title: Oxidative stress, polarization of macrophages and tumour angiogenesis: Efficacy of caffeic acid.
abstract: Macrophage polarization is a process when macrophage expresses different functional programs in response to microenvironmental signals and two extreme forms exist; M1 and M2 macrophages. M1 macrophages are highly microbicidal and anticancer with enhanced ability to kill and phagocytose pathogens, upregulate pro-inflammatory cytokines and reactive molecular species, and present antigens; M2 macrophages and the related tumour associated macrophages (TAMs) regulate tissue remodelling and promote tissue repair and angiogenesis and can amplification of metabolic pathways that can suppress adaptive immune responses. It is demonstrated that ROS production, critical for the activation and functions of M1 macrophages, is necessary for the differentiation of M2 macrophages and TAMs, and that antioxidant therapy blocks TAMs differentiation and tumorigenesis in mouse models of cancer. In order to study how caffeic acid (CA), a natural antioxidant, affects macrophage function, polarization, angiogenesis and tumour growth we injected mice with Ehrlich ascites tumour (EAT) cells and treated them for 10 days with CA in a dose of 40 and/or 80 mg kg(-1.) Macrophage polarization was further characterized by quantifying secreted pro- and anti-inflammatory cytokines, nitric oxide and arginase 1 activity. CA may increase the cytotoxic actions of M1 macrophages and inhibit tumour growth; inhibitory activity on TAMs may be mediated through its antioxidative activity. Taken together, we conclude that the antitumour activity of CA was the result of the synergistic activities of different mechanisms by which CA acts on proliferation, angiogenesis, immunomodulation and survival. The continuous administration of CA efficiently blocked the occurrence of TAMs and markedly suppressed tumorigenesis in mouse cancer models. Targeting TAMs by antioxidants can be a potentially effective method for cancer treatment.
authors.affiliation: Department of Animal Physiology, Faculty of Science, University of Zagreb, Zagreb, Croatia. Electronic address: norsolic@yahoo.com.
authors.forename: Nada
authors.initials: N
authors.lastname: Oršolić
authors.affiliation: Department of Animal Physiology, Faculty of Science, University of Zagreb, Zagreb, Croatia.
authors.forename: Martina
authors.initials: M
authors.lastname: Kunštić
authors.affiliation: Department of Animal Physiology, Faculty of Science, University of Zagreb, Zagreb, Croatia.
authors.forename: Marina
authors.initials: M
authors.lastname: Kukolj
authors.affiliation: Department of Zoology, Faculty of Science, University of Zagreb, Zagreb, Croatia.
authors.forename: Romana
authors.initials: R
authors.lastname: Gračan
authors.affiliation: General Hospital Zabok, Croatia.
authors.forename: Johann
authors.initials: J
authors.lastname: Nemrava
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use*; D002109:Caffeic Acids / Q000494:pharmacology / Q000627:therapeutic use*; D002286:Carcinoma, Ehrlich Tumor / Q000098:blood supply* / Q000188:drug therapy* / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000032:analysis; D008264:Macrophages / Q000187:drug effects* / Q000473:pathology; D008297:Male; D051379:Mice; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000473:pathology; D009569:Nitric Oxide / Q000032:analysis; D018384:Oxidative Stress / Q000187:drug effects*; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis
chemical_list: D000975:Antioxidants; D002109:Caffeic Acids; D016207:Cytokines; D042461:Vascular Endothelial Growth Factor A; D009569:Nitric Oxide; C040048:caffeic acid
keywords: Angiogenesis; Caffeic acid; Ehrlich ascites tumour; Macrophages; Oxidative stress