Abstract
Outcomes have not improved for metastatic osteosarcoma for several decades. In part, this failure to develop better therapies stems from a lack of understanding of osteosarcoma biology, given the rarity of the disease and the high genetic heterogeneity at the time of diagnosis. We report here the successful establishment of a new human osteosarcoma cell line, COS-33, from a patient-derived xenograft and demonstrate retention of the biological features of the original tumor. We found high mTOR signaling activity in the cultured cells, which were sensitive to a small molecule inhibitor, rapamycin, a suppressor of the mTOR pathway. Suppressed mTOR signaling after treatment with rapamycin was confirmed by decreased phosphorylation of the S6 ribosomal protein. Increasing concentrations of rapamycin progressively inhibited cell proliferation in vitro. We observed significant inhibitory effects of the drug on cell migration, invasion, and colony formation in the cultured cells. Furthermore, we found that only a strong osteogenic inducer, bone morphogenetic protein-2, promoted the cells to differentiate into mature mineralizing osteoblasts, indicating that the COS-33 cell line may have impaired osteoblast differentiation. Grafted COS-33 cells exhibited features typical of osteosarcoma, such as production of osteoid and tumorigenicity in vivo. In addition, we revealed that the COS-33 cell line retained a complex karyotype, a homozygous deletion of the TP53 gene, and typical histological features from its original tumor. Our novel cellular model may provide a valuable platform for studying the etiology and molecular pathogenesis of osteosarcoma as well as for testing novel drugs for future genome-informed targeted therapy.
Highlights
Osteosarcoma (OS) is the most common primary bone cancer in adolescents and in the elderly
We showed that mammalian target of rapamycin (mTOR) inhibitor rapamycin inhibits COS-33 cell proliferation, migration, invasion, and clonogenicity
We demonstrated that the cell line retains its osteoblastic cells of origin, karyotype, tumor protein p53 (TP53) mutation status, and histological features in comparison to the parental patient-derived xenografts (PDX) tumor from which it originates
Summary
Osteosarcoma (OS) is the most common primary bone cancer in adolescents and in the elderly. Current multimodal therapy consisting of surgery combined with drug treatment using chemotherapy agents (cisplatin, doxorubicin, ifosfamide, and high-dose methotrexate) achieves a five-year survival rate of approximately 60–70% for localized OS, while the rate for patients with metastases is less than 30% [2]. Recent genomic studies with patient tumor samples and models of human OS have improved our understanding of the disease etiology and have provided a road map for drug development [3,4,5,6]. The clinical and survival outcomes for patients with OS have not improved over the last four decades This is in part due to the rarity of the disease and the high genetic heterogeneity at diagnosis, which together challenge us to better understand OS biology in order to make discoveries that can improve clinical care [7]. One way to overcome the difficulty in assessing OS patient samples is to establish new cell lines and to thoroughly characterize the existing models
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