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      Inflammatory cell-associated tumors. Not only macrophages (TAMs), fibroblasts (TAFs) and neutrophils (TANs) can infiltrate the tumor microenvironment. The unique role of tumor associated platelets (TAPs)

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          Abstract

          It is well known that various inflammatory cells infiltrate cancer cells. Next to TAMs (tumor-associated macrophages), TAFs (tumor-associated fibroblasts) and TANs (tumor-associated neutrophils) also platelets form the tumor microenvironment. Taking into account the role of platelets in the development of cancer, we have decided to introduce a new term: tumor associated platelets—TAPs. To the best of our knowledge, thus far this terminology has not been employed by anyone. Platelets are the first to appear at the site of the inflammatory process that accompanies cancer development. Within the first few hours from the start of the colonization of cancer cells platelet-tumor aggregates are responsible for neutrophils recruitment, and further release a number of factors associated with tumor growth, metastasis and neoangiogenesis. On the other hand, it also has been indicated that factors delivered from platelets can induce a cytotoxic effect on the proliferating neoplastic cells, and even enhance apoptosis. Undoubtedly, TAPs’ role seems to be more complex when compared to tumor associated neutrophils and macrophages, which do not allow for their division into TAP P1 and TAP P2, as in the case of TANs and TAMs. In this review we discuss the role of TAPs as an important element of tumor invasiveness and as a potentially new therapeutic target to prevent cancer development. Nevertheless, better exploring the interactions between platelets and tumor cells could help in the formulation of new therapeutic goals that support or improve the effectiveness of cancer treatment.

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          The online version of this article (10.1007/s00262-020-02758-7) contains supplementary material, which is available to authorized users.

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          Most cited references159

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          CCL2 recruits inflammatory monocytes to facilitate breast tumor metastasis

          Macrophages abundantly found in the tumor microenvironment enhance malignancy 1 . At metastatic sites a distinct population of metastasis associated macrophages (MAMs) promote tumor cell extravasation, seeding and persistent growth 2 . Our study has defined the origin of these macrophages by showing Gr1+ inflammatory monocytes (IMs) are preferentially recruited to pulmonary metastases but not primary mammary tumors, a process also found for human IMs in pulmonary metastases of human breast cancer cells. The recruitment of these CCR2 (receptor for chemokine CCL2) expressing IMs and subsequently MAMs and their interaction with metastasizing tumor cells is dependent on tumor and stromal synthesized CCL2 (FigS1). Inhibition of CCL2/CCR2 signaling using anti-CCL2 antibodies blocks IM recruitment and inhibits metastasis in vivo and prolongs the survival of tumor-bearing mice. Depletion of tumor cell-derived CCL2 also inhibits metastatic seeding. IMs promote tumor cell extravasation in a process that requires monocyte-derived VEGF. CCL2 expression and macrophage infiltration are correlated with poor prognosis and metastatic disease in human breast cancer (Fig S2) 3-6 . Our data provides the mechanistic link between these two clinical associations and indicates new therapeutic targets for treating metastatic breast disease.
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            Fibroblasts in cancer.

            Tumours are known as wounds that do not heal - this implies that cells that are involved in angiogenesis and the response to injury, such as endothelial cells and fibroblasts, have a prominent role in the progression, growth and spread of cancers. Fibroblasts are associated with cancer cells at all stages of cancer progression, and their structural and functional contributions to this process are beginning to emerge. Their production of growth factors, chemokines and extracellular matrix facilitates the angiogenic recruitment of endothelial cells and pericytes. Fibroblasts are therefore a key determinant in the malignant progression of cancer and represent an important target for cancer therapies.
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              Tumor-Associated Macrophages as Major Players in the Tumor Microenvironment

              During tumor progression, circulating monocytes and macrophages are actively recruited into tumors where they alter the tumor microenvironment to accelerate tumor progression. Macrophages shift their functional phenotypes in response to various microenvironmental signals generated from tumor and stromal cells. Based on their function, macrophages are divided broadly into two categories: classical M1 and alternative M2 macrophages. The M1 macrophage is involved in the inflammatory response, pathogen clearance, and antitumor immunity. In contrast, the M2 macrophage influences an anti-inflammatory response, wound healing, and pro-tumorigenic properties. Tumor-associated macrophages (TAMs) closely resemble the M2-polarized macrophages and are critical modulators of the tumor microenvironment. Clinicopathological studies have suggested that TAM accumulation in tumors correlates with a poor clinical outcome. Consistent with that evidence, experimental and animal studies have supported the notion that TAMs can provide a favorable microenvironment to promote tumor development and progression. In this review article, we present an overview of mechanisms responsible for TAM recruitment and highlight the roles of TAMs in the regulation of tumor angiogenesis, invasion, metastasis, immunosuppression, and chemotherapeutic resistance. Finally, we discuss TAM-targeting therapy as a promising novel strategy for an indirect cancer therapy.
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                Author and article information

                Contributors
                piekarskav@yahoo.com
                o.koper@wp.pl
                justyna.zinczuk@umb.edu.pl
                ewa.kratz@umed.wroc.pl
                joanna.kaminska@umb.edu.pl
                Journal
                Cancer Immunol Immunother
                Cancer Immunol Immunother
                Cancer Immunology, Immunotherapy
                Springer Berlin Heidelberg (Berlin/Heidelberg )
                0340-7004
                1432-0851
                3 November 2020
                3 November 2020
                2021
                : 70
                : 6
                : 1497-1510
                Affiliations
                [1 ]GRID grid.48324.39, ISNI 0000000122482838, Department of Clinical Laboratory Diagnostics, , Medical University of Bialystok, ; Waszyngtona 15A, 15-269 Bialystok, Poland
                [2 ]GRID grid.4495.c, ISNI 0000 0001 1090 049X, Department of Laboratory Diagnostics, Faculty of Pharmacy, , Wroclaw Medical University, ; Borowska Street 211A, 50-556 Wrocław, Poland
                Author information
                http://orcid.org/0000-0003-4170-0997
                http://orcid.org/0000-0001-5199-2773
                http://orcid.org/0000-0003-2391-3307
                http://orcid.org/0000-0003-2948-4574
                http://orcid.org/0000-0002-2986-4852
                Article
                2758
                10.1007/s00262-020-02758-7
                8139882
                33146401
                0ce79002-00e6-4b4c-ae06-4bb9756b46f7
                © The Author(s) 2020

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 6 May 2020
                : 15 October 2020
                Funding
                Funded by: None
                Funded by: Medical University of Bialystok
                Categories
                Review
                Custom metadata
                © Springer-Verlag GmbH Germany, part of Springer Nature 2021

                Oncology & Radiotherapy
                tumor associated platelets (taps),platelet activation,cancer development,tumor microenvironment

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