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.Key words: Chemotaxis . Damage associated molecular patterns . Mesenchymal stem cells . Proliferation . Supporting Information available online See accompanying Commentary by Pistoia and Raffaghello IntroductionRegardless of the origin and site of neoplastic cells, necrotic cell death is a characteristic feature of advanced solid tumor mainly due to three conditions: (i) inadequate nutrition supply to tumor cells as a consequence of imbalance between tumor growth and angiogenesis, (ii) the host's cytotoxic immune response to the tumor, and (iii) downregulation of programmed (apoptotic) cell death by the tumor itself. Released factors following necrotic cell death are also referred to as damage associated molecular patterns (DAMPs). DAMPs can critically impact the tumor microenvironment by enhancing angiogenesis or influencing [5,6]. MSCs are pluripotent progenitor cells that contribute to the maintenance and regeneration of a variety of connective tissues, including bone, adipose, cartilage, and muscle [7]. Although MSCs reside predominantly in the bone marrow, they are also distributed throughout many other tissues, where they are thought to serve as local sources of dormant stem cells [8]. The contributions of MSCs to tissue formation become apparent in cases of tissue remodelling after injury or chronic inflammation. These conditions are typically accompanied by mobilization of multipotent MSCs from bone marrow and their subsequent recruitment to the site of damage [8]. MSCs have been shown to contribute to the formation of fibrous scars after injury [9]. Systemically transferred MSCs have been described to migrate into colon carcinomas [10]. In the setting of wound he...

Simple stress or necrotic cell death with subsequent release of damage-associated molecular patterns (DAMPs) is a characteristic feature of most advanced tumors. DAMPs within the tumor microenvironment stimulate tumor-associated cells, including dendritic cells and mesenchymal stromal cells (MSCs). The presence of tumor-infiltrating MSCs is associated with tumor progression and metastasis. Oxidized necrotic material loses its stimulatory capacity for MSCs. As a DAMP, S100A4 is sensitive to oxidation whereas uric acid (UA) acts primarily as an antioxidant. We tested these two biologic moieties separately and in combination for their activity on MSCs. Similar to necrotic tumor material, S100A4 and UA both dose-dependently induced chemotaxis of MSCs with synergistic effects when combined. Substituting for UA, alternative antioxidants (vitamin C, DTT, and N-acetylcysteine) also enhanced the chemotactic activity of S100A4 in a synergistic manner. This emphasizes the reducing potential of UA being, at least in part, responsible for the observed synergy. With regard to MSC proliferation, both S100A4 and UA inhibited MSCs without altering survival or inducing differentiation toward adipo-, osteo-, or chondrocytes. In the presence of S100A4 or UA, MSCs gained an immunosuppressive capability and stably induced IL-10– and IDO-expressing lymphocytes that maintained their phenotype following proliferation. We have thus demonstrated that both S100A4 and UA act as DAMPs and, as such, may play a critical role in promoting some aspects of MSC-associated immunoregulation. Our findings have implications for therapeutic approaches targeting the tumor microenvironment and addressing the immunosuppressive nature of unscheduled cell death within the tumor microenvironment.

Thermotolerant Campylobacter spp. (Campylobacter jejuni, C. coli, C. lari, and C. upsaliensis) are leading causes of food-borne diarrhea in humans. In this study, the usefulness of fluorescence in situ hybridization (FISH) for the identification of Campylobacter isolates was investigated. A hierarchical FISH probe set that included six group-, genus-, and species-specific probes was developed and evaluated with 12 reference strains and 94 clinical isolates of Campylobacter, Arcobacter, and Helicobacter. FISH correctly identified all isolates to the genus level and detected all thermotolerant Campylobacter isolates. The assay showed high degrees of sensitivity for the identification of C. jejuni (90%), C. coli (97%), C. lari (81%), and C. upsaliensis (100%) to the species level.

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