Heterotypic models of osteosarcoma recapitulate tumor heterogeneity and biological behavior

Abstract

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.

Small animal models for the study of bone sarcoma pathogenesis:characteristics, therapeutic interests and limitations

“…Similarly, Tome et al reported 5 × 10 5 143B-LM4 cells per nude mouse was able to generate tumours in immunodeficient [34] . Another study reports the use of the OS-1 and OS-2 canine osteosarcoma cells (1 × 10 5 cells resuspended in 10 µL PBS and intra-tibially injected into nude mice), to assess their tumour characteristics and metastatic features [35] . Finally, Shimozaki et al, injected a suspension of 5 × 10 5 143B cells diluted in Matrigel™, directly into the medullar cavity of the tibia of nude mice [36] .…”

A comparison of risk factors for metastasis at diagnosis in humans and dogs with osteosarcoma

“…Yet studies have shown the opposite to be true, perhaps because young adults are under reduced parental surveillance or have limited knowledge of their own physical health . Instead, certain OS tumors in both humans and dogs may be biologically predetermined to successfully metastasize, regardless of time to diagnosis . Using both human and dog OS, future research should ascertain whether evolutionarily conserved pathways are needed to develop the metastatic OS phenotype, and whether patterns of gene expression could be used to categorize intrinsically aggressive molecular subtypes of OS in both species.…”

The Role of Pre-Clinical 3-Dimensional Models of Osteosarcoma

“…Moreover, these models are a useful tool for screening drugs [ 29 , 30 ]. Arguably, the induction of OS by intraosseous injection is one of the most relevant murine models for studying this disease, with studies recapitulating OS tumour heterogeneity [ 31 ], as well as providing biological understanding of activation pathways [ 32 ]. The fundamental limitation of this model is the use of mature OS cells, which does not provide information on tumour initiation.…”