bit.27119. Epub 2019 Aug 1.

Fluid shear stress stimulates breast cancer cells to display invasive and chemoresistant phenotypes while upregulating PLAU in a 3D bioreactor.

Author information

1
Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan.
2
Department of Materials Science and Engineering, University of Michigan, Ann Arbor, Michigan.
3
Macromolecular Science and Engineering, University of Michigan, Ann Arbor, Michigan.

Abstract

Breast cancer cells experience a range of shear stresses in the tumor microenvironment (TME). However most current in vitro three-dimensional (3D) models fail to systematically probe the effects of this biophysical stimuli on cancer cell metastasis, proliferation, and chemoresistance. To investigate the roles of shear stress within the mammary and lung pleural effusion TME, a bioreactor capable of applying shear stress to cells within a 3D extracellular matrix was designed and characterized. Breast cancer cells were encapsulated within an interpenetrating network hydrogel and subjected to shear stress of 5.4 dynes cm-2 for 72 hr. Finite element modeling assessed shear stress profiles within the bioreactor. Cells exposed to shear stress had significantly higher cellular area and significantly lower circularity, indicating a motile phenotype. Stimulated cells were more proliferative than static controls and showed higher rates of chemoresistance to the anti-neoplastic drug paclitaxel. Fluid shear stress-induced significant upregulation of the PLAU gene and elevated urokinase activity was confirmed through zymography and activity assay. Overall, these results indicate that pulsatile shear stress promotes breast cancer cell proliferation, invasive potential, chemoresistance, and PLAU signaling.

KEYWORDS:

3D bioreactor; PLAU; breast cancer; interpenetrating hydrogel; mechanotransduction; shear stress

PMID:
31317530
DOI:
10.1002/bit.27119

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