RANKL-induced CCL22/macrophage-derived chemokine produced from osteoclasts potentially promotes the bone metastasis of lung cancer expressing its receptor CCR4
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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-κB 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.
KeywordsOsteoclast differentiation CCL22/MDC CCR4 Bone metastasis Human lung cancer
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We thank Dr. Ryohei Ogawa (Department of Radiological Sciences, Faculty of Medicine) and Dr. Tatsuro Miyahara (Department of Toxicology, Faculty of Pharmaceutical Sciences) for helpful advice and Mr. Mamoru Nakamura and Dr. Hikaru Seto (Department of Radiology, Faculty of Medicine, Toyama Medical and Pharmaceutical University), Mr. Iwamoto Shinichi (Applied Medical Research Laboratory) for technical support. The authors also express their appreciation to Dr. Yoichi Kameda (Department of Pathology, Kanagawa Cancer Center), Dr. Kenya Shitara (Tokyo Research Laboratories, Kyowa Hakko Kogyo Co., Ltd), Dr. Kouji Matsushima (Department of Molecular Preventive Medicine, School of Medicine, The University of Tokyo) and Dr. Ryuzo Ueda (Department of Internal Medicine and Molecular Science, Nagoya City University Graduate School of Medical Science) for helpful suggestions.
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