Scott Milcah C, Tomiyasu Hirotaka, Garbe John R, Cornax Ingrid, Amaya Clarissa, O'Sullivan M Gerard, Subramanian Subbaya, Bryan Brad A, Modiano Jaime F
Animal Cancer Care and Research Program, University of Minnesota, St Paul, MN 55108, USA.
Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St Paul, MN 55108, USA.
Dis Model Mech. 2016 Dec 1;9(12):1435-1444. doi: 10.1242/dmm.026849. Epub 2016 Nov 3.
Osteosarcoma (OS) is a heterogeneous and rare disease with a disproportionate impact because it mainly affects children and adolescents. Lamentably, more than half of patients with OS succumb to metastatic disease. Clarification of the etiology of the disease, development of better strategies to manage progression, and methods to guide personalized treatments are among the unmet health needs for OS patients. Progress in managing the disease has been hindered by the extreme heterogeneity of OS; thus, better models that accurately recapitulate the natural heterogeneity of the disease are needed. For this study, we used cell lines derived from two spontaneous canine OS tumors with distinctly different biological behavior (OS-1 and OS-2) for heterotypic in vivo modeling that recapitulates the heterogeneous biology and behavior of this disease. Both cell lines demonstrated stability of the transcriptome when grown as orthotopic xenografts in athymic nude mice. Consistent with the behavior of the original tumors, OS-2 xenografts grew more rapidly at the primary site and had greater propensity to disseminate to lung and establish microscopic metastasis. Moreover, OS-2 promoted formation of a different tumor-associated stromal environment than OS-1 xenografts. OS-2-derived tumors comprised a larger percentage of the xenograft tumors than OS-1-derived tumors. In addition, a robust pro-inflammatory population dominated the stromal cell infiltrates in OS-2 xenografts, whereas a mesenchymal population with a gene signature reflecting myogenic signaling dominated those in the OS-1 xenografts. Our studies show that canine OS cell lines maintain intrinsic features of the tumors from which they were derived and recapitulate the heterogeneous biology and behavior of bone cancer in mouse models. This system provides a resource to understand essential interactions between tumor cells and the stromal environment that drive the progression and metastatic propensity of OS.
骨肉瘤（OS）是一种异质性罕见疾病，因其主要影响儿童和青少年而造成了不成比例的影响。遗憾的是，超过一半的骨肉瘤患者死于转移性疾病。阐明该疾病的病因、制定更好的疾病进展管理策略以及指导个性化治疗的方法，是骨肉瘤患者尚未满足的健康需求。骨肉瘤的极端异质性阻碍了疾病管理方面的进展；因此，需要能准确概括该疾病自然异质性的更好模型。在本研究中，我们使用了源自两种具有明显不同生物学行为的自发性犬骨肉瘤肿瘤（OS-1和OS-2）的细胞系进行异型体内建模，以概括该疾病的异质生物学和行为。当在无胸腺裸鼠体内作为原位异种移植生长时，两种细胞系均表现出转录组的稳定性。与原始肿瘤的行为一致，OS-2异种移植在原发部位生长更快，并且更倾向于扩散到肺部并形成微小转移。此外，与OS-1异种移植相比，OS-2促进形成了不同的肿瘤相关基质环境。源自OS-2的肿瘤在异种移植肿瘤中所占的百分比高于源自OS-1的肿瘤。此外，在OS-2异种移植中，强大的促炎细胞群主导了基质细胞浸润，而具有反映肌源性信号的基因特征的间充质细胞群则主导了OS-1异种移植中的基质细胞浸润。我们的研究表明，犬骨肉瘤细胞系保留了其来源肿瘤的固有特征，并在小鼠模型中概括了骨癌的异质生物学和行为。该系统为理解驱动骨肉瘤进展和转移倾向的肿瘤细胞与基质环境之间的重要相互作用提供了一种资源。
