Department of Sarcoma Medical Oncology, Division of Cancer Medicine, The University of Texas, MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, Texas 77030, United States.
ACS Biomater Sci Eng. 2020 Jan 13;6(1):539-552. doi: 10.1021/acsbiomaterials.9b01068. Epub 2019 Dec 13.
The tumor microenvironment harbors essential components required for cancer progression including biochemical signals and mechanical cues. To study the effects of microenvironmental elements on Ewing's sarcoma (ES) pathogenesis, we tissue-engineered an acellular three-dimensional (3D) bone tumor niche from electrospun poly(ε-caprolactone) (PCL) scaffolds that incorporate bone-like architecture, extracellular matrix (ECM), and mineralization. PCL-ECM constructs were generated by decellularizing PCL scaffolds harboring cultures of osteogenic human mesenchymal stem cells. The PCL-ECM constructs simulated in vivo-like tumor architecture and increased the proliferation of ES cells compared to PCL scaffolds alone. Compared to monolayer controls, 3D environments facilitated the downregulation of the canonical insulin-like growth factor 1 receptor (IGF-1R) signal cascade through mechanistic target of rapamycin (mTOR), both of which are targets of recent clinical trials. In addition to the downregulation of canonical IGF-1R signaling, 3D environments promoted a reduction in the clathrin-dependent nuclear localization and transcriptional activity of IGF-1R. In vitro drug testing revealed that 3D environments generated cell phenotypes that were resistant to mTOR inhibition and chemotherapy. Our versatile PCL-ECM constructs allow for the investigation of the roles of various microenvironmental elements in ES tumor growth, cancer cell morphology, and induction of resistant cell phenotypes.
肿瘤微环境包含促进癌症进展的必需成分，包括生化信号和机械线索。为了研究微环境因素对尤文肉瘤（ES）发病机制的影响，我们从具有类似骨结构、细胞外基质（ECM）和矿化的电纺聚己内酯（PCL）支架构建了无细胞三维（3D）骨肿瘤小生境。PCL-ECM 构建体是通过脱细胞化含有成骨人类间充质干细胞培养物的 PCL 支架产生的。与单独的 PCL 支架相比，PCL-ECM 构建体模拟了类似于体内的肿瘤结构，并且增加了 ES 细胞的增殖。与单层对照相比，3D 环境通过雷帕霉素（mTOR）下游调节了经典胰岛素样生长因子 1 受体（IGF-1R）信号级联的下调，这两者都是最近临床试验的靶点。除了经典 IGF-1R 信号的下调外，3D 环境还促进了 IGF-1R 的网格蛋白依赖性核定位和转录活性的降低。体外药物测试表明，3D 环境产生了对 mTOR 抑制和化学疗法具有抗性的细胞表型。我们的多功能 PCL-ECM 构建体允许研究各种微环境因素在 ES 肿瘤生长、癌细胞形态和诱导耐药细胞表型中的作用。
