title: Tissue-Engineered Model of Human Osteolytic Bone Tumor.
abstract: Ewing's sarcoma (ES) is a poorly differentiated pediatric tumor of aggressive behavior characterized by propensity to metastasize to bone. Interactions between the tumor and bone cells orchestrate a vicious cycle in which tumor cells induce osteoclast differentiation and activation to cause osteolytic lesions, broken bones, pain, and hypercalcemia. The lack of controllable models that can recapitulate osteolysis in ES impedes the development of new therapies and limits our understanding of how tumor cells invade bone. In response to this need, tissue-engineered models are now being developed to enable quantitative, predictive studies of human tumors. In this study, we report a novel bioengineered model of ES that incorporates the osteolytic process. Our strategy is based on engineering human bone containing both osteoclasts and osteoblasts within three-dimensional mineralized bone matrix. We show that the bone matrix is resorbed by mature osteoclasts while the new bone matrix is formed by osteoblasts, leading to calcium release and bone remodeling. Introduction of ES cell aggregates into the bone niche induced decreases in bone density, connectivity, and matrix deposition. Additionally, therapeutic reagents, such as zoledronic acid, which have demonstrated efficacy in ES treatment, inhibited bone resorption mediated by osteoclasts in the tumor model.
authors.affiliation: 1 Department of Biomedical Engineering, Columbia University , New York, New York.
authors.forename: Aranzazu
authors.initials: A
authors.lastname: Villasante
authors.affiliation: 1 Department of Biomedical Engineering, Columbia University , New York, New York.|2 Department of Chemistry, Materials and Chemical Engineering "G. Natta," Politecnico di Milano, Milan, Italy .
authors.forename: Alessandro
authors.initials: A
authors.lastname: Marturano-Kruik
authors.affiliation: 1 Department of Biomedical Engineering, Columbia University , New York, New York.
authors.forename: Samuel T
authors.initials: ST
authors.lastname: Robinson
authors.affiliation: 1 Department of Biomedical Engineering, Columbia University , New York, New York.
authors.forename: Zen
authors.initials: Z
authors.lastname: Liu
authors.affiliation: 1 Department of Biomedical Engineering, Columbia University , New York, New York.
authors.forename: X Edward
authors.initials: XE
authors.lastname: Guo
authors.affiliation: 1 Department of Biomedical Engineering, Columbia University , New York, New York.|3 Department of Medicine, Columbia University , New York, New York.
authors.forename: Gordana
authors.initials: G
authors.lastname: Vunjak-Novakovic
mesh_terms: D050071:Bone Density Conservation Agents / Q000494:pharmacology; D001859:Bone Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D002454:Cell Differentiation; D002478:Cells, Cultured; D004164:Diphosphonates / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008954:Models, Biological; D010006:Osteoblasts / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D010014:Osteolysis / Q000503:physiopathology*; D012512:Sarcoma, Ewing / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D023822:Tissue Engineering / Q000379:methods*; D000077211:Zoledronic Acid
chemical_list: D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D007093:Imidazoles; D000077211:Zoledronic Acid
keywords: Ewing's sarcoma; osteoclasts; osteolysis; tissue engineering; tumor model