Mesenchymal Stem Cell Treatment Reduces Tumor Growth and Pulmonary Metastasis in Ewing's Sarcoma

Abstract

Background: Ewing's sarcoma (ES) is the second most common bone tumor in children. Survival has not improved in the last decade and once pulmonary metastatic disease is evident, survival is dismal. Mesenchymal stem cell (MSC) therapy has shown potential benefit for Kaposi's sarcoma; however, the role of progenitor cell therapies for cancer remains controversial. MSC treatment of ES or pulmonary metastatic disease has not been demonstrated. We have developed an orthotopic xenograft model of ES in which mice develop spontaneous pulmonary metastasis. Within this model, we demonstrate the use of MSCs to target ES lung metastasis. Methods: Human ES cells were transfected with luciferase and injected into the rib of nude mice followed by imaging to determine the presence of pulmonary metastasis. MSCs were then harvested from the bone marrow of Sprague Dawley rats and expanded in culture. After characterization by flow cytometry, MSCs were injected into the tail vein of nude mice with established local tumor or pulmonary metastasis. Mice were treated with intravenous MSCs weekly, after which tumor explants were evaluated for angiogenesis and apoptosis. Bioluminescent imaging was used to quantify change in tumor burden during treatment. Results: MSC's initially homed to the sites of primary tumor and pulmonary metastasis. Decreased growth rate and volume of pulmonary metastasis was seen in mice treated with MSCs compared to control animals. (p=0.004) No difference in primary tumor size or microscopic angiogenesis was observed in MSC treated animals; however, an increase in apoptosis was seen in the primary tumors. (95% confidence interval 22-123, p=0.0006) Conclusions: MSC treatment of ES slows growth of pulmonary metastasis. MSCs have more affinity for pulmonary metastasis and can effect a greater decrease in tumor growth in the lungs compared to the primary tumor site. The mechanism for this effect may be via increasing apoptosis of tumor cells.