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      Tumor-associated macrophages: from basic research to clinical application

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          Abstract

          The fact that various immune cells, including macrophages, can be found in tumor tissues has long been known. With the introduction of concept that macrophages differentiate into a classically or alternatively activated phenotype, the role of tumor-associated macrophages (TAMs) is now beginning to be elucidated. TAMs act as “protumoral macrophages,” contributing to disease progression. TAMs can promote initiation and metastasis of tumor cells, inhibit antitumor immune responses mediated by T cells, and stimulate tumor angiogenesis and subsequently tumor progression. As the relationship between TAMs and malignant tumors becomes clearer, TAMs are beginning to be seen as potential biomarkers for diagnosis and prognosis of cancers, as well as therapeutic targets in these cases. In this review, we will discuss the origin, polarization, and role of TAMs in human malignant tumors, as well as how TAMs can be used as diagnostic and prognostic biomarkers and therapeutic targets of cancer in clinics.

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          Most cited references47

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          Macrophage regulation of tumor responses to anticancer therapies.

          Tumor-associated macrophages (TAMs) promote key processes in tumor progression, like angiogenesis, immunosuppression, invasion, and metastasis. Increasing studies have also shown that TAMs can either enhance or antagonize the antitumor efficacy of cytotoxic chemotherapy, cancer-cell targeting antibodies, and immunotherapeutic agents--depending on the type of treatment and tumor model. TAMs also drive reparative mechanisms in tumors after radiotherapy or treatment with vascular-targeting agents. Here, we discuss the biological significance and clinical implications of these findings, with an emphasis on novel approaches that effectively target TAMs to increase the efficacy of such therapies. Copyright © 2013 Elsevier Inc. All rights reserved.
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            Carcinoma-produced factors activate myeloid cells through TLR2 to stimulate metastasis.

            Metastatic progression depends on genetic alterations intrinsic to cancer cells as well as the inflammatory microenvironment of advanced tumours. To understand how cancer cells affect the inflammatory microenvironment, we conducted a biochemical screen for macrophage-activating factors secreted by metastatic carcinomas. Here we show that, among the cell lines screened, Lewis lung carcinoma (LLC) were the most potent macrophage activators leading to production of interleukin-6 (IL-6) and tumour-necrosis factor-alpha (TNF-alpha) through activation of the Toll-like receptor (TLR) family members TLR2 and TLR6. Both TNF-alpha and TLR2 were found to be required for LLC metastasis. Biochemical purification of LLC-conditioned medium (LCM) led to identification of the extracellular matrix proteoglycan versican, which is upregulated in many human tumours including lung cancer, as a macrophage activator that acts through TLR2 and its co-receptors TLR6 and CD14. By activating TLR2:TLR6 complexes and inducing TNF-alpha secretion by myeloid cells, versican strongly enhances LLC metastatic growth. These results explain how advanced cancer cells usurp components of the host innate immune system, including bone-marrow-derived myeloid progenitors, to generate an inflammatory microenvironment hospitable for metastatic growth.
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              Macrophage expression of hypoxia-inducible factor-1 alpha suppresses T-cell function and promotes tumor progression.

              T cells can inhibit tumor growth, but their function in the tumor microenvironment is often suppressed. Many solid tumors exhibit abundant macrophage infiltration and low oxygen tension, yet how hypoxic conditions may affect innate immune cells and their role in tumor progression is poorly understood. Targeted deletion of the hypoxia-responsive transcription factor hypoxia-inducible factor-1α (HIF-1α) in macrophages in a progressive murine model of breast cancer resulted in reduced tumor growth, although vascular endothelial growth factor-A levels and vascularization were unchanged. Tumor-associated macrophages can suppress tumor-infiltrating T cells by several mechanisms, and we found that hypoxia powerfully augmented macrophage-mediated T-cell suppression in vitro in a manner dependent on macrophage expression of HIF-1α. Our findings link the innate immune hypoxic response to tumor progression through induction of T-cell suppression in the tumor microenvironment. © 2010 AACR.
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                Author and article information

                Contributors
                +86 371 66295320 , yizhang@zzu.edu.cn
                Journal
                J Hematol Oncol
                J Hematol Oncol
                Journal of Hematology & Oncology
                BioMed Central (London )
                1756-8722
                28 February 2017
                28 February 2017
                2017
                : 10
                : 58
                Affiliations
                [1 ]GRID grid.412633.1, Biotherapy Center, , The First Affiliated Hospital of Zhengzhou University, ; No.1 Jianshe East Road, Zhengzhou, 450052 Henan Province China
                [2 ]GRID grid.412633.1, Cancer Center, , The First Affiliated Hospital of Zhengzhou University, ; No.1 Jianshe East Road, Zhengzhou, 450052 Henan Province China
                [3 ]ISNI 0000 0001 2189 3846, GRID grid.207374.5, School of Life Science, , Zhengzhou University, ; No.100 Kexue Road, Zhengzhou, 450001 Henan Province China
                Article
                430
                10.1186/s13045-017-0430-2
                5329931
                28241846
                71af21a1-a2fe-4b38-888c-8b1fde768332
                © The Author(s). 2017

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 23 January 2017
                : 23 February 2017
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: 81602024
                Award ID: 81171986
                Award Recipient :
                Categories
                Review
                Custom metadata
                © The Author(s) 2017

                Oncology & Radiotherapy
                tumor-associated macrophages (tams),tumor microenvironment,protumoral activities,biomarker,therapeutic target

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