Abstract
Ewing sarcoma (EwS) is a highly malignant bone and soft tissue tumor primarily affecting children and young adults. While most patients initially respond well to conventional front-line therapy, frequent metastasis results in poor 5-year overall survival rates for this disease. Accordingly, there is a critical need to develop better models to understand EwS metastasis. We and others previously used the ex vivo pulmonary metastasis assay (PuMA) to study lung metastasis in solid tumors including osteosarcoma (OS), but this technique has to date not been achievable for EwS. PuMA involves tail vein injection of fluorescent tumor cells into NOD-SCID mice, followed by their visualization in long-term cultures of tumor-bearing lung explants. Here we demonstrate successful implementation of PuMA for EwS cells using NOD-SCID-IL2 receptor gamma null (NSG) immunocompromised mice, which demonstrated high engraftment of EwS cell lines compared to NOD-SCID mice. This may be linked to immune permissiveness required by EwS cells, as increased basal cytotoxicity of EwS cells was observed in NOD-SCID compared to NSG lung sections, possibly due to the absence of natural killer (NK) cell activity in the latter. Together, our data demonstrate the utility of NSG mice for PuMA modeling of EwS lung metastasis.
Highlights
Ewing sarcoma (EwS) is characterized in the majority of cases by the expression of EWSR1-FLI1 or EWSR1-ERG fusion proteins [1, 2]
Our results demonstrate the successful adaptation of the pulmonary metastasis assay (PuMA) system for studying EwS lung colonization, by substituting B medium for PC medium, and utilizing NSG mice rather than NOD-SCID mice as the host strain
While NOD-SCID and NSG mouse models both are characterized by T and B cell depletion, loss of C5 complement, and impaired innate immunity, NSG mice are deficient in natural killer (NK) cells due to the absence of functional receptors for IL2 and other cytokines [16]
Summary
EwS is characterized in the majority of cases by the expression of EWSR1-FLI1 or EWSR1-ERG fusion proteins [1, 2]. These oncoproteins function as chimeric transcription factors to regulate a broad range of candidate genes, leading to characteristic signatures of expression for these tumors [3,4,5]. The 5-year overall survival of patients with metastasis at diagnosis or with recurrent disease remains dismal [7], highlighting the pressing need for extensive study into the mechanisms regulating EwS metastasis toward potential development of preventative therapeutic treatments. To facilitate the rapid progression of research into EwS metastasis, the development of cutting-edge methods that enable robust examination of in vivo tumorigenic behavior is essential.
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