title: RANKL synthesized by both stromal cells and cancer cells plays a crucial role in osteoclastic bone resorption induced by oral cancer.
abstract: The molecular mechanisms underlying bone destruction by invading oral cancer are not well understood. Using IHC, we demonstrated that receptor activator of nuclear factor-κB ligand (RANKL)-positive fibroblasts and cancer cells were located at sites of bone invasion in human oral cancers. HSC3 and HO-1-N-1, human oral cancer cell lines, expressed RANKL and stimulated Rankl expression in the UAMS-32 murine osteoblastic cell line. We discriminated the roles of RANKL synthesized by stromal cells and cancer cells in cancer-associated bone resorption by using species-specific RANKL antibodies against murine RANKL and human RANKL, respectively. Osteoclastogenesis induced by the conditioned medium of HSC3 and HO-1-N-1 cells in a co-culture of murine bone marrow cells and UAMS-32 cells was inhibited by the addition of antibodies against either mouse or human RANKL. HSC3-induced bone destruction was greatly inhibited by the administration of anti-mouse RANKL antibody in a xenograft model. HO-1-N-1-induced bone destruction was inhibited by the administration of either anti-mouse or anti-human RANKL antibody. Bone destruction induced by the transplantation of human RANKL-overexpressing cells (HSC3-R2) was greatly inhibited by the injection of anti-human RANKL antibody. The present study revealed that RANKL produced by both stromal and cancer cells is involved in oral cancer-induced osteoclastic bone resorption. These results provide important information for understanding the cellular and molecular basis of cancer-associated bone destruction and the mechanism of action underlying RANKL antibody (denosumab) therapy.
authors.affiliation: Section of Oral Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Sato
authors.forename: Ji-Won
authors.initials: JW
authors.lastname: Lee
authors.forename: Kei
authors.initials: K
authors.lastname: Sakamoto
authors.forename: Tadahiro
authors.initials: T
authors.lastname: Iimura
authors.forename: Kou
authors.initials: K
authors.lastname: Kayamori
authors.forename: Hisataka
authors.initials: H
authors.lastname: Yasuda
authors.forename: Masanobu
authors.initials: M
authors.lastname: Shindoh
authors.forename: Masako
authors.initials: M
authors.lastname: Ito
authors.forename: Ken
authors.initials: K
authors.lastname: Omura
authors.forename: Akira
authors.initials: A
authors.lastname: Yamaguchi
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism; D001862:Bone Resorption / Q000209:etiology* / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051379:Mice; D009062:Mouth Neoplasms / Q000150:complications* / Q000235:genetics / Q000473:pathology*; D009361:Neoplasm Invasiveness; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D010012:Osteogenesis / Q000187:drug effects / Q000235:genetics; D053244:Osteoprotegerin / Q000378:metabolism; D053245:RANK Ligand / Q000096:biosynthesis* / Q000235:genetics; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000906:Antibodies; D053244:Osteoprotegerin; D053245:RANK Ligand