NSG Mice Facilitate ex vivo Characterization of Ewing Sarcoma Lung Metastasis Using the PuMA Model

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.

Neuroprotective Effect of Azithromycin Following Induction of Optic Nerve Crush in Wild Type and Immunodeficient Mice

“…A similar study by Varano et al [ 13 ] investigating the effect of intraperitoneal AZ on retinal ischemia in a male Wistar rat model found that it had a neuroprotective effect. Ours is the first study, to the best of our knowledge, to examine an ONC model in NSG mice, which are usually used to investigate cancer, not ischemic or inflammatory diseases [ 27 , 28 , 29 ]. We propose that NSG mice might also serve for the study of the latter conditions, as a neuroinflammatory response is relevant in a wide spectrum of ocular diseases, including diabetic retinopathy [ 30 ].…”

State of the Art Modelling of the Breast Cancer Metastatic Microenvironment: Where Are We?

“…Using this model, Khan et al, [ 75 ] have demonstrated that genetic knockdown of lung microenvironment derived E-, L- and P-selectins results in significantly impaired metastatic progression of TNBC. The PuMA has also been used to identify and test novel therapeutic targets in other cancer models that undergo lung metastasis including Ewing sarcoma [ 76 , 77 ], osteosarcoma [ 78 ] and melanoma [ 79 ].…”

Preclinical models for the study of pediatric solid tumors: focus on bone sarcomas

“…Using this method, we and several other research groups have shown distal metastasis typical for EwS in secondary bone, lungs, and liver. In addition, xenograft murine models were used to harvest organs and characterize ex vivo lung-specific metastasis in EwS ( 127 , 128 ). Further, xenografts have been reported to be used to test and characterize cell lines that may be developed to be chemoresistant ( 129 – 131 ), radiation-adapted ( 132 ), or designed as organ-specific metastatic cell lines ( 128 ).…”