Tumor Associated Macrophages (TAMs) In the World of Cancer

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Tumor Associated Macrophages (TAMs) In the World of Cancer

Journal Title: Biomedical Journal of Scientific & Technical Research (BJSTR) - Year 2018, Vol 9, Issue 1

Abstract

Cancer is a disease extremely difficult to defeat. Besides tumor cells, the microenvironment is influencing progress and metastasis. Recently, it has been discovered that macrophages may promote progress of the tumors. Those tumors associated macrophages (TAMs) are still not completely defined and their role not fully described. If the phenotype of the macrophages can influence the outcome of the tumor disease, the focus should be on TAMs and their potential in development of personalized therapy in fighting metastatic tumors. Steps necessary for the change from normal to malignant cell include numerous alterations in cell physiology. For example, cancer cells gain mutations and do not respond to external inhibitory signals. Additionally, changes in their DNA allow them to proliferate without need for the external growth factors [1,2]. Moreover, surrounding environment in necessary for the progression of tumors. In 1863, Rudolf Virchow proposed that tumor initiates at the site of chronic inflammation and that tissue injury with inflammation may increase cell proliferation and cancer progression [3]. In 1986, Dvorak made an expression "tumors are wound that never heals", thus comparing tumor with parasites evoking wound healing response to obtain the surrounding stroma for their survival and growth [4,5]. Inflammation may involve macrophages, neutrophils, pro-inflammatory cytokines, vasoactive amines and reactive oxygen species (ROS) [6]. Although, in immunocompetent hosts, immunogenic cancer cells are regularly eliminated by the cells of the immune system and weakly immunogenic variants grow to form tumors [2], tumor microenvironment changes the function of macrophages from the pro-inflammatory (i.e. tumoricidal) to pro-tumoral phenotype, thus macrophages promote tumor development [7]. The main features of macrophages are heterogeneity and plasticity. Two extreme phenotypes are M1, that are classically activated macrophages characterized by IL-12highIL-23highIL-10low and on the other end M2, characterized by IL-10highIL-12lowIL-23low [8]. The hypoxic tumor microenvironment through production of lactic acid and Hypoxia-inducible factor 1-alpha (HIF-1a), induces an M2-type polarization [8,9]. It has been suggested that tumor associated macrophages (TAMs), component of the stroma of progressing tumors, express characteristics of M2-phenotype [8]. Tumor-associated macrophages (TAMs) are present in the tumor microenvironment and considered necessary for the tumor progression and metastasis [10]. In humans, TAMs are usually identified by expression of CD163, CD204, or CD206 on the cell surface [11]. In lung, breast, and thyroid cancer tissue samples there was higher CD163-positive macrophage densities than in normal tissues. Moreover, CD163-positive macrophage density negatively correlates with five-year cancer survival rate in several human cancers (10). TAMs originate from the bone marrow monocytes. Monocyte infiltration in tumors is dependent on chemokines (e.g. CCL2, CCL5, CXCL12) and the growth factor, the colony stimulating factor 1 (CSF-1), also known as macrophage colony stimulating factor (M-CSF) [12]. There are two ways how TAMs support tumor progression. Firstly, TAMs positively influence tumor growth, angiogenicity, and extracellular matrix (ECM) degradation, and secondly, suppress potential antitumor immune response [13]. Tumor growth is supported by production of cytokines and growth factors (IL-6, low concentrations of Tumor necrosis factor, TNF and Epidermal growth factor, EGF). Furthermore, TAMs secrete pro-angiogenic factors, such as Vascular endothelial growth factor (VEGF) and IL-8 [12]. The hypoxic microenvironment influences the increased expression of endothelin 1 and 2 by tumor cells, that stimulate the release of Matrix metalloproteinases (MMP2 and MMP9) from macrophages, promoting ECM degradation [14]. It was already shown, that endothelin 1 is implicated in the fibrotic process and that induces M2-phenotype in cultured human macrophages [15]. Moreover, TAMs produce IL-10 and Transforming growth factor p (TGFP), also known as immune suppressing cytokines. Additionally, production of chemokines CCL20 and CCL22, recruit regulatory T cells (Treg) thus negatively influences the immune reaction against tumor antigens [12]. IL-10-immunosuppressive role may be due to its ability to inhibit Nuclear factor kappa-light-chain-enhancer of activated B cells (NFkB) activity, since NFkB plays a central role in the control of inflammation and immunity [16].

Authors and Affiliations

Bihorac Ajna

Keywords

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EP ID EP586196
DOI 10.26717/BJSTR.2018.09.001757
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