Trauzold A, Siegmund D, Schniewind B, Sipos B, Egberts J, Zorenkov D, Emme D, Röder C, Kalthoff H, Wajant H
Section of Molecular Oncology, Clinic for General Surgery and Thoracic Surgery, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
Oncogene. 2006 Nov 30;25(56):7434-9. doi: 10.1038/sj.onc.1209719. Epub 2006 Jun 5.
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has attracted considerable attention for its potential use in tumor therapy, as some recombinant variants of this ligand induce apoptosis in tumor cells without harming most normal cells. Here, we show that TRAIL strongly induces the expression of the proinflammatory cytokines interleukin-8 and monocyte chemoattractant protein 1 and enhances the invasion of apoptosis-resistant pancreatic ductal adenocarcinoma cells in vitro by upregulation of the urokinase-type plasminogen activator expression. Most importantly, we also demonstrate for the first time that TRAIL treatment results in strongly increased distant metastasis of pancreatic tumors in vivo. We orthotopically transplanted human pancreatic ductal adenocarcinoma cells to the pancreata of severe combined immunodeficiency mice and observed a dramatic increase in metastatic spread including a sixfold increase in the volume and fourfold increase in the number of liver metastases upon TRAIL treatment. Our results point to the necessity to carefully evaluate in vivo side effects of TRAIL and to select therapy conditions that not only enhance apoptosis induction but in addition prevent proinvasive and proinflammatory non-apoptotic TRAIL signaling.
肿瘤坏死因子相关凋亡诱导配体（TRAIL）因其在肿瘤治疗中的潜在应用而备受关注，因为该配体的一些重组变体可诱导肿瘤细胞凋亡，而不损害大多数正常细胞。在此，我们表明TRAIL强烈诱导促炎细胞因子白细胞介素-8和单核细胞趋化蛋白1的表达，并通过上调尿激酶型纤溶酶原激活剂的表达增强体外抗凋亡胰腺导管腺癌细胞的侵袭。最重要的是，我们还首次证明TRAIL治疗导致体内胰腺肿瘤远处转移显著增加。我们将人胰腺导管腺癌细胞原位移植到严重联合免疫缺陷小鼠的胰腺中，观察到TRAIL治疗后转移扩散显著增加，包括肝转移体积增加六倍和数量增加四倍。我们的结果表明，有必要仔细评估TRAIL的体内副作用，并选择不仅能增强凋亡诱导，而且能防止促侵袭和促炎非凋亡TRAIL信号传导的治疗条件。
