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      Membrane Bound CRT Fragment Accelerates Tumor Growth of Melanoma B16 Cell In Vivo through Promoting M2 Polarization via TLR4

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          Abstract

          Calreticulin (CRT) is a major calcium-binding luminal resident protein on the endoplasmic reticulum that can also be released extracellular as well as anchored on surface of cells. Previously, we demonstrated that soluble recombinant CRT fragment 39-272 (CRT/39-272) exhibited potent immunostimulatory effects as well as immunoregulation effects on immune cells. Here, we constructed stable B16 melanoma cell lines expressing recombinant CRT/39-272 on the membrane (B16-tmCRT/39-272) to investigate the roles of cell surface CRT on tumor progression. We found that B16-tmCRT/39-272 cells subcutaneously inoculated into C57BL/6 mice exhibited stronger tumorigenicity than the B16-EGFP control cells. The tumor associated macrophages infiltrated in tumors were mainly M2 phenotype. Regulatory T cells (Tregs) were also expanded more in bearing mice. Consistent with the in vivo results, B16-tmCRT/39-272 promoted macrophage polarization toward F4/80 +CD206 + M2 macrophages and promoted transforming growth factor beta (TGF- β) secretion in vitro, which could promote naïve CD4 + T cell differentiation into Tregs. These results imply that the tmCRT/39-272 could accelerate tumor development by enhancing M2 macrophage polarization to induce TGF- β secretion, and then promoted Treg differentiation in the tumor microenvironment. Our data may provide useful clues for better understanding of the potentiating roles of CRT in tumorigenesis.

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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 tumor microenvironment

            A tumor is not simply a group of cancer cells, but rather a heterogeneous collection of infiltrating and resident host cells, secreted factors and extracellular matrix. Tumor cells stimulate significant molecular, cellular and physical changes within their host tissues to support tumor growth and progression. An emerging tumor microenvironment is a complex and continuously evolving entity. The composition of the tumor microenvironment varies between tumor types, but hallmark features include immune cells, stromal cells, blood vessels, and extracellular matrix. It is believed that the "tumor microenvironment is not just a silent bystander, but rather an active promoter of cancer progression" (Truffi et al., 2020). Early in tumor growth, a dynamic and reciprocal relationship develops between cancer cells and components of the tumor microenvironment that supports cancer cell survival, local invasion and metastatic dissemination. To overcome a hypoxic and acidic microenvironment, the tumor microenvironment coordinates a program that promotes angiogenesis to restore oxygen and nutrient supply and remove metabolic waste. Tumors become infiltrated with diverse adaptive and innate immune cells that can perform both pro- and anti- tumorigenic functions (Figure 1). An expanding literature on the tumor microenvironment has identified new targets within it for therapeutic intervention.
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              Tumor-associated macrophages in tumor metastasis: biological roles and clinical therapeutic applications

              Tumor metastasis is a major contributor to the death of cancer patients. It is driven not only by the intrinsic alterations in tumor cells, but also by the implicated cross-talk between cancer cells and their altered microenvironment components. Tumor-associated macrophages (TAMs) are the key cells that create an immunosuppressive tumor microenvironment (TME) by producing cytokines, chemokines, growth factors, and triggering the inhibitory immune checkpoint proteins release in T cells. In doing so, TAMs exhibit important functions in facilitating a metastatic cascade of cancer cells and, meanwhile, provide multiple targets of certain checkpoint blockade immunotherapies for opposing tumor progression. In this article, we summarize the regulating networks of TAM polarization and the mechanisms underlying TAM-facilitated metastasis. Based on the overview of current experimental evidence dissecting the critical roles of TAMs in tumor metastasis, we discuss and prospect the potential applications of TAM-focused therapeutic strategies in clinical cancer treatment at present and in the future.
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                Author and article information

                Contributors
                Journal
                J Immunol Res
                J Immunol Res
                jir
                Journal of Immunology Research
                Hindawi
                2314-8861
                2314-7156
                2022
                6 October 2022
                : 2022
                : 4626813
                Affiliations
                1Institute of Biology and Medical Sciences, School of Biology and Basic Medical Sciences, Soochow University, Suzhou 215123, China
                2Department of Laboratory Medicine, Gusu School, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou 215002, China
                3Key Laboratory of Systemic Biomedical Study, Suzhou 215123, China
                Author notes

                Academic Editor: Yingping Wu

                Author information
                https://orcid.org/0000-0002-5967-8110
                https://orcid.org/0000-0003-2412-0325
                https://orcid.org/0000-0002-8532-4789
                https://orcid.org/0000-0002-8968-3252
                Article
                10.1155/2022/4626813
                9560857
                36249426
                3478f377-91f6-4fe8-8a78-89a22fc9499b
                Copyright © 2022 Hong-Min Wang et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 9 June 2022
                : 9 September 2022
                Funding
                Funded by: Foundation for Gusu Health Youth Talent of Suzhou
                Award ID: GSWS2021044
                Funded by: Natural Science Foundation of Jiangsu Province
                Award ID: BK20191179
                Funded by: Priority Academic Program Development of Jiangsu Higher Education Institutions
                Funded by: National Natural Science Foundation of China
                Award ID: 81971995
                Award ID: 31200649
                Categories
                Research Article

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