RANKL-induced CCL22/macrophage-derived chemokine produced from osteoclasts potentially promotes the bone metastasis of lung cancer expressing its receptor CCR4.
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.
Nakamura
Eliane Shizuka
ES
Division of Pathogenic Biochemistry, Institute of Natural Medicine, University of Toyama, Toyama, 930-0194, Japan.
Koizumi
Keiichi
K
Kobayashi
Mitsuo
M
Saitoh
Yurika
Y
Arita
Yoshihisa
Y
Nakayama
Takashi
T
Sakurai
Hiroaki
H
Yoshie
Osamu
O
Saiki
Ikuo
I
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
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