title: Cyclooxygenase-2 inhibition blocks M2 macrophage differentiation and suppresses metastasis in murine breast cancer model.
abstract: Tumor cells are often associated with abundant macrophages that resemble the alternatively activated M2 subset. Tumor-associated macrophages (TAMs) inhibit anti-tumor immune responses and promote metastasis. Cyclooxygenase-2 (COX-2) inhibition is known to prevent breast cancer metastasis. This study hypothesized that COX-2 inhibition affects TAM characteristics potentially relevant to tumor cell metastasis. We found that the specific COX-2 inhibitor, etodolac, inhibited human M2 macrophage differentiation, as determined by decreased CD14 and CD163 expressions and increased TNFα production. Several key metastasis-related mediators, such as vascular endothelial growth factor-A, vascular endothelial growth factor-C, and matrix metalloproteinase-9, were inhibited in the presence of etodolac as compared to untreated M2 macrophages. Murine bone marrow derived M2 macrophages also showed enhanced surface MHCII IA/IE and CD80, CD86 expressions together with enhanced TNFα expressions with etodolac treatment during differentiation. Using a BALB/c breast cancer model, we found that etodolac significantly reduced lung metastasis, possibly due to macrophages expressing increased IA/IE and TNFα, but decreased M2 macrophage-related genes expressions (Ym1, TGFβ). In conclusion, COX-2 inhibition caused loss of the M2 macrophage characteristics of TAMs and may assist prevention of breast cancer metastasis.
authors.affiliation: Department of Microbiology and Immunology, and Institute of Endemic Disease, Seoul National University College of Medicine, Seoul, South Korea.
authors.forename: Yi-Rang
authors.initials: YR
authors.lastname: Na
authors.forename: Yi-Na
authors.initials: YN
authors.lastname: Yoon
authors.forename: Da-In
authors.initials: DI
authors.lastname: Son
authors.forename: Seung-Hyeok
authors.initials: SH
authors.lastname: Seok
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D017308:Etodolac / Q000494:pharmacology; D005260:Female; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D008175:Lung Neoplasms / Q000473:pathology / Q000556:secondary*; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000473:pathology*; D015674:Mammary Neoplasms, Animal / Q000201:enzymology* / Q000276:immunology / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009362:Neoplasm Metastasis; D010641:Phenotype
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D016207:Cytokines; D018836:Inflammation Mediators; D017308:Etodolac