Anti-tumor Effects of Eribulin Depend on the Modulation of Tumor Microenvironment by Vascular Remodeling in Mouse Models

Summary

We previously reported that eribulin mesylate (eribulin), a tubulin-binding drug (TBD), could remodel tumor vasculature (i.e., increased tumor vessels and perfusion) in human breast cancer xenograft models; however, a role of this vascular remodeling in anti-tumor effects is not fully understood. Here, we investigated the effects of eribulin-induced vascular remodeling on anti-tumor activities in multiple human cancer xenograft models. Microvessel densities (MVDs) were evaluated by immunohistochemistry (CD31 staining), and anti-tumor effects were examined in 10 human cancer xenograft models. Eribulin significantly increased MVDs compared to the controls in 6 out of 10 models with a correlation between enhanced MVD levels and anti-tumor effects (R²=0.54). Because of increased MVDs, we next utilized radiolabeled liposomes to examine if eribulin treatment would result in increased tumoral accumulation levels of these macromolecules, and indeed, we found that eribulin, unlike vinorelbine (another TBD) enhanced them. Since eribulin increased accumulation of radiolabeled liposomes, we postulated that this treatment might enhance anti-tumor effect of Doxil (a liposomal anti-cancer agent) and facilitate the recruitment of immune cells into the tumor. As expected, eribulin enhanced anti-tumor activity of Doxil in post-erlotinib treatment H1650 (PE-H1650) xenograft model. Furthermore, infiltrating CD11b-positive immune cells were significantly increased in multiple eribulin-treated xenografted tumors, and natural killer (NK) cell depletion reduced anti-tumor effects of eribulin. These findings suggested a contribution of the immune cells for anti-tumor activities of eribulin. Taken together, our results suggested vascular remodeling induced by eribulin would act as a microenvironment modulator, and consequently, this alteration enhanced anti-tumor effects of eribulin.

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