Tohoku J. Exp. Med., 2019 June, 248(2)
Expression Profiling of Receptor-Activator of Nuclear Factor-Kappa B Ligand in Soft Tissue Tumors
TETSURO YAMAGISHI,1 HIROYUKI KAWASHIMA,1 AKIRA OGOSE,2 TAKASHI ARIIZUMI,1 NAOKI OIKE,1 TARO SASAKI,3 HIROSHI HATANO,3 RIUKO OHASHI,4 HAJIME UMEZU,5 YOICHI AJIOKA4,6 and NAOTO ENDO1
1Division of Orthopedic Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Niigata, Japan
2Department of Orthopedic Surgery, Uonuma Kikan Hospital, Minamiuonuma, Niigata, Japan
3Department of Orthopedic Surgery, Niigata Cancer Center Hospital, Niigata, Niigata, Japan
4Histopathology Core Facility, Niigata University Faculty of Medicine, Niigata, Niigata, Japan
5Division of Pathology, Niigata University Medical and Dental Hospital, Niigata, Niigata, Japan
6Division of Molecular and Diagnostic Pathology, Niigata University Faculty of Medicine, Niigata, Niigata, Japan
Bone and soft tissue tumors are derived from mesenchymal cells, and they are hard to treat. Receptor-activator of nuclear factor-kappa B ligand (RANKL) is an essential cytokine for osteoclast differentiation and activation and is expressed on the surface of osteoblasts or stromal cells. In this study, to explore the potential of denosumab treatment for soft tissue tumors, we analyzed the expression profiles of RANKL mRNA in 425 tumor specimens of 33 histological types by real-time RT-PCR. Denosumab is a monoclonal antibody that prevents the binding of RANKL to receptor-activator of nuclear factor-kappa B (RANK). For comparison, the relative expression levels of RANK and osteoprotegerin (OPG) mRNAs were also measured. OPG functions as a soluble decoy receptor for RANKL. Higher expression levels of RANKL mRNA were detected in calcifying aponeurotic fibroma, fibrosarcoma, calcifying epithelioma, myositis ossificans, heterotopic calcification, giant cell tumor of the tendon sheath (GCTTS), and pigmented villonodular synovitis (PVNS), compared with the levels of other tumor types. Moreover, the expression levels of RANK mRNA were highest in GCTTS, followed by myositis ossificans and PVNS, whereas the expression levels of OPG mRNA were greatly varied among these histological types. We then analyzed RANKL protein expression by immunohistochemistry in 57 tumor specimens with higher expression levels of RANKL mRNA. RANKL-positive cells were detected in GCTTS, PVNS, myositis ossificans, heterotopic calcification, and calcifying aponeurotic fibroma. In conclusion, RANKL is expressed in subsets of soft tissue tumors with calcification, and denosumab is a potential therapeutic option for soft tissue tumors expressing RANKL.
keywords —— calcification; immunohistochemistry; mRNA; receptor-activator of nuclear factor-kappa B ligand; soft tissue tumor
© 2019 Tohoku University Medical Press
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Tohoku J. Exp. Med., 2019, 248, 87-97
Correspondence: Hiroyuki Kawashima, Division of Orthopedic Surgery, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata, Niigata 950-8510, Japan.
e-mail: inskawa@med.niigata-u.ac.jp