The Animal Cancer Center, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, Colorado 80523, USA.
Cancer Res. 2012 Jan 1;72(1):249-59. doi: 10.1158/0008-5472.CAN-11-2315. Epub 2011 Nov 8.
Osteosarcoma has a high mortality rate and remains in need of more effective therapeutic approaches. Survivin is an inhibitor of apoptosis family member protein that blocks apoptosis and drives proliferation in human cancer cells where it is commonly elevated. In this study, we illustrate the superiority of a canine osteosarcoma model as a translational tool for evaluating survivin-directed therapies, owing to the striking similarities in gross and microscopic appearance, biologic behavior, gene expression, and signaling pathway alterations. Elevated survivin expression in primary canine osteosarcoma tissue correlated with increased histologic grade and mitotic index and a decreased disease-free interval (DFI). Survivin attenuation in canine osteosarcoma cells inhibited cell-cycle progression, increased apoptosis, mitotic arrest, and chemosensitivity, and cooperated with chemotherapy to significantly improve in vivo tumor control. Our findings illustrate the utility of a canine system to more accurately model human osteosarcoma and strongly suggest that survivin-directed therapies might be highly effective in its treatment.
骨肉瘤死亡率高，仍需要更有效的治疗方法。Survivin 是凋亡抑制因子家族成员蛋白，可阻止细胞凋亡并促进人类癌细胞增殖，其在人类癌细胞中通常升高。在这项研究中，我们展示了犬骨肉瘤模型作为评估 survivin 靶向治疗的转化工具的优越性，这主要归因于其在大体和微观表现、生物学行为、基因表达和信号通路改变方面的显著相似性。在原发性犬骨肉瘤组织中，survivin 的表达升高与组织学分级和有丝分裂指数增加以及无病间隔（DFI）缩短相关。在犬骨肉瘤细胞中抑制 survivin 的表达可抑制细胞周期进程，增加细胞凋亡、有丝分裂停滞和化疗敏感性，并与化疗协同作用，显著改善体内肿瘤控制。我们的研究结果说明了犬系统在更准确地模拟人类骨肉瘤方面的实用性，并强烈表明 survivin 靶向治疗可能对其治疗非常有效。
