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,Robert Fürst,Angelika Ullrich,Uli Kazmaier

doi:10.18632/oncotarget.20746

Rebecca Schwenk, Tanja Stehning + Show 4 more

Open Access

https://doi.org/10.18632/oncotarget.20746

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Journal: Oncotarget	Publication Date: Sep 8, 2017
Citations: 7	License type: cc-by

Affiliation: Goethe University Frankfurt, Saarland University

Abstract

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.

Highlights

Microtubule-targeting agents (MTAs) are the most frequently used chemotherapeutic drugs
We analyzed the influence of PT on the interaction of nontumor endothelial cells and breast cancer cells in vitro, since we hypothesized that PT influences the metastatic process – at least in part – via a direct action on the endothelium
We showed that the treatment of endothelial cells with PT strongly increased the adhesion of breast cancer cells to interendothelial gaps, but reduces their transmigration through the endothelial monolayer

Summary

Introduction

Microtubule-targeting agents (MTAs) are the most frequently used chemotherapeutic drugs. Microtubules are highly dynamic structures composed of continuously assembling and disassembling α,β-tubulin heterodimers (dynamic instability) They are present in all dividing and non-dividing cells and play an essential role in a wide range of cellular processes. Due to the clinical success of the approved MTAs, and because of their major drawbacks, such as resistance and side effects, the search for new classes of MTAs is still ongoing In this context, in 2000, Sasse et al described a novel group of highly potent microtubule-depolymerizing natural products referred to as tubulysins [4]. In 2000, Sasse et al described a novel group of highly potent microtubule-depolymerizing natural products referred to as tubulysins [4] These compounds, which are produced by myxobacteria (e.g. Archangium www.impactjournals.com/oncotarget gephyra), represent linear tetrapeptides that bind at the vinca domain of β-tubulin [4,5,6,7]. It exerts profound anti-vascular actions on already existing tumor vessels in vivo in A-Mel-3 amelanotic melanoma tumors and in vitro on primary endothelial cells [16]

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