Hypoxia is a condition that together with low pH, high amounts of reactive oxygen species (ROS), and increased adenosine levels characterize tumor microenvironment. Mast cells (MCs) are part of tumor microenvironment, but the effect of hypoxia on the production of MC-derived cytokines has not been fully described. Using the hypoxia marker pimonidazole in vivo, we found that MCs were largely located in the low-oxygen areas within B16-F1 mice melanoma tumors. In vitro, hypoxia promoted ROS production, a ROS-dependent increase of intracellular calcium, and the production of MCP 1 (CCL-2) in murine bone marrow–derived MCs. Hypoxia-induced CCL-2 production was sensitive to the antioxidant trolox and to nifedipine, a blocker of L-type voltage-dependent Ca2+ channels (LVDCCs). Simultaneously with CCL-2 production, hypoxia caused the ROS-dependent glutathionylation and membrane translocation of the α1c subunit of Cav1.2 LVDCCs. Relationship between ROS production, calcium rise, and CCL-2 synthesis was also observed when cells were treated with H2O2. In vivo, high CCL-2 production was detected on hypoxic zones of melanoma tumors (where tryptase-positive MCs were also found). Pimonidazole and CCL-2 positive staining diminished when B16-F1 cell–inoculated animals were treated with trolox, nifedipine, or the adenosine receptor 2A antagonist KW6002. Our results show that MCs are located preferentially in hypoxic zones of melanoma tumors, hypoxia-induced CCL-2 production in MCs requires calcium rise mediated by glutathionylation and membrane translocation of LVDCCs, and this mechanism of CCL-2 synthesis seems to operate in other cells inside melanoma tumors, with the participation of the adenosine receptor 2A.
Mast cells (MCs) constitute an essential cell lineage that participates in innate and adaptive immune responses and whose phenotype and function are influenced by tissue-specific conditions. Their mechanisms of activation in type I hypersensitivity reactions have been the subject of multiple studies, but the signaling pathways behind their activation by innate immunity stimuli are not so well described. Here, we review the recent evidence regarding the main molecular elements and signaling pathways connecting the innate immune receptors and hypoxic microenvironment to cytokine synthesis and the secretion of soluble or exosome-contained mediators in this cell type. When known, the positive and negative control mechanisms of those pathways are presented, together with their possible implications for the understanding of mast cell-driven chronic inflammation. Finally, we discuss the relevance of the knowledge about signaling in this cell type in the recognition of MCs as central elements on innate immunity, whose remarkable plasticity converts them in sensors of micro-environmental discontinuities and controllers of tissue homeostasis.
Mast cells (MCs) are tissue-resident immune cells that are important players in diseases associated with chronic inflammation such as cancer. Since MCs can infiltrate solid tumors and promote or limit tumor growth, a possible polarization of MCs to pro-tumoral or anti-tumoral phenotypes has been proposed and remains as a challenging research field. Here, we review the recent evidence regarding the complex relationship between MCs and tumor cells. In particular, we consider: (1) the multifaceted role of MCs on tumor growth suggested by histological analysis of tumor biopsies and studies performed in MC-deficient animal models; (2) the signaling pathways triggered by tumor-derived chemotactic mediators and bioactive lipids that promote MC migration and modulate their function inside tumors; (3) the possible phenotypic changes on MCs triggered by prevalent conditions in the tumor microenvironment (TME) such as hypoxia; (4) the signaling pathways that specifically lead to the production of angiogenic factors, mainly VEGF; and (5) the possible role of MCs on tumor fibrosis and metastasis. Finally, we discuss the novel literature on the molecular mechanisms potentially related to phenotypic changes that MCs undergo into the TME and some therapeutic strategies targeting MC activation to limit tumor growth.
Mast cells (MCs) are well-known cells for their important role in initiating allergic response through of cross-linking of FcɛRI receptor with IgE-Ag complexes. As participants on inflammatory reactions, they are exposed to environmental conditions such as hypoxia, which on MC-dependent cytokine secretion has not been described. Here, we show that bone marrow derived MCs (BMMCs) exposed to hypoxia, produce important amounts of CCL2 mRNA and protein, that is maximal secreted between 12 and 24 hours. CCL2 production induced by hypoxia was sensitive to the antioxidant trolox and L-type Ca2+ channel blocker nifedipine. In order to analyze the possible mechanism involved on hypoxia-induced CCL2 production, we found that this conditions caused an increase on reactive oxygen species (ROS) that was maximal after one hour. We also observed an increase on [Ca2+]i two hours after hypoxia, which was sensitive to trolox. With the aim to confirm this mechanism, BMMCs were treated with H2O2 and as expected, H2O2 caused an increase on ROS and [Ca2+]i in BMMCs. Ca2+ increase produced by H2O2 was sensitive to nifedipine. CCL2 mRNA accumulation and CCL2 protein secretion induced by H2O2 was sensitive to trolox and nifedipine too. When trolox and nifedipine were used in the B16-F1 murine model of melanoma, a close relationship between ROS, Ca2+ rise and CCL2 production was found, since those compounds were able to prevent pimonidazole-positive areas and CCL2 accumulation inside tumors. Our data suggest that conditions prevalent in tumor microenvironment contribute to the generation of ROS and L-type Ca2+ channel-dependent Ca2+ entry in MCs, causing the secretion of the potent immunosuppressor chemokine CCL2.
Although presence of mast cells (MCs) to sites with low oxygen concentration (such as inflamed tissues with compromised blood flux and solid tumors) has been reported, the effects of hypoxia on the cytokine profile produced by MCs under those conditions has not been fully explored. We used the murine B16 melanoma model to quantify the presence of MCs in normoxic or hypoxic zones of the tumor and, bone marrow-derived mast cells (BMMCs) subjected to a 1% O2 atmosphere to characterize the production of specific cytokines and chemokines by this cell type in hypoxic conditions. Hypoxic areas of melanoma tumors were identified with hypoxyprobe and the number of MCs was determined by confocal analysis of tryptase positive cells. Using this methodology, important MCs presence in hypoxic zones of the tumor was detected. In vitro, BMMCs subjected to hypoxia were able to produce VEGF and the potent chemokine CCL2. Chemokine production in hypoxia was sensitive to the antioxidant Trolox and the IKK inhibitor BAY117085. CCL2 production was also induce by monomeric IgE by a mechanism also sensitive to Trolox and BAY117085. CCL2 production triggered by hypoxia or monomeric IgE was sensitive to calcium chelator BAPTA and the L-type calcium channel blocker Nifedipine. Our results show that MCs are importantly recruited to hypoxic sites of melanoma tumors and that hypoxia induces the production of the chemokine CCL2 by a mechanism that require the production of reactive oxygen species (ROS) and intracellular calcium rise through the activation of L-type calcium channels. Also, data indicate that monomeric IgE triggers a very similar response than hypoxia does to lead to the production of CCL2 in mast cells.
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