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首页> 外文期刊>Neoplasia: an international journal for oncology research >Cycling Hypoxia Induces a Specific Amplified Inflammatory Phenotype in Endothelial Cells and Enhances Tumor-Promoting Inflammation In Vivo
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Cycling Hypoxia Induces a Specific Amplified Inflammatory Phenotype in Endothelial Cells and Enhances Tumor-Promoting Inflammation In Vivo

机译：循环缺氧在内皮细胞中诱导特异的扩增炎症表型，并增强肿瘤促进体内炎症

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Abnormal architecture of the tumor blood network, as well as heterogeneous erythrocyte flow, leads to temporal fluctuations in tissue oxygen tension exposing tumor and stromal cells to cycling hypoxia. Inflammation is another feature of tumor microenvironment and is considered as a new enabling characteristic of tumor progression. As cycling hypoxia is known to participate in tumor aggressiveness, the purpose of this study was to evaluate its role in tumor-promoting inflammation. Firstly, we assessed the impact of cycling hypoxia in vitro on endothelial inflammatory response induced by tumor necrosis factor α. Results showed that endothelial cells exposed to cycling hypoxia displayed an amplified proinflammatory phenotype, characterized by an increased expression of inflammatory cytokines, namely, interleukin (IL)-6 and IL-8; by an increased expression of adhesion molecules, in particular intercellular adhesion molecule–1 (ICAM-1); and consequently by an increase in THP-1 monocyte adhesion. This exacerbation of endothelial inflammatory phenotype occurs through nuclear factor–κB overactivation. Secondly, the role of cycling hypoxia was studied on overall tumor inflammation in vivo in tumor-bearing mice. Results showed that cycling hypoxia led to an enhanced inflammation in tumors as prostaglandin-endoperoxide synthase 2 (PTGS2), IL-6, CXCL1 (C-X-C motif ligand 1), and macrophage inflammatory protein 2 (murine IL-8 functional homologs) mRNA expression was increased and as a higher leukocyte infiltration was evidenced. Furthermore, cycling hypoxia–specific inflammatory phenotype, characterized by a simultaneous (baculoviral inhibitor of apoptosis repeat-containing 5)low/PTGS2high/ICAM-1high/IL-6high/IL-8high expression, is associated with a poor prognosis in human colon cancer. This new phenotype could thus be used in clinic to more precisely define prognosis for colon cancer patients. In conclusion, our findings evidenced for the first time the involvement of cycling hypoxia in tumor-promoting inflammation amplification.
机译：肿瘤血迹的异常架构以及异质性红细胞流动，导致组织氧气张力暴露于循环缺氧的组织氧张力中的时间波动。炎症是肿瘤微环境的另一个特征，被认为是肿瘤进展的新能力特征。众所周知，作为循环缺氧参与肿瘤侵袭性，本研究的目的是评估其在肿瘤促进炎症中的作用。首先，我们评估了循环缺氧在体外对肿瘤坏死因子α诱导的内皮炎症反应的影响。结果表明，暴露于循环缺氧的内皮细胞显示出扩增的促炎性表型，其特征在于炎症细胞因子的表达增加，即白细胞介素（IL）-6和IL-8;通过增加粘附分子的表达，特别是细胞间粘附分子-1（ICAM-1）;因此，通过增加THP-1单核细胞粘附。通过核因子-κB过剂发生这种情况，内皮炎症表型的这种恶化。其次，研究了循环缺氧的作用对携带肿瘤小鼠体内的整体肿瘤炎症进行了研究。结果表明，循环缺氧导致肿瘤中增强的炎症，作为前列腺素 - 内甲氧化物合酶2（PTGS2），IL-6，CXCL1（CXC MOTIF配体1），和巨噬细胞炎症蛋白2（鼠IL-8功能同源物）mRNA表达随着更高的白细胞浸润，证明了更高的白细胞渗透。此外，循环缺氧特异性炎症表型，其特征在于同时（含有凋亡的凋亡尿道抑制剂5）低/ PTGS2High / ICAM-1High / IL-6High / IL-8High表达，与人结肠癌的预后不良有关。因此，这种新的表型可以在临床中使用更精确地定义结肠癌患者的预后。总之，我们的研究结果首次证明了循环缺氧在促进肿瘤炎症扩增中的参与。

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