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      Tumor-Associated Macrophages as Multifaceted Regulators of Breast Tumor Growth

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          Abstract

          Breast cancer is the most commonly occurring cancer in women of Western countries and is the leading cause of cancer-related mortality. The breast tumor microenvironment contains immune cells, fibroblasts, adipocytes, mesenchymal stem cells, and extracellular matrix. Among these cells, macrophages or tumor-associated macrophages (TAMs) are the major components of the breast cancer microenvironment. TAMs facilitate metastasis of the breast tumor and are responsible for poor clinical outcomes. High TAM density was also found liable for the poor prognosis of breast cancer. These observations make altering TAM function a potential therapeutic target to treat breast cancer. The present review summarizes the origin of TAMs, mechanisms of macrophage recruitment and polarization in the tumor, and the contributions of TAMs in tumor progression. We have also discussed our current knowledge about TAM-targeted therapies and the roles of miRNAs and exosomes in re-educating TAM function.

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          Most cited references160

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          Macrophage plasticity and polarization: in vivo veritas.

          Diversity and plasticity are hallmarks of cells of the monocyte-macrophage lineage. In response to IFNs, Toll-like receptor engagement, or IL-4/IL-13 signaling, macrophages undergo M1 (classical) or M2 (alternative) activation, which represent extremes of a continuum in a universe of activation states. Progress has now been made in defining the signaling pathways, transcriptional networks, and epigenetic mechanisms underlying M1-M2 or M2-like polarized activation. Functional skewing of mononuclear phagocytes occurs in vivo under physiological conditions (e.g., ontogenesis and pregnancy) and in pathology (allergic and chronic inflammation, tissue repair, infection, and cancer). However, in selected preclinical and clinical conditions, coexistence of cells in different activation states and unique or mixed phenotypes have been observed, a reflection of dynamic changes and complex tissue-derived signals. The identification of mechanisms and molecules associated with macrophage plasticity and polarized activation provides a basis for macrophage-centered diagnostic and therapeutic strategies.
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            Macrophage diversity enhances tumor progression and metastasis.

            There is persuasive clinical and experimental evidence that macrophages promote cancer initiation and malignant progression. During tumor initiation, they create an inflammatory environment that is mutagenic and promotes growth. As tumors progress to malignancy, macrophages stimulate angiogenesis, enhance tumor cell migration and invasion, and suppress antitumor immunity. At metastatic sites, macrophages prepare the target tissue for arrival of tumor cells, and then a different subpopulation of macrophages promotes tumor cell extravasation, survival, and subsequent growth. Specialized subpopulations of macrophages may represent important new therapeutic targets. Copyright 2010 Elsevier Inc. All rights reserved.
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              The M1 and M2 paradigm of macrophage activation: time for reassessment

              Macrophages are endowed with a variety of receptors for lineage-determining growth factors, T helper (Th) cell cytokines, and B cell, host, and microbial products. In tissues, macrophages mature and are activated in a dynamic response to combinations of these stimuli to acquire specialized functional phenotypes. As for the lymphocyte system, a dichotomy has been proposed for macrophage activation: classic vs. alternative, also M1 and M2, respectively. In view of recent research about macrophage functions and the increasing number of immune-relevant ligands, a revision of the model is needed. Here, we assess how cytokines and pathogen signals influence their functional phenotypes and the evidence for M1 and M2 functions and revisit a paradigm initially based on the role of a restricted set of selected ligands in the immune response.
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                Author and article information

                Contributors
                Role: Academic Editor
                Role: Academic Editor
                Journal
                Int J Mol Sci
                Int J Mol Sci
                ijms
                International Journal of Molecular Sciences
                MDPI
                1422-0067
                18 June 2021
                June 2021
                : 22
                : 12
                : 6526
                Affiliations
                [1 ]Nutritional Sciences, Texas Tech University, Lubbock, TX 79409, USA; tabassum.maliha@ 123456rocketmail.com (M.T.M.); naima.moustaid-moussa@ 123456ttu.edu (N.M.-M.)
                [2 ]Obesity Research Institute, Texas Tech University, Lubbock, TX 79409, USA
                [3 ]Texas A&M University Health Sciences Center, College Station, TX 77843, USA; matt.kay@ 123456tamu.edu (M.K.K.); mchoudhury@ 123456tamu.edu (M.C.)
                [4 ]Cancer Center, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; min.kang@ 123456ttuhsc.edu
                [5 ]Department of Biological and Environmental Sciences, Qatar University, Doha 2713, Qatar; mrahman@ 123456qu.edu.qa
                [6 ]Natural and Medical Sciences Research Center, University of Nizwa, Birkat Al-Mouz 616, Oman; aharrasi@ 123456unizwa.edu.om
                [7 ]Mechanical Engineering, Texas Tech University, Lubbock, TX 79409, USA; fazle.hussain@ 123456ttu.edu
                Author notes
                Author information
                https://orcid.org/0000-0002-7909-8375
                https://orcid.org/0000-0002-0815-5942
                https://orcid.org/0000-0002-7508-8030
                https://orcid.org/0000-0002-4879-2663
                Article
                ijms-22-06526
                10.3390/ijms22126526
                8233875
                34207035
                ae96d240-ab2d-4ebc-9f04-6e0c7f9eb1fd
                © 2021 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( https://creativecommons.org/licenses/by/4.0/).

                History
                : 19 April 2021
                : 28 May 2021
                Categories
                Review

                Molecular biology
                tumor-associated macrophages,breast cancer,tumor microenvironment,macrophage polarization,immunosuppression,angiogenesis,metastasis,exosomes,mirna

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