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      Friend or Foe: S100 Proteins in Cancer

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          Abstract

          S100 proteins are widely expressed small molecular EF-hand calcium-binding proteins of vertebrates, which are involved in numerous cellular processes, such as Ca 2+ homeostasis, proliferation, apoptosis, differentiation, and inflammation. Although the complex network of S100 signalling is by far not fully deciphered, several S100 family members could be linked to a variety of diseases, such as inflammatory disorders, neurological diseases, and also cancer. The research of the past decades revealed that S100 proteins play a crucial role in the development and progression of many cancer types, such as breast cancer, lung cancer, and melanoma. Hence, S100 family members have also been shown to be promising diagnostic markers and possible novel targets for therapy. However, the current knowledge of S100 proteins is limited and more attention to this unique group of proteins is needed. Therefore, this review article summarises S100 proteins and their relation in different cancer types, while also providing an overview of novel therapeutic strategies for targeting S100 proteins for cancer treatment.

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          Most cited references240

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          S100 proteins in cancer.

          In humans, the S100 protein family is composed of 21 members that exhibit a high degree of structural similarity, but are not functionally interchangeable. This family of proteins modulates cellular responses by functioning both as intracellular Ca(2+) sensors and as extracellular factors. Dysregulated expression of multiple members of the S100 family is a common feature of human cancers, with each type of cancer showing a unique S100 protein profile or signature. Emerging in vivo evidence indicates that the biology of most S100 proteins is complex and multifactorial, and that these proteins actively contribute to tumorigenic processes such as cell proliferation, metastasis, angiogenesis and immune evasion. Drug discovery efforts have identified leads for inhibiting several S100 family members, and two of the identified inhibitors have progressed to clinical trials in patients with cancer. This Review highlights new findings regarding the role of S100 family members in cancer diagnosis and treatment, the contribution of S100 signalling to tumour biology, and the discovery and development of S100 inhibitors for treating cancer.
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            Metal chelation and inhibition of bacterial growth in tissue abscesses.

            Bacterial infection often results in the formation of tissue abscesses, which represent the primary site of interaction between invading bacteria and the innate immune system. We identify the host protein calprotectin as a neutrophil-dependent factor expressed inside Staphylococcus aureus abscesses. Neutrophil-derived calprotectin inhibited S. aureus growth through chelation of nutrient Mn2+ and Zn2+: an activity that results in reprogramming of the bacterial transcriptome. The abscesses of mice lacking calprotectin were enriched in metal, and staphylococcal proliferation was enhanced in these metal-rich abscesses. These results demonstrate that calprotectin is a critical factor in the innate immune response to infection and define metal chelation as a strategy for inhibiting microbial growth inside abscessed tissue.
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              S100 proteins in mouse and man: from evolution to function and pathology (including an update of the nomenclature).

              The S100 protein family is the largest subgroup within the superfamily of proteins carrying the Ca2+-binding EF-hand motif. Despite their small molecular size and their conserved functional domain of two distinct EF-hands, S100 proteins developed a plethora of tissue-specific intra- and extracellular functions. Accordingly, various diseases such as cardiomyopathies, neurodegenerative and inflammatory disorders, and cancer are associated with altered S100 protein levels. Here, we review the different S100 protein functions and related diseases from an evolutionary point of view. We analyzed the structural variations, which are the basis of functional diversification, as well as the genomic organization of the S100 family in human and compared it with the S100 repertoires in mouse and rat. S100 genes and proteins are highly conserved between the different mammalian species. Moreover, we identified evolutionary related subgroups of S100 proteins within the three species, which share functional similarity and form subclusters on the genomic level. The available S100-specific mouse models are summarized and the consequences of our results are discussed with regard to the use of genetically engineered mice as human disease models. An update of the S100 nomenclature is included, because some of the recently identified S100 genes and pseudogenes had to be renamed. Copyright 2004 Elsevier Inc.
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                Author and article information

                Journal
                Cancers (Basel)
                Cancers (Basel)
                cancers
                Cancers
                MDPI
                2072-6694
                24 July 2020
                August 2020
                : 12
                : 8
                : 2037
                Affiliations
                [1 ]Department of General and Visceral Surgery, Ulm University Hospital, Albert-Einstein-Allee 23, 89081 Ulm, Germany; chantal.allgoewer@ 123456uni-ulm.de (C.A.); anna-laura.kretz@ 123456uni-ulm.de (A.-L.K.); mathias.wittau@ 123456uniklinik-ulm.de (M.W.); sekretariat.chirurgie1@ 123456uniklinik-ulm.de (D.H.-B.)
                [2 ]Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University Hospital Cologne, Weyertal 115b, 50931 Cologne, Germany; s.vonkarstedt@ 123456uni-koeln.de
                [3 ]CECAD Cluster of Excellence, University of Cologne, Joseph-Stelzmann-Straße 26, 50931 Cologne, Germany
                [4 ]Center of Molecular Medicine Cologne, Medical Faculty, University Hospital of Cologne, Weyertal 115b, 50931 Cologne, Germany
                Author notes
                [* ]Correspondence: johannes.lemke@ 123456uniklinik-ulm.de ; Tel.: +49-731-500-53691
                [†]

                These authors contributed equally to this work.

                Author information
                https://orcid.org/0000-0002-7816-5919
                https://orcid.org/0000-0003-2142-6097
                Article
                cancers-12-02037
                10.3390/cancers12082037
                7465620
                32722137
                0da81ce5-3efd-40b5-8e2e-76aefcc5878f
                © 2020 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 ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 29 June 2020
                : 23 July 2020
                Categories
                Review

                s100 proteins,ca2+-dependent signalling,biomarkers,cancer therapy

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