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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.

SUBMITTER: Villasante A

PROVIDER: S-EPMC5314970 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Studies of anticancer therapies in traditional cell culture models can demonstrate efficacy of direct-acting compounds but lack the 3-dimensional arrangement of the tumor cells and their tissue-specific microenvironments, both of which are important modulators of treatment effects in vivo. Bone cells reside in complex environments that regulate their fate and function. A bioengineered human bone-tumor model has been shown to provide a microphysiological niche for studies of cancer cell behavior. Here, we demonstrate successful transfer between 2 laboratories and utility of this model in efficacy studies using well-established chemotherapeutic agents. The bioengineered human bone-tumor model consisted of Ewing sarcoma (RD-ES) cancer cell aggregates infused into tissue-engineered bone that was grown from human mesenchymal stem cell-derived differentiated into osteoblasts within mineralized bone scaffolds. The tumor model was maintained in culture for over 5 weeks and subjected to clinically relevant doses of linsitinib, doxorubicin, cisplatin, methotrexate, vincristine, dexamethasone, or MAP (methotrexate, doxorubicin, and cisplatin combination). Drug administration cycles were designed to mimic clinical treatment regimens. The bioengineered tumors were evaluated days to weeks after the cessation of treatment to monitor the potential for relapse, using bioengineered bone and ES cell monolayers as controls. Drug binding to the scaffolds and media proteins and gene expression were also evaluated. We show that a bioengineered human bone tumor can be used as a microphysiological model for preclinical studies of anticancer drugs. We found that anticancer efficacy was achieved at concentrations approximating the human Cmax, in contrast to traditional ES cell monolayers. These studies show that the bone-tumor model can be successfully transferred between laboratories and has predictive power in preclinical studies. The effects of drugs on the bone tumors and healthy bone were studied in parallel, in support of the utility of this model for identification of new therapeutic targets.

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Tissue-Engineered Model of Human Osteolytic Bone Tumor.

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