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

      1 , 1 , 2 , 1 , 1 , 1 , 2 , 3
      Biotechnology and Bioengineering
      Wiley

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          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 (IPN) hydrogel and subjected to shear stress of 5.4 dynes cm −2 for 72 hours. 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.

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          Role of extracellular matrix assembly in interstitial transport in solid tumors.

          The extracellular matrix (ECM) may contribute to the drug resistance of a solid tumor by preventing the penetration of therapeutic agents. We measured differences in interstitial resistance to macromolecule (IgG) motion in four tumor types and found an unexpected correspondence between transport resistance and the mechanical stiffness. The interstitial diffusion coefficient of IgG was measured in situ by fluorescence redistribution after photobleaching. Tissue elastic modulus and hydraulic conductivity were measured by confined compression of excised tissue. In apparent contradiction to an existing paradigm, these functional properties are correlated with total tissue content of collagen, not glycosaminoglycan. An extended collagen network was observed in the more penetration-resistant tumors. Collagenase treatment of the more penetration-resistant tumors significantly increased the IgG interstitial diffusion rate. We conclude that collagen influences the tissue resistance to macromolecule transport, possibly by binding and stabilizing the glycosaminoglycan component of the ECM. These findings suggest a new method to screen tumors for potential resistance to macromolecule-based therapy. Moreover, collagen and collagen-proteoglycan bonds are identified as potential targets of treatment to improve macromolecule delivery.
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            Author and article information

            Contributors
            Journal
            Biotechnology and Bioengineering
            Biotechnology and Bioengineering
            Wiley
            0006-3592
            1097-0290
            August 05 2019
            November 2019
            August 2019
            November 2019
            : 116
            : 11
            : 3084-3097
            Affiliations
            [1 ]Department of Biomedical EngineeringUniversity of Michigan Ann Arbor Michigan
            [2 ]Department of Materials Science and EngineeringUniversity of Michigan Ann Arbor Michigan
            [3 ]Macromolecular Science and EngineeringUniversity of Michigan Ann Arbor Michigan
            Article
            10.1002/bit.27119
            6774895
            31317530
            27162ba5-17cd-442d-bf2f-a98e9bd9870b
            © 2019

            http://onlinelibrary.wiley.com/termsAndConditions#am

            http://onlinelibrary.wiley.com/termsAndConditions#vor

            http://doi.wiley.com/10.1002/tdm_license_1.1

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