Center for Engineered Cancer Testbeds, Materials and Nanotechnology Program, Department of Civil and Environmental Engineering, North Dakota State University, Fargo, ND 58108, United States of America.
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Biofabrication. 2021 Apr 2;13(3). doi: 10.1088/1758-5090/abd9d6.
Metastatic prostate cancer spreads preferentially to the bone, causing skeletal complications associated with significant morbidity and a poor prognosis, despite current therapeutic approaches. Hence, it is imperative to understand the complex metastatic cascade to develop therapeutic interventions for treating metastatic prostate cancer. Increasing evidence suggests the synergistic role of biochemical and biophysical cues in cancer progression at metastases. However, the mechanism underlying the crosstalk between interstitial flow-induced mechanical stimuli and prostate cancer progression at the bone microenvironment remains poorly understood. To this end, we have developed a three-dimensional (3D)dynamic model of prostate cancer bone metastasis using perfusion bioreactor and compared our results with static conditions to delineate the role of flow-induced shear stress on prostate cancer progression at metastases. We observed an increase in human mesenchymal stem cell (hMSCs) proliferation and differentiation rate under the dynamic culture. The hMSCs form cell agglutinates under static culture, whereas the hMSCs exhibited a directional alignment with broad and flattened morphology under dynamic culture. Further, the expression of mesenchymal to epithelial transition biomarkers is increased in bone metastasized prostate cancer models, and large changes are observed in the cellular and tumoroid morphologies under dynamic culture. Evaluation of cell adhesion proteins indicated that the altered cancer cell morphologies resulted from the constant force pulling due to increased E-cadherin and phosphorylated focal adhesion kinase proteins under shear stress. Overall, we report a successful 3Ddynamic model to recapitulate bone metastatic prostate cancer behavior under dynamic conditions.
转移性前列腺癌优先扩散到骨骼，导致与重大发病率和预后不良相关的骨骼并发症，尽管目前有治疗方法。因此，了解复杂的转移级联反应对于开发治疗转移性前列腺癌的治疗干预措施至关重要。越来越多的证据表明，生化和生物物理线索在转移部位的癌症进展中具有协同作用。然而，细胞外间质流引起的机械刺激与前列腺癌在骨微环境中进展之间的串扰机制仍知之甚少。为此，我们使用灌注生物反应器开发了一种前列腺癌骨转移的三维（3D）动态模型，并将我们的结果与静态条件进行比较，以阐明流诱导剪切应力对转移部位前列腺癌进展的作用。我们观察到在动态培养下，人骨髓间充质干细胞（hMSCs）的增殖和分化率增加。在静态培养下，hMSCs 形成细胞聚集体，而在动态培养下，hMSCs 表现出定向排列，具有宽阔和平坦的形态。此外，在骨转移前列腺癌模型中，间充质向上皮转化生物标志物的表达增加，并且在动态培养下观察到细胞和肿瘤形态的巨大变化。细胞黏附蛋白的评估表明，由于剪切应力下 E-钙黏蛋白和磷酸化粘着斑激酶蛋白的增加导致恒定力的拉动，改变了癌细胞形态。总的来说，我们报告了一种成功的 3D 动态模型，可在动态条件下再现骨转移前列腺癌的行为。
