title: CXCL10 promotes osteolytic bone metastasis by enhancing cancer outgrowth and osteoclastogenesis.
abstract: Amplification of the chemokines CXCL10 and RANKL has been suggested to promote osteoclast differentiation and osteolytic bone metastasis, but a function for endogenous CXCL10 in these processes is not well established. In this study, we show that endogenous CXCL10 is critical to recruit cancer cells to bone, support osteoclast differentiation and promote for the formation of osteolytic bone metastases. Neutralizing CXCL10 antibody reduced migration of cancer cells expressing the CXCL10 receptor CXCR3, and loss of CXCR3 or CXCL10 decreased bone tumor burden in vivo. Bone colonization augmented host production of CXCL10, which was required for cancer growth and subsequent osteolysis. Direct interactions between cancer cells and macrophages further stimulated CXCL10 production from macrophages. Growth of bone metastases required CXCL10-stimulated adhesion of cancer cells to type I collagen as well as RANKL-mediated osteoclast formation. Together, our findings show that CXCL10 facilitates trafficking of CXCR3-expressing cancer cells to bone, which augments its own production and promotes osteoclastic differentiation. CXCL10 therefore may represent a therapeutic target for osteolytic bone metastasis.
authors.affiliation: Department of Cell and Developmental Biology, Dental Research Institute, School of Dentistry, Seoul National University, Seoul, Republic of Korea.
authors.forename: Jong-Ho
authors.initials: JH
authors.lastname: Lee
authors.forename: Ha-Neui
authors.initials: HN
authors.lastname: Kim
authors.forename: Kyung-Ok
authors.initials: KO
authors.lastname: Kim
authors.forename: Won Jong
authors.initials: WJ
authors.lastname: Jin
authors.forename: Seungbok
authors.initials: S
authors.lastname: Lee
authors.forename: Hong-Hee
authors.initials: HH
authors.lastname: Kim
authors.forename: Hyunil
authors.initials: H
authors.lastname: Ha
authors.forename: Zang Hee
authors.initials: ZH
authors.lastname: Lee
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000556:secondary*; D002454:Cell Differentiation / Q000502:physiology; D002460:Cell Line; D045744:Cell Line, Tumor; D054357:Chemokine CXCL10 / Q000502:physiology*; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D051379:Mice; D010010:Osteoclasts / Q000473:pathology*; D010014:Osteolysis; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D059016:Tumor Microenvironment
chemical_list: C114753:CXCL10 protein, human; D054357:Chemokine CXCL10