title: 5-Fluoruracil blocked giant cell tumor progression by suppressing osteoclastogenesis through NF-kappaB signals and blocking angiogenesis.
abstract: Giant cell tumor of bone (GCTB) is a bone destroying tumor comprised of spindle-like stromal cells and monocytes of myeloid lineage that are differentiated into osteoclast-like multinucleated giant cells. Nuclear factor-Kappa B (NF-κB) has been identified to be essential for GCT progression. Herein, we found that 5-Fluorouracil (5-FU), a widely used chemotherapeutics, is a promising anticancer agent for GCT both targeting spindle-like stromal cells and osteoclast giant cells through NF-κB pathway. In this study, in vitro 5-FU not only directly blocked both stromal cell- and RANKL-induced osteoclastogenesis through NF-κB pathway, but also indirectly inhibited osteoclast formation and angiogenesis by suppressing the expression of osteoclast-activating factors including IL-1β, MCP-1 and tumor angiogenesis factor VEGF in stromal cells. In vivo, we found that 5-FU blocked GCT progression through NF-κB pathway by utilizing our chick embryo chorioallantoic membrane (CAM) model. Taken together, our results suggest that 5-FU can inhibit GCT development by suppressing osteoclast formation through NF-κB pathway and blocking angiogenesis, and may serve as a novel agent in the treatment of GCT.
authors.affiliation: Department of Bone Tumor Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Dianwen
authors.initials: D
authors.lastname: Song
authors.affiliation: Department of Bone Tumor Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Tong
authors.initials: T
authors.lastname: Meng
authors.affiliation: Department of Bone Tumor Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Xu
authors.affiliation: Department of Bone Tumor Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Tianhui
authors.initials: T
authors.lastname: Hou
authors.affiliation: Department of Bone Tumor Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, China.
authors.forename: ZaiJun
authors.initials: Z
authors.lastname: Lin
authors.affiliation: Department of Bone Tumor Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Huabin
authors.initials: H
authors.lastname: Yin
authors.affiliation: Department of Bone Tumor Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Li
authors.affiliation: Department of Bone Tumor Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Department of Bone Tumor Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Wang
authors.affiliation: Department of Bone Tumor Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Shuai
authors.initials: S
authors.lastname: Han
authors.affiliation: Department of Bone Tumor Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Tianqi
authors.initials: T
authors.lastname: Fan
authors.affiliation: Department of Bone Tumor Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Wujun
authors.initials: W
authors.lastname: Miao
authors.affiliation: Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, China.
authors.forename: Mingyao
authors.initials: M
authors.lastname: Liu
authors.affiliation: Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Luo
authors.affiliation: Department of Bone Tumor Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, China. Electronic address: brilliant212@163.com.
authors.forename: Wang
authors.initials: W
authors.lastname: Zhou
authors.affiliation: Department of Bone Tumor Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, China. Electronic address: zhenxili.ecnu@gmail.com.
authors.forename: Zhenxi
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Bone Tumor Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, China. Electronic address: jianruxiao83@163.com.
authors.forename: Jianru
authors.initials: J
authors.lastname: Xiao
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use; D001862:Bone Resorption; D002454:Cell Differentiation; D019070:Cell Lineage; D018932:Chemokine CCL2 / Q000378:metabolism; D002642:Chick Embryo; D049033:Chorioallantoic Membrane / Q000187:drug effects; D042783:Endothelial Cells / Q000166:cytology; D005472:Fluorouracil / Q000627:therapeutic use*; D018212:Giant Cell Tumor of Bone / Q000188:drug therapy* / Q000473:pathology*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000166:cytology; D016328:NF-kappa B / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D010010:Osteoclasts / Q000166:cytology* / Q000187:drug effects; D053245:RANK Ligand / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D000964:Antimetabolites, Antineoplastic; C111835:CCL2 protein, human; D018932:Chemokine CCL2; D053583:Interleukin-1beta; D016328:NF-kappa B; D053245:RANK Ligand; D042461:Vascular Endothelial Growth Factor A; D005472:Fluorouracil
keywords: 5-FU; Angiogenesis; Giant cell tumor; NF-κB pathway; Osteoclastgenesis