| Autor: |
Griffin KH; Department of Orthopaedic Surgery, University of California Davis Health, Sacramento, CA 95817.; School of Veterinary Medicine, University of California, Davis, CA 95616., Thorpe SW; Department of Orthopaedic Surgery, University of California Davis Health, Sacramento, CA 95817., Sebastian A; Physical and Life Sciences, Lawrence Livermore National Laboratory, Livermore, CA 94550., Hum NR; Physical and Life Sciences, Lawrence Livermore National Laboratory, Livermore, CA 94550., Coonan TP; Department of Biomedical Engineering, University of California, Davis, CA 95616., Sagheb IS; Department of Biomedical Engineering, University of California, Davis, CA 95616., Loots GG; Department of Orthopaedic Surgery, University of California Davis Health, Sacramento, CA 95817.; Physical and Life Sciences, Lawrence Livermore National Laboratory, Livermore, CA 94550., Randall RL; Department of Orthopaedic Surgery, University of California Davis Health, Sacramento, CA 95817., Leach JK; Department of Orthopaedic Surgery, University of California Davis Health, Sacramento, CA 95817.; Department of Biomedical Engineering, University of California, Davis, CA 95616. |
| Abstrakt: |
Osteosarcoma (OS) is the most common primary malignant bone cancer in children and adolescents. While numerous other cancers now have promising therapeutic advances, treatment options for OS have remained unchanged since the advent of standard chemotherapeutics and offer less than a 25% 5-y survival rate for those with metastatic disease. This dearth of clinical progress underscores a lack of understanding of OS progression and necessitates the study of this disease in an innovative system. Here, we adapt a previously described engineered bone marrow (eBM) construct for use as a three-dimensional platform to study how microenvironmental and immune factors affect OS tumor progression. We form eBM by implanting acellular bone-forming materials in mice and explanting the cellularized constructs after 8 wk for study. We interrogate the influence of the anatomical implantation site on eBM tissue quality, test ex vivo stability under normoxic (5% O 2 ) and standard (21% O 2 ) culture conditions, culture OS cells within these constructs, and compare them to human OS samples. We show that eBM stably recapitulates the composition of native bone marrow. OS cells exhibit differential behavior dependent on metastatic potential when cultured in eBM, thus mimicking in vivo conditions. Furthermore, we highlight the clinical applicability of eBM as a drug-screening platform through doxorubicin treatment and show that eBM confers a protective effect on OS cells that parallel clinical responses. Combined, this work presents eBM as a cellular construct that mimics the complex bone marrow environment that is useful for mechanistic bone cancer research and drug screening. |
