title: Human mesenchymal stem cells respond to native but not oxidized damage associated molecular pattern molecules from necrotic (tumor) material.
abstract: Necrosis is a characteristic feature of advanced solid tumors. Released necrotic factors, also referred to as damage associated molecular patterns (DAMPs), are known to critically impact the tumor microenvironment by enhancing angiogenesis or influencing the immune response. We have recently shown that DAMPs can act as chemoattractants and activators of granulocytes. We demonstrate that necrotic material from both normal and tumor cells promotes proliferation and trafficking of human mesenchymal stem cells (MSCs). We characterize the protein high mobility group box 1 (HMGB1) as a crucial member of DAMPs within necrotic material. In addition, we show that DAMPs interfere with expression of indoleamine 2, 3-dioxygenase (IDO) in MSCs. The biological activity of necrotic material toward MSCs is abolished once these DAMPs are oxidized. MSCs found within tumor tissue can act as immunoregulatory cells and are able to promote tumor metastasis, thus playing a crucial role within the tumor microenvironment. Here, we reveal DAMPs to be crucial factors in the setting of MSC biology within the tumor microenvironment. The tumor microenvironment is characterized by reducing and hypoxic conditions that protect DAMPs from oxidation. Based on our results, oxidizing conditions should be considered for therapeutic approaches that target the tumor microenvironment.
authors.affiliation: Institute for Transfusion Medicine, University of Ulm, Ulm, Germany. r.lotfi@blutspende.de
authors.forename: Ramin
authors.initials: R
authors.lastname: Lotfi
authors.forename: Judith
authors.initials: J
authors.lastname: Eisenbacher
authors.forename: Ghasem
authors.initials: G
authors.lastname: Solgi
authors.forename: Karin
authors.initials: K
authors.lastname: Fuchs
authors.forename: Tatjana
authors.initials: T
authors.lastname: Yildiz
authors.forename: Christian
authors.initials: C
authors.lastname: Nienhaus
authors.forename: Markus T
authors.initials: MT
authors.lastname: Rojewski
authors.forename: Hubert
authors.initials: H
authors.lastname: Schrezenmeier
mesh_terms: D017209:Apoptosis; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D002478:Cells, Cultured; D002630:Chemotactic Factors / Q000378:metabolism; D002633:Chemotaxis; D024243:HMGB1 Protein / Q000378:metabolism*; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000502:physiology*; D009336:Necrosis; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology*; D010084:Oxidation-Reduction; D059016:Tumor Microenvironment; D048069:Tumor Necrosis Factors / Q000378:metabolism*
chemical_list: D002630:Chemotactic Factors; D024243:HMGB1 Protein; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D048069:Tumor Necrosis Factors