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      Crosstalk between cancer and immune cells: Role of tumor‐associated macrophages in the tumor microenvironment

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          Abstract

          Tumor microenvironment is a complex system that contains multiple cells and cytokines. Among the multiple immune cells, macrophage is particularly abundant and plays an important role throughout the tumor progression process, namely, tumor‐associated macrophage (TAM) in this special tumor microenvironment. Many kinds of cytokines from TAMs and other immune cells in tumor niche are involved in the linkage of inflammation, immunity and tumorigenesis. Inflammatory responses induced by TAMs are crucial to tumor development of different stages. This review highlights the critical role of TAMs in the linkage of inflammation, immunity, and cancer. It outlines the molecules of inflammatory cytokines, chemokines, and growth factors mainly from TAMs in tumor microenvironment and their functions in tumor development during the major issues of angiogenesis, chronic inflammation, and immune suppression. Additionally, the signaling pathways involved in tumor progression and the crosstalk between them are also summarized.

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          Most cited references80

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          Persistent DNA damage signaling triggers senescence-associated inflammatory cytokine secretion

          Cellular senescence suppresses cancer by stably arresting the proliferation of damaged cells1. Paradoxically, senescent cells also secrete factors that alter tissue microenvironments2. The pathways regulating this secretion are unknown. We show that damaged human cells develop persistent chromatin lesions bearing hallmarks of DNA double-strand breaks (DSBs), which initiate increased secretion of inflammatory cytokines such as interleukin-6 (IL-6). Cytokine secretion occurred only after establishment of persistent DNA damage signaling, usually associated with senescence, not after transient DNA damage responses (DDR). Initiation and maintenance of this cytokine response required the DDR proteins ATM, NBS1 and CHK2, but not the cell cycle arrest enforcers p53 and pRb. ATM was also essential for IL-6 secretion during oncogene-induced senescence and by damaged cells that bypass senescence. Further, DDR activity and IL-6 were elevated in human cancers, and ATM-depletion suppressed the ability of senescent cells to stimulate IL-6-dependent cancer cell invasiveness. Thus, in addition to orchestrating cell cycle checkpoints and DNA repair, a novel and important role of the DDR is to allow damaged cells to communicate their compromised state to the surrounding tissue.
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            Understanding the Mysterious M2 Macrophage through Activation Markers and Effector Mechanisms

            The alternatively activated or M2 macrophages are immune cells with high phenotypic heterogeneity and are governing functions at the interface of immunity, tissue homeostasis, metabolism, and endocrine signaling. Today the M2 macrophages are identified based on the expression pattern of a set of M2 markers. These markers are transmembrane glycoproteins, scavenger receptors, enzymes, growth factors, hormones, cytokines, and cytokine receptors with diverse and often yet unexplored functions. This review discusses whether these M2 markers can be reliably used to identify M2 macrophages and define their functional subdivisions. Also, it provides an update on the novel signals of the tissue environment and the neuroendocrine system which shape the M2 activation. The possible evolutionary roots of the M2 macrophage functions are also discussed.
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              Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis.

              New blood vessel formation (angiogenesis) is a fundamental event in the process of tumor growth and metastatic dissemination. Hence, the molecular basis of tumor angiogenesis has been of keen interest in the field of cancer research. The vascular endothelial growth factor (VEGF) pathway is well established as one of the key regulators of this process. The VEGF/VEGF-receptor axis is composed of multiple ligands and receptors with overlapping and distinct ligand-receptor binding specificities, cell-type expression, and function. Activation of the VEGF-receptor pathway triggers a network of signaling processes that promote endothelial cell growth, migration, and survival from pre-existing vasculature. In addition, VEGF mediates vessel permeability, and has been associated with malignant effusions. More recently, an important role for VEGF has emerged in mobilization of endothelial progenitor cells from the bone marrow to distant sites of neovascularization. The well-established role of VEGF in promoting tumor angiogenesis and the pathogenesis of human cancers has led to the rational design and development of agents that selectively target this pathway. Studies with various anti-VEGF/VEGF-receptor therapies have shown that these agents can potently inhibit angiogenesis and tumor growth in preclinical models. Recently, an anti-VEGF antibody (bevacizumab), when used in combination with chemotherapy, was shown to significantly improve survival and response rates in patients with metastatic colorectal cancer and thus, validate VEGF pathway inhibitors as an important new treatment modality in cancer therapy.
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                Author and article information

                Contributors
                guobohx@163.com
                Journal
                Cancer Med
                Cancer Med
                10.1002/(ISSN)2045-7634
                CAM4
                Cancer Medicine
                John Wiley and Sons Inc. (Hoboken )
                2045-7634
                20 June 2019
                August 2019
                : 8
                : 10 ( doiID: 10.1002/cam4.v8.10 )
                : 4709-4721
                Affiliations
                [ 1 ] School of Life Sciences Northwestern Polytechnical University Xi'an China
                [ 2 ] Institute of Pharmaceutical Science King's College London London UK
                [ 3 ] Department of Ophthalmology West China Hospital of Sichuan University Chengdu China
                Author notes
                [*] [* ] Correspondence

                Bo Guo, Department of Ophthalmology, West China Hospital of Sichuan University, Chengdu 610041, China.

                Email: guobohx@ 123456163.com

                Author information
                https://orcid.org/0000-0001-5647-529X
                Article
                CAM42327
                10.1002/cam4.2327
                6712467
                31222971
                95d50d65-2f6e-46d9-a320-6a62802d76e6
                © 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 27 March 2019
                : 08 May 2019
                : 10 May 2019
                Page count
                Figures: 3, Tables: 1, Pages: 13, Words: 9381
                Funding
                Funded by: Shaanxi Postdoctoral Science Foundation
                Award ID: 2018BSHYDZZ02
                Funded by: Fundamental Research Funds for the Central Universities
                Award ID: 3102017OQD078
                Funded by: Qingdao Science and Technology Project
                Award ID: 18-6-1-94-nsh
                Funded by: China Postdoctoral Science Foundation
                Award ID: 2017M623247
                Categories
                Review
                Cancer Biology
                Reviews
                Custom metadata
                2.0
                cam42327
                August 2019
                Converter:WILEY_ML3GV2_TO_NLMPMC version:5.6.7 mode:remove_FC converted:28.08.2019

                Oncology & Radiotherapy
                angiogenesis,chronic inflammation,immune suppression,tams,tumor
                Oncology & Radiotherapy
                angiogenesis, chronic inflammation, immune suppression, tams, tumor

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