Research Papers:

The pretubulysin-induced exposure of collagen is caused by endothelial cell retraction that results in an increased adhesion and decreased transmigration of tumor cells

Rebecca Schwenk, Tanja Stehning, Iris Bischoff, Angelika Ullrich, Uli Kazmaier and Robert Fürst _

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Oncotarget. 2017; 8:77622-77633. https://doi.org/10.18632/oncotarget.20746

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Rebecca Schwenk1, Tanja Stehning1, Iris Bischoff1, Angelika Ullrich2, Uli Kazmaier2 and Robert Fürst1

1Institute of Pharmaceutical Biology, Goethe University, Frankfurt, Germany

2Institute of Organic Chemistry, Saarland University, Saarbrücken, Germany

Correspondence to:

Robert Fürst, email: [email protected]

Keywords: tumor cell adhesion, tumor cell transmigration, endothelium, extracellular matrix, pretubulysin

Received: December 10, 2016     Accepted: August 04, 2017     Published: September 08, 2017


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 in vivo. The aim of the present study was to analyze the impact of PT on the interaction of endothelial and tumor cells in vitro 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 via 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.

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