Schwenk Rebecca, Stehning Tanja, Bischoff Iris, Ullrich Angelika, Kazmaier Uli, Fürst Robert
Institute of Pharmaceutical Biology, Goethe University, Frankfurt, Germany.
Institute of Organic Chemistry, Saarland University, Saarbrücken, Germany.
Oncotarget. 2017 Sep 8;8(44):77622-77633. doi: 10.18632/oncotarget.20746. eCollection 2017 Sep 29.
Microtubule-targeting agents (MTAs) are the most widely used chemotherapeutic drugs. Pretubulysin (PT), a biosynthetic precursor of the myxobacterial tubulysins, was recently identified as a novel MTA. Besides its strong anti-tumoral activities, PT attenuates tumor angiogenesis, exerts anti-vascular actions on tumor vessels and decreases cancer metastasis formation . The aim of the present study was to analyze the impact of PT on the interaction of endothelial and tumor cells to gain insights into the mechanism underlying its anti-metastatic effect. The influence of PT on tumor cell adhesion and transmigration onto/through the endothelium as well as its influence on cell adhesion molecules and the chemokine system CXCL12/CXCR4 was investigated. Treatment of human endothelial cells with PT increased the adhesion of breast cancer cells to the endothelial monolayer, whereas their transmigration through the endothelium was strongly reduced. Interestingly, the PT-induced upregulation of ICAM-1, VCAM-1 and CXCL12 were dispensable for the PT-evoked tumor cell adhesion. Tumor cells preferred to adhere to collagen exposed within PT-triggered endothelial gaps β1-integrins on the tumor cell surface. Taken together, our study provides, at least in part, an explanation for the anti-metastatic potential of PT.
微管靶向剂（MTAs）是使用最广泛的化疗药物。前管溶素（PT）是粘细菌管溶素的生物合成前体，最近被鉴定为一种新型的微管靶向剂。除了具有强大的抗肿瘤活性外，PT还能减弱肿瘤血管生成，对肿瘤血管发挥抗血管作用，并减少癌症转移灶的形成。本研究的目的是分析PT对内皮细胞与肿瘤细胞相互作用的影响，以深入了解其抗转移作用的潜在机制。研究了PT对肿瘤细胞黏附于内皮细胞并向内皮细胞迁移以及对细胞黏附分子和趋化因子系统CXCL12/CXCR4的影响。用PT处理人内皮细胞增加了乳腺癌细胞对内皮细胞单层的黏附，而其穿过内皮细胞的迁移则显著减少。有趣的是，PT诱导的ICAM-1、VCAM-1和CXCL12上调对于PT引发的肿瘤细胞黏附并非必需。肿瘤细胞更倾向于黏附在PT引发的内皮间隙中暴露的胶原蛋白上，这依赖于肿瘤细胞表面的β1整合素。综上所述，我们的研究至少部分地解释了PT的抗转移潜力。
