The IL-17-IL-17RA axis is required to promote osteosarcoma progression in mice

• Published in: Scientific reports Vol. 13; no. 1; p. 21572
• Main Authors: Yoshimura, Naoto, Kariya, Ryusho, Shimada, Masaki, Tateyama, Makoto, Matsunaga, Hideto, Shibata, Yuto, Tanimura, Shuntaro, Takata, Kosei, Arima, Takahiro, Kawakami, Junki, Maeda, Kazuya, Fukuma, Yuko, Uragami, Masaru, Ideo, Katsumasa, Sugimoto, Kazuki, Yonemitsu, Ryuji, Matsushita, Kozo, Hisanaga, Satoshi, Yugami, Masaki, Uehara, Yusuke, Masuda, Tetsuro, Nakamura, Takayuki, Tokunaga, Takuya, Karasugi, Tatsuki, Sueyoshi, Takanao, Sato, Hiro, Iwakura, Yoichiro, Araki, Kimi, Kobayashi, Eisuke, Okada, Seiji, Miyamoto, Takeshi
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 07.12.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 631/250; 631/67; 692/4028; Animals; Biopsy; Bone cancer; Bone imaging; Bone Neoplasms - pathology; Bone tumors; CD4 antigen; Cell Differentiation; Chemotherapy; Humanities and Social Sciences; Humans; Inflammation; Interleukin 17; Interleukin-17 - genetics; Interleukin-17 - metabolism; Magnetic resonance imaging; Metastases; Mice; Mortality; multidisciplinary; Ossification (ectopic); Osteoblastogenesis; Osteosarcoma; Osteosarcoma - pathology; Osteosarcoma cells; Receptors, Interleukin-17 - metabolism; Sarcoma; Science; Science (multidisciplinary); Survival; Therapeutic targets; Transplantation; Tumorigenesis
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-023-49016-1

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.