title: Flow perfusion effects on three-dimensional culture and drug sensitivity of Ewing sarcoma.
abstract: Three-dimensional tumor models accurately describe different aspects of the tumor microenvironment and are readily available for mechanistic studies of tumor biology and for drug screening. Nevertheless, these systems often overlook biomechanical stimulation, another fundamental driver of tumor progression. To address this issue, we cultured Ewing sarcoma (ES) cells on electrospun poly(ε-caprolactone) 3D scaffolds within a flow perfusion bioreactor. Flow-derived shear stress provided a physiologically relevant mechanical stimulation that significantly promoted insulin-like growth factor-1 (IGF1) production and elicited a superadditive release in the presence of exogenous IGF1. This finding is particularly relevant, given the central role of the IGF1/IGF-1 receptor (IGF-1R) pathway in ES tumorigenesis and as a promising clinical target. Additionally, flow perfusion enhanced in a rate-dependent manner the sensitivity of ES cells to IGF-1R inhibitor dalotuzumab (MK-0646) and showed shear stress-dependent resistance to the IGF-1R blockade. This study demonstrates shear stress-dependent ES cell sensitivity to dalotuzumab, highlighting the importance of biomechanical stimulation on ES-acquired drug resistance to IGF-1R inhibition. Furthermore, flow perfusion increased nutrient supply throughout the scaffold, enriching ES culture over static conditions. Our use of a tissue-engineered model, rather than human tumors or xenografts, enabled precise control of the forces experienced by ES cells, and therefore provided at least one explanation for the remarkable antineoplastic effects observed by some ES tumor patients from IGF-1R targeted therapies, in contrast to the lackluster effect observed in cells grown in conventional monolayer culture.
authors.affiliation: Department of Chemical and Biomolecular Engineering, Rice University, Houston, TX 77005; Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77054;
authors.forename: Marco
authors.initials: M
authors.lastname: Santoro
authors.affiliation: Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77054;
authors.forename: Salah-Eddine
authors.initials: SE
authors.lastname: Lamhamedi-Cherradi
authors.affiliation: Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77054;
authors.forename: Brian A
authors.initials: BA
authors.lastname: Menegaz
authors.affiliation: Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77054; mikos@rice.edu jaludwig@mdanderson.org.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Ludwig
authors.affiliation: Department of Chemical and Biomolecular Engineering, Rice University, Houston, TX 77005; Department of Bioengineering, Rice University, Houston, TX 77030 mikos@rice.edu jaludwig@mdanderson.org.
authors.forename: Antonios G
authors.initials: AG
authors.lastname: Mikos
mesh_terms: D000911:Antibodies, Monoclonal / Q000737:chemistry; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000737:chemistry*; D001696:Biomechanical Phenomena; D019149:Bioreactors; D002470:Cell Survival; D004354:Drug Screening Assays, Antitumor; D004867:Equipment Design; D005434:Flow Cytometry; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008024:Ligands; D008855:Microscopy, Electron, Scanning; D008856:Microscopy, Fluorescence; D010477:Perfusion; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors; D012512:Sarcoma, Ewing / Q000378:metabolism / Q000473:pathology*; D015398:Signal Transduction; D013314:Stress, Mechanical; D023822:Tissue Engineering / Q000379:methods; D014407:Tumor Cells, Cultured / Q000187:drug effects
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D008024:Ligands; D007334:Insulin-Like Growth Factor I; C569480:dalotuzumab; D017526:Receptor, IGF Type 1
keywords: biological therapy; mechanical stimulation; tissue engineering; tumor model