title: RANKL-induced CCL22/macrophage-derived chemokine produced from osteoclasts potentially promotes the bone metastasis of lung cancer expressing its receptor CCR4.
abstract: Chemokines are now known to play an important role in cancer growth and metastasis. Here we report that differentiating osteoclasts constitutively produce CCL22 (also called macrophage-derived chemokine) and potentially promote bone metastasis of lung cancer expressing its receptor CCR4. We first examined expression of chemokines by differentiating osteoclasts. CCL22 was selectively upregulated in osteoclast-like cells derived from RAW264.7 cells and mouse bone marrow cells upon stimulation with RANKL (receptor activator of nuclear factor-kappaB ligand). In addition, a human lung cancer cell line SBC-5 that efficiently metastasized to bone when intravenously injected into NK cell-depleted SCID mice was found to express CCR4. Stimulation of SBC-5 cells with CCL22 induced cell migration and also enhanced phosphorylation of protein kinase B/Akt and extracellular signal-regulated kinase (ERK). Furthermore, immunohistochemical analysis of bone metastasis lesions demonstrated close co-localization of tartrate-resistant alkaline phosphatase (TRAP)-positive osteoclasts expressing CCL22 and SBC-5 cells expressing CCR4. Collectively, these results suggest that osteoclasts may promote bone metastasis of cancer cells expressing CCR4 in the bone marrow by producing its ligand CCL22.
authors.affiliation: Division of Pathogenic Biochemistry, Institute of Natural Medicine, University of Toyama, Toyama, 930-0194, Japan.
authors.forename: Eliane Shizuka
authors.initials: ES
authors.lastname: Nakamura
authors.forename: Keiichi
authors.initials: K
authors.lastname: Koizumi
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Kobayashi
authors.forename: Yurika
authors.initials: Y
authors.lastname: Saitoh
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Arita
authors.forename: Takashi
authors.initials: T
authors.lastname: Nakayama
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Sakurai
authors.forename: Osamu
authors.initials: O
authors.lastname: Yoshie
authors.forename: Ikuo
authors.initials: I
authors.lastname: Saiki
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000473:pathology / Q000556:secondary*; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement; D054422:Chemokine CCL22; D019742:Chemokines, CC / Q000096:biosynthesis / Q000502:physiology*; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology*; D051379:Mice; D008815:Mice, Inbred Strains; D016513:Mice, SCID; D008954:Models, Biological; D009362:Neoplasm Metastasis; D010010:Osteoclasts / Q000502:physiology*; D053245:RANK Ligand / Q000502:physiology*; D054398:Receptors, CCR4; D019707:Receptors, Chemokine / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C515482:CCL22 protein, human; C515354:CCR4 protein, human; C515483:Ccl22 protein, mouse; C515355:Ccr4 protein, mouse; D054422:Chemokine CCL22; D019742:Chemokines, CC; D053245:RANK Ligand; D054398:Receptors, CCR4; D019707:Receptors, Chemokine