title: ROS play a critical role in the differentiation of alternatively activated macrophages and the occurrence of tumor-associated macrophages.
abstract: Differentiation to different types of macrophages determines their distinct functions. Tumor-associated macrophages (TAMs) promote tumorigenesis owing to their proangiogenic and immune-suppressive functions similar to those of alternatively activated (M2) macrophages. We report that reactive oxygen species (ROS) production is critical for macrophage differentiation and that inhibition of superoxide (O(2-)) production specifically blocks the differentiation of M2 macrophages. We found that when monocytes are triggered to differentiate, O(2-) is generated and is needed for the biphasic ERK activation, which is critical for macrophage differentiation. We demonstrated that ROS elimination by butylated hydroxyanisole (BHA) and other ROS inhibitors blocks macrophage differentiation. However, the inhibitory effect of ROS elimination on macrophage differentiation is overcome when cells are polarized to classically activated (M1), but not M2, macrophages. More importantly, the continuous administration of the ROS inhibitor BHA efficiently blocked the occurrence of TAMs and markedly suppressed tumorigenesis in mouse cancer models. Targeting TAMs by blocking ROS can be a potentially effective method for cancer treatment.
authors.affiliation: Cell and Cancer Biology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 37 Convent Drive, RM1130, Bethesda, MD 20892, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Swati
authors.initials: S
authors.lastname: Choksi
authors.forename: Kun
authors.initials: K
authors.lastname: Chen
authors.forename: Yelena
authors.initials: Y
authors.lastname: Pobezinskaya
authors.forename: Ilona
authors.initials: I
authors.lastname: Linnoila
authors.forename: Zheng-Gang
authors.initials: ZG
authors.lastname: Liu
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism; D063646:Carcinogenesis / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D002460:Cell Line; D002465:Cell Movement / Q000235:genetics / Q000502:physiology; D049109:Cell Proliferation; D002478:Cells, Cultured; D005260:Female; D006367:HeLa Cells; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D009000:Monocytes / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species; D013481:Superoxides