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      Damage-associated molecular patterns in cancer: A double-edged sword

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      , ,
      Oncogene
      Cell death, HMGB1, ATP, FPR1, Calreticulin, chemotherapy, radiation

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          Abstract

          Damage-associated molecular patterns (DAMPs) are released in response to cell death and stress, and are potent triggers of sterile inflammation. Recent evidence suggests that DAMPs may also have a key role in the development of cancer as well as in the host response to cytotoxic anti-tumor therapy. As such, DAMPs may exert protective functions by alerting the immune system to the presence of dying tumor cells, thereby triggering immunogenic tumor cell death. On the other hand, cell death and release of DAMPs may also trigger chronic inflammation and thereby promote the development or progression of tumors. Here, we will review the contribution of candidate DAMPs and their receptors and discuss the evidence for DAMPs as tumor-promoting and anti-tumor effectors as well as unsolved questions such as DAMP release from non-tumor cells as well as the existence of tumor-specific DAMPs.

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          Most cited references75

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          Cell-surface calreticulin initiates clearance of viable or apoptotic cells through trans-activation of LRP on the phagocyte.

          Apoptotic-cell removal is critical for development, tissue homeostasis, and resolution of inflammation. Although many candidate systems exist, only phosphatidylserine has been identified as a general recognition ligand on apoptotic cells. We demonstrate here that calreticulin acts as a second general recognition ligand by binding and activating LDL-receptor-related protein (LRP) on the engulfing cell. Since surface calreticulin is also found on viable cells, a mechanism preventing inadvertent uptake was sought. Disruption of interactions between CD47 (integrin-associated protein) on the target cell and SIRPalpha (SHPS-1), a heavily glycosylated transmembrane protein on the engulfing cell, permitted uptake of viable cells in a calreticulin/LRP-dependent manner. On apoptotic cells, CD47 was altered and/or lost and no longer activated SIRPalpha. These changes on the apoptotic cell create an environment where "don't eat me" signals are rendered inactive and "eat me" signals, including calreticulin and phosphatidylserine, congregate together and signal for removal.
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            Monocytic cells hyperacetylate chromatin protein HMGB1 to redirect it towards secretion.

            High Mobility Group 1 protein (HMGB1) is a chromatin component that, when leaked out by necrotic cells, triggers inflammation. HMGB1 can also be secreted by activated monocytes and macrophages, and functions as a late mediator of inflammation. Secretion of a nuclear protein requires a tightly controlled relocation program. We show here that in all cells HMGB1 shuttles actively between the nucleus and cytoplasm. Monocytes and macrophages acetylate HMGB1 extensively upon activation with lipopolysaccharide; moreover, forced hyperacetylation of HMGB1 in resting macrophages causes its relocalization to the cytosol. Cytosolic HMGB1 is then concentrated by default into secretory lysosomes, and secreted when monocytic cells receive an appropriate second signal.
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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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                Author and article information

                Journal
                8711562
                6325
                Oncogene
                Oncogene
                Oncogene
                0950-9232
                1476-5594
                10 February 2016
                18 April 2016
                17 November 2016
                23 November 2016
                : 35
                : 46
                : 5931-5941
                Affiliations
                Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, NY 10032, USA
                Department of Internal Medicine I, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
                Institute of Human Nutrition, Columbia University, New York, NY 10032, USA
                Author notes
                Contact information: Robert F. Schwabe; Department of Medicine, Columbia University, Russ Berrie Pavilion, Room 415, 1150 St. Nicholas Ave, New York, NY 10032; rfs2102@ 123456columbia.edu ; Tel: (212) 851-5462, Fax: (212) 851-5461
                [*]

                These authors have contributed equally.

                Article
                NIHMS754049
                10.1038/onc.2016.104
                5119456
                27086930
                05870244-a366-4201-bd17-348d439bb556

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                Article

                Oncology & Radiotherapy
                cell death,hmgb1,atp,fpr1,calreticulin,chemotherapy,radiation
                Oncology & Radiotherapy
                cell death, hmgb1, atp, fpr1, calreticulin, chemotherapy, radiation

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