Tumor necrosis factor-α promotes malignant pleural effusion
Tumor necrosis factor-α promotes malignant pleural effusion
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DOI：
10.1158/0008-5472.can-07-1064
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发表时间：
2007-10-15
期刊：
影响因子：
11.2
通讯作者：
Kalomenidis, Ioannis
中科院分区：
文献类型：
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作者：
Stathopoulos, Georgios T.;Kollintza, Androniki;Kalomenidis, Ioannis
肿瘤坏死因子（TNF）-α存在于人类肿瘤的微环境中，包括恶性胸腔积液（MPE）。尽管细胞因子是由肿瘤和宿主细胞在胸膜腔中产生的，但其对 MPE 形成的影响尚不清楚。在这些研究中，我们试图确定 TNF-α 在 MPE 发病机制中的作用，并评估其在临床前模型中中和的治疗效果。为此，通过胸膜内注射小鼠肺腺癌细胞在免疫活性小鼠中产生 MPE。使用 TNF-α 基因缺陷小鼠的联合实验和体内 TNF-α 中和来评估肿瘤来源和宿主来源的 TNF-α 的作用。为了扩大临床前数据的范围，我们测定了人癌细胞系和人 MPE 中的 TNF-α 和血管内皮生长因子 (VEGF) 表达。在 MPE 模型中，存在宿主和肿瘤来源的 TNF-α。 TNF-α 中和显着限制了肿瘤扩散、积液形成、血管渗透性过高、TNF-α 和 VEGF 表达以及血管生成，从而提高了生存率。相反，这些变量在 TNF-α 基因充足的小鼠和 TNF-α 基因缺陷的小鼠之间没有差异。在小鼠癌细胞中，TNF-α 通过核因子-κ B 和中性鞘磷脂酶依赖性途径发挥作用，分别诱导 TNF-α 和 VEGF。这些结果在人类癌细胞中得到重现，并且检测到人类 MPE 的 TNF-ot 和 VEGF 含量之间存在相关性。我们得出结论，肿瘤源性 TNF-α 在小鼠 MPE 的发生中发挥重要作用，并提供临床前证据支持 TNF-α 阻断对恶性胸膜疾病的功效。
Tumor necrosis factor (TNF)-alpha is present in the microenvironment of human tumors, including malignant pleural effusion (MPE). Although the cytokine is produced in the pleural cavity by both tumor and host cells, its effects on MPE formation are unknown. In these studies, we sought to determine the role of TNF-alpha in the pathogenesis of MPE and to assess the therapeutic effects of its neutralization in a preclinical model. For this, MPEs were generated in immunocompetent mice using intrapleural injection of mouse lung adenocarcinoma cells. The roles of tumor- and host-derived TNF-alpha were assessed using combined experimentation with TNF-alpha gene-deficient mice and in vivo TNF-alpha neutralization. To expand the scope of preclinical data, TNF-alpha and vascular endothelial growth factor (VEGF) expression were determined in human cancer cell lines and human MPE. In the MPE model, TNF-alpha of host and tumor origin was present. TNF-alpha neutralization significantly limited tumor dissemination, effusion formation, vascular hyperpermeability, TNF-alpha and VEGF expression, and angiogenesis, thereby improving survival. In contrast, these variables were not different between TNF-alpha gene-sufficient and TNF-alpha gene-deficient mice. In mouse cancer cells, TNF-alpha functioned via nuclear factor-kappa B-and neutral sphingomyelinase-dependent pathways to induce TNF-alpha and VEGF, respectively. These results were recapitulated in human cancer cells, and a correlation was detected between TNF-ot and VEGF content of human MPE. We conclude that tumor-derived TNF-alpha is important in the development of MPE in mice, and provide preclinical evidence supporting the efficacy of TNF-alpha blockade against malignant pleural disease.