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Modeling Stroma-Induced Drug Resistance in a Tissue-Engineered Tumor Model of Ewing Sarcoma.

ABSTRACT: Three-dimensional (3D) tumor models are gaining traction in the research community given their capacity to mimic aspects of the tumor microenvironment absent in monolayer systems. In particular, the ability to spatiotemporally control cell placement within ex vivo 3D systems has enabled the study of tumor-stroma interactions. Furthermore, by regulating biomechanical stimuli, one can reveal how biophysical cues affect stromal cell phenotype and how their phenotype impacts tumor drug sensitivity. Both tumor architecture and shear force have profound effects on Ewing sarcoma (ES) cell behavior and are known to elicit ligand-mediated activation of the insulin-like growth factor-1 receptor (IGF-1R), thereby mediating resistance of ES cells to IGF-1R inhibitors. Here, we demonstrate that these same biophysical cues-modeled by coculturing ES cells and mesenchymal stem cells (MSCs) in 3D scaffolds within a flow perfusion bioreactor-activate interleukin-6 and transcription factor Stat3. Critically, an active Stat3 pathway drastically alters the equilibrium of IGF-1R-targeted ligands (IGF-1) and antagonists (IGFBP-3) secreted by MSCs. To elucidate how this might promote ES tumor growth under physiological shear-stress conditions, ES cells and MSCs were co-cultured by using a flow perfusion bioreactor at varying ratios that simulate a wide range of native MSC abundance. Our results indicate that ES cells and MSCs stimulate each other's growth. Co-targeting IGF-1R and Stat3 enhanced antineoplastic activity over monotherapy treatment. Although this discovery requires prospective clinical validation in patients, it reveals the power of employing a more physiological tissue-engineered 3D tumor model to elucidate how tumor cells co-opt stromal cells to acquire drug resistance.

SUBMITTER: Santoro M

PROVIDER: S-EPMC5240012 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Modeling Stroma-Induced Drug Resistance in a Tissue-Engineered Tumor Model of Ewing Sarcoma.

Santoro Marco M Menegaz Brian A BA Lamhamedi-Cherradi Salah-Eddine SE Molina Eric R ER Wu Danielle D Priebe Waldemar W Ludwig Joseph A JA Mikos Antonios G AG

Tissue engineering. Part A 20170101 1-2

Three-dimensional (3D) tumor models are gaining traction in the research community given their capacity to mimic aspects of the tumor microenvironment absent in monolayer systems. In particular, the ability to spatiotemporally control cell placement within ex vivo 3D systems has enabled the study of tumor-stroma interactions. Furthermore, by regulating biomechanical stimuli, one can reveal how biophysical cues affect stromal cell phenotype and how their phenotype impacts tumor drug sensitivity. ...[more]

PMID: 27923328

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Project description:Neuroblastoma is a vascularized pediatric tumor derived from neural crest stem cells that displays vasculogenic mimicry and can express a number of stemness markers, such as SOX2 and NANOG. Tumor relapse is the major cause of succumbing to this disease, and properties attributed to cancer stem-like cells (CSLC), such as drug-resistance and cell plasticity, seem to be the key mechanisms. However, the lack of controllable models that recapitulate the features of human neuroblastoma limits our understanding of the process and impedes the development of new therapies. In response to these limitations, we engineered a perfusable, vascularized in vitro model of three-dimensional human neuroblastoma to study the effects of retinoid therapy on tumor vasculature and drug-resistance.MethodsThe in vitro model of neuroblastoma was generated using cell-sheet engineering and cultured in a perfusion bioreactor. Firstly, we stacked three cell sheets containing SKNBE(2) neuroblastoma cells and HUVEC. Then, a vascular bed made of fibrin, collagen I and HUVEC cells was placed onto a collagen-gel base with 8 microchannels. After gelling, the stacked cell sheets were placed on the vascular bed and cultured in the perfusion bioreactor (perfusion rate: 0.5 mL/min) for 4 days. Neuroblastoma models were treated with 10μM isotretionin in single daily doses for 5 days.ResultsThe bioengineered model recapitulated vasculogenic mimicry (vessel-like structure formation and tumor-derived endothelial cells-TECs), and contained CSLC expressing SOX2 and NANOG. Treatment with Isotretinoin destabilized vascular networks but failed to target vasculogenic mimicry and augmented populations of CSLCs expressing high levels of SOX2. Our results suggest that CSLCs can transdifferentiate into drug resistant CD31+-TECs, and reveal the presence of an intermediate state STEC (stem tumor-derived endothelial cell) expressing both SOX2 and CD31.ConclusionOur results reveal some roles of SOX2 in drug resistance and tumor relapse, and suggest that SOX2 could be a therapeutic target in neuroblastoma.

Dataset Information

Modeling Stroma-Induced Drug Resistance in a Tissue-Engineered Tumor Model of Ewing Sarcoma.

Publications

Modeling Stroma-Induced Drug Resistance in a Tissue-Engineered Tumor Model of Ewing Sarcoma.

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