Effect of Eribulin on Angiogenesis and the Expression of Endothelial Adhesion Molecules

Abstract

Background/Aim: Tumor vasculature is an important component of the tumor microenvironment and deeply affects anticancer immune response. Eribulin is a non-taxane inhibitor of the mitotic spindle. However, off-target effects interfering with the tumor vasculature have been reported. The mechanisms responsible of this effect are still unclear. Materials and Methods: We designed an in vitro study to investigate the effect of eribulin, with or without TGF-β, on neo-angiogenesis, and on the expression of the adhesion molecules ICAM-1 and VCAM-1. We also investigated the effects of paclitaxel and vinorelbine under the same experimental conditions. Results: Eribulin up-regulated the epithelial markers VE-cadherin and CD-31 in HUVEC and inhibited tube formation in HUVEC cells cultured in Matrigel. The drug effectively arrested tube formation even in the presence of TGF-β and counteracted the TGF-β-induced change in cell shape from the endothelial cobblestone-like morphology to an elongated spindle-shaped morphology. We also observed that eribulin was able to upregulate ICAM-1 and to counteract its down-regulation induced by TGF-β. Conclusion: Eribulin exerts different off-label effects: increases vascular remodeling, counteracts the endothelial-to-mesenchymal transition (EndMT) mediated by TGF-β and promotes tumor infiltration by immune cells via increasing the expression of ICAM-1 and transcription of CD31 and VE-cadherin. Moreover, eribulin was able to inhibit vasculature remodeling and the induction of EndMT mediated by TGF-β better than vinorelbine and paclitaxel. The effects observed in this study might have important therapeutic consequence if the drug is combined with immunotherapy.