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

Abstract

Osteosarcoma, Ewing sarcoma and chondrosarcoma are the three main entities of bone sarcoma which collectively encompass more than 50 heterogeneous entities of rare malignancies. In contrast to osteosarcoma and Ewing sarcoma which mainly affect adolescents and young adults and exhibit a high propensity to metastasise to the lungs, chondrosarcoma is more frequently observed after 40 years of age and is characterised by a high frequency of local recurrence. The combination of chemotherapy, surgical resection and radiotherapy has contributed to an improved outcome for these patients. However, a large number of patients still suffer significant therapy related toxicities or die of refractory and metastatic disease. To better delineate the pathogenesis of bone sarcomas and to identify and test new therapeutic options, major efforts have been invested over the past decades in the development of relevant pre-clinical animal models. Nowadays, in vivo models aspire to mimic all the steps and the clinical features of the human disease as accurately as possible and should ideally be manipulable. Considering these features and given their small size, their conduciveness to experiments, their affordability as well as their human-like bone-microenvironment and immunity, murine pre-clinical models are interesting in the context of these pathologies. This chapter will provide an overview of the murine models of bone sarcomas, paying specific attention for the models induced by inoculation of tumour cells. The genetically-engineered mouse models of bone sarcoma will also be summarized.

Sarcoma treatment in the era of molecular medicine

“…CAM assays have been employed to study sarcoma angiogenesis, fibroblast infiltration, tumorigenesis, tumor invasion, and metastasis in CHS, EwS, fibrosarcoma, LPS, and OS (Sys et al , 2013; Patil et al , 2014; Manjunathan & Ragunathan, 2015; Cimpean et al , 2018; Kunz et al , 2019; Perut et al , 2019; Steinestel et al , 2020). Numerous additional in vivo models of inducible or spontaneous sarcomas have been described in non‐mammalian vertebrates (e.g., zebrafish; Leacock et al , 2012; Mohseny et al , 2012; Brown et al , 2017b; Hayes & Langenau, 2017; Ignatius et al , 2018; Fleming et al , 2019) and in mammalians (e.g., mouse, rat, and dog; Cannon, 2015; Jacques et al , 2018; Castillo‐Tandazo et al , 2019; Pomella & Rota, 2020). Genetically modified zebrafish and xenotransplantation of human sarcoma cells in fish were simultaneously proposed.…”

“…The first GEMM overexpressed the AP‐1 transcription factor c‐Fos in murine osteoblasts, which led to the development of OS without inducing metastatic foci (Grigoriadis et al , 1993). More recent models include deletion of Tp53 , Rb , Prx‐1 , or Prkar1a; overexpression of Sonic Hedgehog signaling components; or targeting Apc and Twist , and lead to the formation of metastatic OS (Jacques et al , 2018). Similarly, conditional loss of Tp53 or Ink4a/Arf in an Ext1 ‐driven GEMM results in the formation of CHS (de Andrea et al , 2015).…”

Evaluations of phylogenetic proximity in a group of 67 dogs with osteosarcoma: a pilot study

“…When regrouping breeds by phylogenetic proximity and comparing the prevalence confidence intervals between groups, it appears that groups 4 and 5 are significantly more affected than others 29,30 . This observation suggests that the effect of genetics in OSA prevalence and in phenotype cannot be rejected.…”

Auranofin improves overall survival when combined with standard of care in a pilot study involving dogs with osteosarcoma

“…Translation of our findings with AF into human clinical trials would require safety and efficacy data from a clinically relevant model of osteosarcoma. Traditional xenotransplant models lack the complexity and heterogeneity of spontaneously arising tumours and thus are limited in their ability to inform clinical trials in human osteosarcoma . In contrast, dogs with spontaneous osteosarcoma are a unique and powerful resource, which has been used in the past to inform management of human osteosarcoma .…”