肿瘤微环境
促炎细胞因子
巨噬细胞
肿瘤坏死因子α
细胞毒性T细胞
癌症研究
肿瘤进展
生物
免疫系统
免疫学
肿瘤缺氧
炎症
细胞生物学
医学
癌症
体外
放射治疗
生物化学
内科学
遗传学
作者
Bernhard Brüne,Nadine Courtial,Nathalie Dehne,Shahzad N. Syed,Andreas Weigert
标识
DOI:10.1089/ars.2016.6811
摘要
Significance: Leukocytes and especially macrophages are a major cellular constituent of the tumor mass. The tumor microenvironment not only determines their activity but in turn these cells also contribute to tumor initiation and progression. Recent Advances: Proinflammatory stimulated macrophages upregulate inducible nitric oxide synthase (NOS2) and produce high steady-state NO concentrations. NO provokes tumor cell death by initiating apoptosis and/or necrosis. Mechanisms may comprise p53 accumulation, immunestimulatory activities, and an increased efficacy of chemo- and/or radiotherapy. However, the potential cytotoxic activity of macrophages often is compromised in the tumor microenvironment and instead a protumor activity of macrophages dominates. Contributing factors are signals generated by viable and dying tumor cells, attraction and activation of myeloid-derived suppressor cells, and hypoxia. Limited oxygen availability not only attenuates NOS2 activity but also causes accumulation of hypoxia-inducible factors 1 and 2 (HIF-1/HIF-2). Activation of the HIF system is tightly linked to NO formation and affects the expression of macrophage phenotype markers that in turn add to tumor progression. Critical Issues: To make use of the cytotoxic arsenal of activated macrophages directed against tumor cells, it will be critical to understand how, when, and where these innate immune responses are blocked and whether it will be possible to reinstall their full capacity to kill tumor cells. Future Directions: Low-dose irradiation or proinflammatory activation of macrophages in the tumor microenvironment may open options to boost NOS2 expression and activity and to initiate immunestimulatory features of NO that may help to restrict tumor growth. Antioxid. Redox Signal. 26, 1023–1043.
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