Effect of Eribulin on Angiogenesis and Endothelial Adhesion Molecule Expression.

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.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 in the same experimental conditions.Eribulin up-regulated the epithelial markers VE-cadherin and CD-31 in HUVEC and inhibited tube formation in HUVEC cultured in Matrigel. The drug effectively arrested tube formation even in presence of TGF-β and counteracted the TGF-β-induced change in cell shape from the endothelial cobblestone-like morphology to an elongated spindleshaped morphology.We also observed that eribulin was able to upregulate ICAM-1 and to counteract its downregulation induced by TGF-β.Eribulin therefore exerts different off-label effects: increases vascular remodeling, counteracts the endothelial tomesenchymal transition (EndMT) mediated by TGF-β and promotes tumor infiltration by immune cells by increasing 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 will be administered with immunotherapy.