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Abstract
Osteosarcoma is rare but is the most common bone tumor. Diagnostic tools such as magnetic resonance imaging development of chemotherapeutic agents have increased the survival rate in osteosarcoma patients, although 5-year survival has plateaued at 70%. Thus, development of new treatment approaches is needed. Here, we report that IL-17, a proinflammatory cytokine, increases osteosarcoma mortality in a mouse model with AX osteosarcoma cells. AX cell transplantation into wild-type mice resulted in 100% mortality due to ectopic ossification and multi-organ metastasis. However, AX cell transplantation into IL-17-deficient mice significantly prolonged survival relative to controls. CD4-positive cells adjacent to osteosarcoma cells express IL-17, while osteosarcoma cells express the IL-17 receptor IL-17RA. Although AX cells can undergo osteoblast differentiation, as can patient osteosarcoma cells, IL-17 significantly inhibited that differentiation, indicating that IL-17 maintains AX cells in the undifferentiated state seen in malignant tumors. By contrast, IL-17RA-deficient mice transplanted with AX cells showed survival comparable to wild-type mice transplanted with AX cells. Biopsy specimens collected from osteosarcoma patients showed higher expression of IL-17RA compared to IL-17. These findings suggest that IL-17 is essential to maintain osteosarcoma cells in an undifferentiated state and could be a therapeutic target for suppressing tumorigenesis.
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1 Kumamoto University, Department of Orthopedic Surgery, Kumamoto, Japan (GRID:grid.274841.c) (ISNI:0000 0001 0660 6749)
2 Kobe Gakuin University, Laboratory of Molecular Cell Biology, School of Pharmaceutical Sciences, Koube, Japan (GRID:grid.410784.e) (ISNI:0000 0001 0695 038X); Kumamoto University, Division of Hematopoiesis, Joint Research Center for Human Retrovirus Infection, Kumamoto, Japan (GRID:grid.274841.c) (ISNI:0000 0001 0660 6749)
3 Tokyo University of Science, Division of Experimental Animal Immunology, Center for Animal Disease Models, Research Institute for Biomedical Sciences, Chiba, Japan (GRID:grid.143643.7) (ISNI:0000 0001 0660 6861)
4 Kumamoto University, Division of Developmental Genetics, Institute of Resource Development and Analysis, Kumamoto, Japan (GRID:grid.274841.c) (ISNI:0000 0001 0660 6749); Kumamoto University, Center for Metabolic Regulation of Healthy Aging, Kumamoto, Japan (GRID:grid.274841.c) (ISNI:0000 0001 0660 6749)
5 National Cancer Center Hospital, Division of Musculoskeletal Oncology, Tokyo, Japan (GRID:grid.497282.2)
6 Kumamoto University, Division of Hematopoiesis, Joint Research Center for Human Retrovirus Infection, Kumamoto, Japan (GRID:grid.274841.c) (ISNI:0000 0001 0660 6749)