Stathopoulos Georgios T, Kollintza Androniki, Moschos Charalampos, Psallidas Ioannis, Sherrill Taylor P, Pitsinos Emmanuel N, Vassiliou Spyridoula, Karatza Marilena, Papiris Spyros A, Graf Daniel, Orphanidou Dora, Light Richard W, Roussos Charis, Blackwell Timothy S, Kalomenidis Ioannis
Applied Biomedical Research and Training Center Marianthi Simou, Department of Critical Care and Pulmonary Services, General Hospital Evangelismos, School of Medicine, National and Kapodistrian University of Athens, Greece.
Cancer Res. 2007 Oct 15;67(20):9825-34. doi: 10.1158/0008-5472.CAN-07-1064.
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-kappaB- 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-alpha 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.
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）。尽管这种细胞因子由肿瘤细胞和宿主细胞在胸腔内产生，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，并在临床前模型中评估其拮抗作用的治疗效果。为此，通过向免疫活性小鼠胸腔内注射小鼠肺腺癌细胞来生成MPE。使用TNF-α基因缺陷小鼠进行联合实验并在体内中和TNF-α，以评估肿瘤源性和宿主源性TNF-α的作用。为了扩大临床前数据的范围，我们测定了人类癌细胞系和人类MPE中TNF-α和血管内皮生长因子（VEGF）的表达。在MPE模型中，存在宿主和肿瘤来源的TNF-α。中和TNF-α可显著限制肿瘤播散、胸腔积液形成、血管通透性增加、TNF-α和VEGF表达以及血管生成，从而提高生存率。相比之下，TNF-α基因充足的小鼠和TNF-α基因缺陷的小鼠之间这些变量没有差异。在小鼠癌细胞中，TNF-α分别通过核因子-κB和中性鞘磷脂酶依赖性途径发挥作用，诱导TNF-α和VEGF。这些结果在人类癌细胞中得到重现，并且在人类MPE的TNF-α和VEGF含量之间检测到相关性。我们得出结论，肿瘤源性TNF-α在小鼠MPE的发展中起重要作用，并提供了临床前证据支持TNF-α阻断对恶性胸膜疾病的疗效。
