title: The chemokine CCL2 increases prostate tumor growth and bone metastasis through macrophage and osteoclast recruitment.
abstract: CC chemokine ligand 2 (CCL2, also known as monocyte chemoattractant protein-1) has been demonstrated to recruit monocytes to tumor sites. Monocytes are capable of being differentiated into tumor-associated macrophages (TAMs) and osteoclasts (OCs). TAMs have been shown to promote tumor growth in several cancer types. Osteoclasts have also been known to play an important role in cancer bone metastasis. To investigate the effects of CCL2 on tumorigenesis and its potential effects on bone metastasis of human prostate cancer, CCL2 was overexpressed into a luciferase-tagged human prostate cancer cell line PC-3. In vitro, the conditioned medium of CCL2 overexpressing PC-3luc cells (PC-3(lucCCL2)) was a potent chemoattractant for mouse monocytes in comparison to a conditioned medium from PC-3(lucMock). In addition, CCL2 overexpression increased the growth of transplanted xenografts and increased the accumulation of macrophages in vivo. In a tumor dissemination model, PC-3(lucCCL2) enhanced the growth of bone metastasis, which was associated with more functional OCs. Neutralizing antibodies targeting both human and mouse CCL2 inhibited the growth of PC-3(luc), which was accompanied by a decrease in macrophage recruitment to the tumor. These findings suggest that CCL2 increases tumor growth and bone metastasis through recruitment of macrophages and OCs to the tumor site.
authors.affiliation: Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, MI 48109-5946, USA.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Mizutani
authors.forename: Sudha
authors.initials: S
authors.lastname: Sud
authors.forename: Natalie A
authors.initials: NA
authors.lastname: McGregor
authors.forename: Gari
authors.initials: G
authors.lastname: Martinovski
authors.forename: Brandon T
authors.initials: BT
authors.lastname: Rice
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Craig
authors.forename: Zachary S
authors.initials: ZS
authors.lastname: Varsos
authors.forename: Hernan
authors.initials: H
authors.lastname: Roca
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Pienta
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000556:secondary*; D045744:Cell Line, Tumor; D002465:Cell Movement; D018932:Chemokine CCL2 / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D051379:Mice; D010010:Osteoclasts / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000473:pathology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
chemical_list: C111835:CCL2 protein, human; D018932:Chemokine CCL2