VanCleave Ashley, Palmer Mykayla, Fang Fang, Torres Haydee, Rodezno Tania, Li Qilin, Fuglsby Kirby, Evans Claire, Afeworki Yohannes, Ross Alan, Rao Pulivarthi, Leiferman Patricia, Zheng Siyuan, Houghton Peter, Tao Jianning
Cancer Biology and Immunotherapies Group, Sanford Research, Sioux Falls, SD, USA.
SPUR Scholar Program, University of South Dakota, Sioux Falls, SD, USA.
Oncotarget. 2020 Jul 7;11(27):2597-2610. doi: 10.18632/oncotarget.27611.
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 . 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 addition, we revealed that the COS-33 cell line retained a complex karyotype, a homozygous deletion of the 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.
几十年来，转移性骨肉瘤的治疗效果并未得到改善。部分原因在于，鉴于该疾病的罕见性以及诊断时的高基因异质性，人们对骨肉瘤生物学缺乏了解，从而导致未能开发出更好的治疗方法。我们在此报告，从患者来源的异种移植中成功建立了一种新的人类骨肉瘤细胞系COS-33，并证明其保留了原始肿瘤的生物学特征。我们发现培养的细胞中mTOR信号活性较高，这些细胞对小分子抑制剂雷帕霉素（一种mTOR通路的抑制剂）敏感。用雷帕霉素处理后，mTOR信号受到抑制，这通过S6核糖体蛋白磷酸化的降低得到证实。雷帕霉素浓度的增加逐渐抑制细胞增殖。我们观察到该药物对培养细胞的迁移、侵袭和集落形成具有显著的抑制作用。此外，我们发现只有一种强大的成骨诱导剂骨形态发生蛋白-2能促进细胞分化为成熟的矿化成骨细胞，这表明COS-33细胞系可能存在成骨细胞分化受损的情况。移植的COS-33细胞表现出骨肉瘤的典型特征，如类骨质生成和致瘤性。此外，我们还发现COS-33细胞系保留了复杂的核型、该基因的纯合缺失以及其原始肿瘤的典型组织学特征。我们的新型细胞模型可能为研究骨肉瘤的病因和分子发病机制以及测试新型药物以用于未来基于基因组信息的靶向治疗提供一个有价值的平台。
