Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan.
Department of Materials Science and Engineering, University of Michigan, Ann Arbor, Michigan.
Biotechnol Bioeng. 2019 Nov;116(11):3084-3097. doi: 10.1002/bit.27119. Epub 2019 Aug 1.
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 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.
乳腺癌细胞在肿瘤微环境（TME）中经历一系列切变应力。然而，目前大多数体外三维（3D）模型未能系统地研究这些生物物理刺激对癌细胞转移、增殖和化学抗性的影响。为了研究乳腺和肺胸腔积液 TME 内剪切应力的作用，设计并表征了一种能够在 3D 细胞外基质内对细胞施加切变应力的生物反应器。乳腺癌细胞被包裹在互穿网络水凝胶中，并在 5.4 dynes cm 的切变应力下作用 72 小时。有限元建模评估了生物反应器内的切变应力分布。暴露于切变应力的细胞具有显著更大的细胞面积和显著更低的圆度，表明具有迁移表型。与静态对照相比，受刺激的细胞具有更高的增殖率，并且对抗肿瘤药物紫杉醇表现出更高的耐药性。通过明胶酶谱法和活性测定证实，流体切变应力诱导 PLAU 基因的显著上调和尿激酶活性的升高。总体而言，这些结果表明脉动切变应力促进乳腺癌细胞增殖、侵袭潜能、化学抗性和 PLAU 信号转导。
