Tissue-Engineered Model of Human Osteolytic Bone Tumor

Villasante, Aránzazu; Marturano-Kruik, Alessandro; Robinson, Samuel T.; Liu, Zen; Guo, X. Edward; Vunjak‐Novakovic, Gordana

doi:10.1089/ten.tec.2016.0371

Cited by 22 publications

(21 citation statements)

References 52 publications

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“…(A) In order to better recreate the BM niche of primary bone tumors, our group developed a protocol for the co-culture of functional bone-depositing osteoblasts and bone resorbing osteoclasts within a trabecullar bone scaffold. Ewing sarcoma tumor aggregate introduction results in decreases to bone density, connectivity, and matrix deposition, as observed clinically (Adopted from [165]). (B) The importance of 3D culture of primary bone tumors within tissue engineered BM niche models is evident from exosome analysis: only cancers grown in this context can recapitulate the exosome size (top) and mRNA cargo observed in patients.…”

Section: Dmentioning

confidence: 86%

“…Osteoclasts play a major role in the growth and migration of malignancies in the BM, therefore we incorporated functional human osteoclasts into this bioengineered model of ES (Fig. 5A) [165]. The mix of functional osteoblasts and osteoclasts expectedly led to bone matrix deposition and resorption resulting in calcium release and bone remodeling as would be seen in the native BM niche.…”

Section: Generating Ewing Sarcoma Tumors In a 3d Bone Marrow Nichementioning

confidence: 99%

“…Osteoclasts are also involved in the maintenance of quiescent, drug resistant leukemic cells [210,211]. Our group has shown how osteoclasts can be co-cultured in a BM biomimetic niche [165]. Incorporation of HSPCs and other immune cells could inform novel approaches towards the inclusion of tumor associated macrophages within BM malignancy models, which would be of clinical value given the implication of these cells in drug resistance and metastasis across BM cancers [212][213][214][215].…”

Section: Future Directionsmentioning

confidence: 99%

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Tissue engineered models of healthy and malignant human bone marrow

Chramiec

Vunjak‐Novakovic

2019

Advanced Drug Delivery Reviews

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Tissue engineering is becoming increasingly successful in providing in vitro models of human tissues that can be used for ex vivo recapitulation of functional tissues as well as predictive testing of drug efficacy and safety. From simple tissue models to microphysiological platforms comprising multiple tissue types connected by vascular perfusion, these "tissues on a chip" are emerging as a fast track application for tissue engineering, with great potential for modeling diseases and supporting the development of new drugs and therapeutic targets. We focus here on tissue engineering of the hematopoietic stem and progenitor cell compartment and the malignancies that develop in the human bone and bone marrow. Our overall goal is to demonstrate the utility and interconnectedness of improvements in bioengineering methods developed in one area of bone marrow studies for the remaining, seemingly disparate, bone marrow fields.

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Section: Dmentioning

confidence: 86%

Section: Generating Ewing Sarcoma Tumors In a 3d Bone Marrow Nichementioning

confidence: 99%

Section: Future Directionsmentioning

confidence: 99%

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Tissue engineered models of healthy and malignant human bone marrow

Chramiec

Vunjak‐Novakovic

2019

Advanced Drug Delivery Reviews

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“…As this process is crucial, several groups focused on the development of in vitro models of bone osteolysis by coculturing tumor cells with osteoclasts and osteoblasts. Recently, Villasante et al ( 60 ) engineered a healthy bone tissue by co-culturing osteoblasts derived from hMSC and osteoclasts derived from monocytes isolated from blood samples. First, hMSC were seeded within a decellularized bone scaffold and differentiated toward osteoblasts.…”

Section: D In Vitro Modelsmentioning

confidence: 99%

Three-Dimensional Patient-Derived In Vitro Sarcoma Models: Promising Tools for Improving Clinical Tumor Management

Gaebler

Silvestri²,

Haybaeck

et al. 2017

Front. Oncol.

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Over the past decade, the development of new targeted therapeutics directed against specific molecular pathways involved in tumor cell proliferation and survival has allowed an essential improvement in carcinoma treatment. Unfortunately, the scenario is different for sarcomas, a group of malignant neoplasms originating from mesenchymal cells, for which the main therapeutic approach still consists in the combination of surgery, chemotherapy, and radiation therapy. The lack of innovative approaches in sarcoma treatment stems from the high degree of heterogeneity of this tumor type, with more that 70 different histopathological subtypes, and the limited knowledge of the molecular drivers of tumor development and progression. Currently, molecular therapies are available mainly for the treatment of gastrointestinal stromal tumor, a soft-tissue malignancy characterized by an activating mutation of the tyrosine kinase KIT. Since the first application of this approach, a strong effort has been made to understand sarcoma molecular alterations that can be potential targets for therapy. The low incidence combined with the high level of histopathological heterogeneity makes the development of clinical trials for sarcomas very challenging. For this reason, preclinical studies are needed to better understand tumor biology with the aim to develop new targeted therapeutics. Currently, these studies are mainly based on in vitro testing, since cell lines, and in particular patient-derived models, represent a reliable and easy to handle tool for investigation. In the present review, we summarize the most important models currently available in the field, focusing in particular on the three-dimensional spheroid/organoid model. This innovative approach for studying tumor biology better represents tissue architecture and cell–cell as well as cell–microenvironment crosstalk, which are fundamental steps for tumor cell proliferation and survival.

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“…Additionally, a therapeutic reagent which have demonstrated efficacy in ES treatment, prevented bone resorption mediated by osteoclasts in the tumor model. (18) This model appeared suitable to understand the biology and genetic origin of tumor and underlying reasons of tumor progression. However, choice of the appropriate drug for personalized therapy and discovery of new agents in the treatment of bone cancer require reproducible models unlike the decellularized bone matrix-based models that are not obtained in the same composition for each test.…”

Section: Introductionmentioning

confidence: 99%

A 2-Compartment Bone Tumor Model for Testing the Efficacy of Cancer Drugs

Kömez

Büyüksungur²,

Antmen³

et al. 2019

Preprint

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We produced a three dimensional (3D) bone tumor model (BTM) to study the interactions between healthy and tumor cells in a tumor tissue microenvironment, migration of the tumor cells and the efficacy of an anticancer drug, Doxorubicin, for personalized medicine applications.The model consisted of two compartments: (a) a healthy bone tissue mimic, poly(lactic acid-coglycolic acid) (PLGA)/beta-tricalcium phosphate (β-TCP) sponge that was seeded with human fetal osteoblastic cells (hFOB) and human umbilical vein endothelial cells (HUVECs), and (b) a tumor mimic, a lyophilized collagen sponge that was seeded with human osteosarcoma cells (Saos-2). The tumor component was introduced to a central cavity created in the healthy bone mimic and together they constituted the total 3D model (3D-BTM). The scaffolds were characterized by determining their mechanical properties, studying their topography and stability with compression tests, microCT, SEM, confocal microscopy and gravimetry. Porosities of the sponges were determined from µCT data as 96.7% and 86% for PLGA/TCP and collagen sponges, respectively. The average diameters of the pores were measured by using ImageJ (NIH, USA) as 199±52 µm for PLGA/TCP and 50-150 μm for collagen scaffolds. Young' modulus of the PLGA/TCP and collagen sponges were determined as 4.76MPa and 140kPa, respectively.Cells seeded on the two sponges were studied independently and together on the BTM. Cell proliferation, morphology, calcium phosphate forming capacity and ALP production were studied on both healthy bone and tumor mimics. All types of cells showed cellular extensions and spread on and in the scaffolds indicating good cell-material interactions. Angiogenic developments in BTM were studied along with migration of cells between the components with immunocytochemistry, SEM, microCT, qRT-PCR and agarose gel electrophoresis. Confocal microscopy showed that a direct contact was established between the cells present in different parts of the BTM; and the HUVEC cells within the healthy bone mimic were observed to migrate into the tumor mimic. This was confirmed by the increase in the levels of angiogenic factors VEGF, bFGF, and IL-8 in the tumor component. The IC50 of Doxorubicin on Saos-2 cells was determined as 0.1876 µg.mL -1 . Doxorubicin was administered to the BTM at 2.7 µg.mL -1 concentration and after allowing one day for interaction, the cell number was determined withAlamar Blue cell viability test as 7-fold lesser compared to 24 h earlier. Apoptosis of the osteosarcoma cells was measured by caspase-3 enzyme activity assay. These results demonstrate the suitability of the 3D BTM model for use in the investigation of activities and migrations of cells in a tumor tissue. These will be very useful in studying metastatic capabilities of cells in addition to personalized drug treatments.3

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Tissue-Engineered Model of Human Osteolytic Bone Tumor

Cited by 22 publications

References 52 publications

Tissue engineered models of healthy and malignant human bone marrow

Tissue engineered models of healthy and malignant human bone marrow

Three-Dimensional Patient-Derived In Vitro Sarcoma Models: Promising Tools for Improving Clinical Tumor Management

A 2-Compartment Bone Tumor Model for Testing the Efficacy of Cancer Drugs

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