title: TNFα promotes osteosarcoma progression by maintaining tumor cells in an undifferentiated state.
abstract: Chronic inflammation is frequently associated with tumorigenesis in elderly people. By contrast, young people without chronic inflammation often develop tumors considered independent of chronic inflammation but driven instead by mutations. Thus, whether inflammation has a significant role in tumor progression in tumors driven by mutations remains largely unknown. Here we show that TNFα is required for the tumorigenesis of osteosarcoma, the most common tumor in children and adolescents. We show that transplantation of AX osteosarcoma cells, which harbor mutations driving c-Myc overexpression and Ink4a-deficiency, in wild-type mice promotes lethal tumorigenesis accompanied by ectopic bone formation and multiple metastases, phenotypes seen in osteosarcoma patients. Such tumorigenesis was completely abrogated in TNFα-deficient mice. AX cells have the capacity to undergo osteoblastic differentiation; however, that activity was significantly inhibited by TNFα treatment, suggesting that TNFα maintains AX cells in an undifferentiated state. TNFα inhibition of AX cell osteoblastic differentiation occurred through ERK activation, and a pharmacological TNFα inhibitor effectively inhibited both AX cell tumorigenesis and increased osteoblastic gene expression and increased survival of tumor-bearing mice. Lethal tumorigenesis of AX cells was also abrogated in IL-1α/IL-1β doubly deficient mice. We found that both TNFα and IL-1 maintained AX cells in an undifferentiated state via ERK activation. Thus, inflammatory cytokines are required to promote tumorigenesis even in mutation-induced tumors, and TNFα/IL-1 and ERK may represent therapeutic targets for osteosarcoma.
authors: Department of Orthopedic Surgery, Keio University School of Medicine, Tokyo, Japan.
authors: T
authors: T
authors: Mori
authors: 1] Department of Orthopedic Surgery, Keio University School of Medicine, Tokyo, Japan [2] Department of Musculoskeletal Reconstruction and Regeneration Surgery, Keio University School of Medicine, Tokyo, Japan.
authors: Y
authors: Y
authors: Sato
authors: Department of Orthopedic Surgery, Keio University School of Medicine, Tokyo, Japan.
authors: K
authors: K
authors: Miyamoto
authors: 1] Department of Orthopedic Surgery, Keio University School of Medicine, Tokyo, Japan [2] Department of Integrated Bone Metabolism and Immunology, Keio University School of Medicine, Tokyo, Japan.
authors: T
authors: T
authors: Kobayashi
authors: 1] Division of Gene Regulation, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, Japan [2] Department of Pathophysiology, School of Pharmacy and Pharmaceutical Sciences, Hoshi University, Tokyo, Japan.
authors: T
authors: T
authors: Shimizu
authors: Department of Orthopedic Surgery, Keio University School of Medicine, Tokyo, Japan.
authors: H
authors: H
authors: Kanagawa
authors: Department of Orthopedic Surgery, Keio University School of Medicine, Tokyo, Japan.
authors: E
authors: E
authors: Katsuyama
authors: Department of Orthopedic Surgery, Keio University School of Medicine, Tokyo, Japan.
authors: A
authors: A
authors: Fujie
authors: Department of Orthopedic Surgery, Keio University School of Medicine, Tokyo, Japan.
authors: W
authors: W
authors: Hao
authors: Department of Orthopedic Surgery, Keio University School of Medicine, Tokyo, Japan.
authors: T
authors: T
authors: Tando
authors: Department of Dentistry and Oral Surgery, Keio University School of Medicine, Tokyo, Japan.
authors: R
authors: R
authors: Iwasaki
authors: Department of Dentistry and Oral Surgery, Keio University School of Medicine, Tokyo, Japan.
authors: H
authors: H
authors: Kawana
authors: Department of Orthopedic Surgery, Keio University School of Medicine, Tokyo, Japan.
authors: H
authors: H
authors: Morioka
authors: Department of Orthopedic Surgery, Keio University School of Medicine, Tokyo, Japan.
authors: M
authors: M
authors: Matsumoto
authors: Division of Gene Regulation, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, Japan.
authors: H
authors: H
authors: Saya
authors: Department of Orthopedic Surgery, Keio University School of Medicine, Tokyo, Japan.
authors: Y
authors: Y
authors: Toyama
authors: 1] Department of Orthopedic Surgery, Keio University School of Medicine, Tokyo, Japan [2] Department of Integrated Bone Metabolism and Immunology, Keio University School of Medicine, Tokyo, Japan.
authors: T
authors: T
authors: Miyamoto
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000378:metabolism* / Q000473:pathology; D002454:Cell Differentiation; D018450:Disease Progression; D005347:Fibroblasts / Q000502:physiology; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D020935:MAP Kinase Signaling System; D051379:Mice; D018345:Mice, Knockout; D009368:Neoplasm Transplantation; D010006:Osteoblasts / Q000378:metabolism; D012516:Osteosarcoma / Q000378:metabolism* / Q000473:pathology; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*; D015854:Up-Regulation
chemical_list: D015850:Interleukin-6; D018124:Receptors, Tumor Necrosis Factor; C439524:TNF protein, human; D014409:Tumor Necrosis Factor-alpha