title: Bone resorption facilitates osteoblastic bone metastatic colonization by cooperation of insulin-like growth factor and hypoxia.
abstract: Bone metastasis is a multistep process that includes cancer cell dissemination, colonization, and metastatic growth. Furthermore, this process involves complex, reciprocal interactions between cancer cells and the bone microenvironment. Bone resorption is known to be involved in both osteolytic and osteoblastic bone metastasis. However, the precise roles of the bone resorption in the multistep process of osteoblastic bone metastasis remain unidentified. In this study, we show that bone resorption plays important roles in cancer cell colonization during the initial stage of osteoblastic bone metastasis. We applied bioluminescence/X-ray computed tomography multimodal imaging that allows us to spatiotemporally analyze metastasized cancer cells and bone status in osteoblastic bone metastasis models. We found that treatment with receptor activator of factor-κB ligand (RANKL) increased osteoblastic bone metastasis when given at the same time as intracardiac injection of cancer cells, but failed to increase metastasis when given 4 days after cancer cell injection, suggesting that RANKL-induced bone resorption facilitates growth of cancer cells colonized in the bone. We show that insulin-like growth factor-1 released from the bone during bone resorption and hypoxia-inducible factor activity in cancer cells cooperatively promoted survival and proliferation of cancer cells in bone marrow. These results suggest a mechanism that bone resorption and hypoxic stress in the bone microenvironment cooperatively play an important role in establishing osteoblastic metastasis.
authors.affiliation: Tokyo Institute of Technology Graduate School of Bioscience and Biotechnology, Tokyo, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Kuchimaru
authors.forename: Takuya
authors.initials: T
authors.lastname: Hoshino
authors.forename: Tomoya
authors.initials: T
authors.lastname: Aikawa
authors.forename: Hisataka
authors.initials: H
authors.lastname: Yasuda
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Kobayashi
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Kadonosono
authors.forename: Shinae
authors.initials: S
authors.lastname: Kizaka-Kondoh
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000473:pathology; D001859:Bone Neoplasms / Q000556:secondary*; D001862:Bone Resorption / Q000378:metabolism* / Q000473:pathology*; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D004789:Enzyme Activation; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D012516:Osteosarcoma / Q000556:secondary*; D053245:RANK Ligand / Q000494:pharmacology*; D013002:Somatomedins / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014183:Transplantation, Heterologous; D059016:Tumor Microenvironment
chemical_list: D051793:Hypoxia-Inducible Factor 1; D053245:RANK Ligand; D013002:Somatomedins; C505689:Tnfsf11 protein, mouse; D016212:Transforming Growth Factor beta
keywords: Bone resorption; IGF/IGFR signal; hypoxia; multimodality in vivo imaging; osteoblastic bone metastasis