title: Essential roles of the interaction between cancer cell-derived chemokine, CCL4, and intra-bone CCR5-expressing fibroblasts in breast cancer bone metastasis.
abstract: From a murine breast cancer cell line, 4T1, we established a subclone, 4T1.3, which consistently metastasizes to bone upon its injection into the mammary fat pad. 4T1.3 clone exhibited similar proliferation rate and migration capacity as the parental clone. However, the intra-bone injection of 4T1.3 clone caused larger tumors than that of the parental cells, accompanied with increases in fibroblast, but not osteoclast or osteoblast numbers. 4T1.3 clone displayed an enhanced expression of a chemokine, CCL4, but not its specific receptor, CCR5. CCL4 shRNA-transfection of 4T1.3 clone had few effects on its in vitro properties, but reduced the tumorigenicity arising from the intra-bone injection. Moreover, intra-bone injection of 4T1.3 clone caused smaller tumors in mice deficient in CCR5 or those receiving CCR5 antagonist than in wild-type mice. The reduced tumor formation was associated with attenuated accumulation of CCR5-positive fibroblasts expressing connective tissue growth factor (CTGF)/CCN2. Tumor cell-derived CCL4 could induce fibroblasts to express CTGF/CCN2, which could support 4T1.3 clone proliferation under hypoxic culture conditions. Thus, the CCL4-CCR5 axis can contribute to breast cancer metastasis to bone by mediating the interaction between cancer cells and fibroblasts in bone cavity.
authors.affiliation: Division of Molecular Bioregulation, Cancer Research Institute, Kanazawa University, Kanazawa 920-1192, Japan.
authors.forename: Soichiro
authors.initials: S
authors.lastname: Sasaki
authors.affiliation: Division of Molecular Bioregulation, Cancer Research Institute, Kanazawa University, Kanazawa 920-1192, Japan.
authors.forename: Tomohisa
authors.initials: T
authors.lastname: Baba
authors.affiliation: Division of Cancer Cell Biology, Cancer Research Institute, Kanazawa University, Kanazawa 920-1192, Japan.
authors.forename: Tatsunori
authors.initials: T
authors.lastname: Nishimura
authors.affiliation: Division of Pathogenic Biochemistry, Institute of Natural Medicine, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Hayakawa
authors.affiliation: Division of Nephrology, Department of Laboratory Medicine, Kanazawa University, Kanazawa 920-8641, Japan; Japan Science and Technology Agency, Core Research for Evolutional Science and Technology (CREST), Tokyo, Japan.
authors.forename: Shin-Ichi
authors.initials: S
authors.lastname: Hashimoto
authors.affiliation: Division of Cancer Cell Biology, Cancer Research Institute, Kanazawa University, Kanazawa 920-1192, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Gotoh
authors.affiliation: Division of Molecular Bioregulation, Cancer Research Institute, Kanazawa University, Kanazawa 920-1192, Japan. Electronic address: mukaida@staff.kanazawa-u.ac.jp.
authors.forename: Naofumi
authors.initials: N
authors.lastname: Mukaida
mesh_terms: D000818:Animals; D023102:Anoikis; D001859:Bone Neoplasms / Q000378:metabolism* / Q000556:secondary; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000072645:Cancer-Associated Fibroblasts / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D054407:Chemokine CCL4 / Q000235:genetics / Q000378:metabolism*; D024042:Collagen Type I / Q000378:metabolism; D055513:Connective Tissue Growth Factor / Q000378:metabolism; D005260:Female; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D019899:Paracrine Communication; D034622:RNA Interference; D019713:Receptors, CCR5 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden; D000072258:Tumor Hypoxia
chemical_list: C526318:CCN2 protein, mouse; C000592874:CCR5 protein, mouse; D054407:Chemokine CCL4; D024042:Collagen Type I; D019713:Receptors, CCR5; D055513:Connective Tissue Growth Factor
keywords: Bone metastasis; Breast cancer; CCL4; CCR5; CTGF; Fibrosis