Open AccessAntitumor effects of eribulin depend on modulation of the tumor microenvironment by vascular remodeling in mouse models
Author(s) -
Ito Ken,
Hamamichi Shusei,
Abe Takanori,
Akagi Tsuyoshi,
Shirota Hiroshi,
Kawano Satoshi,
Asano Makoto,
Asano Osamu,
Yokoi Akira,
Matsui Junji,
Umeda Izumi O.,
Fujii Hirofumi
Publication year - 2017
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.13392
Subject(s) - eribulin , cancer research , tumor microenvironment , pharmacology , angiogenesis , immune system , medicine , cancer , breast cancer , immunology , metastatic breast cancer , tumor cells
We previously reported that eribulin mesylate (eribulin), a tubulin‐binding drug ( TBD ), could remodel tumor vasculature (i.e. increase tumor vessels and perfusion) in human breast cancer xenograft models. However, the role of this vascular remodeling in antitumor effects is not fully understood. Here, we investigated the effects of eribulin‐induced vascular remodeling on antitumor activities in multiple human cancer xenograft models. Microvessel densities ( MVD ) were evaluated by immunohistochemistry ( CD 31 staining), and antitumor effects were examined in 10 human cancer xenograft models. Eribulin significantly increased MVD compared to the controls in six out of 10 models with a correlation between enhanced MVD levels and antitumor effects ( R 2 = 0.54). Because of increased MVD , we next used radiolabeled liposomes to examine whether eribulin treatment would result in increased tumoral accumulation levels of these macromolecules and, indeed, we found that eribulin, unlike vinorelbine (another TBD ) enhanced them. As eribulin increased accumulation of radiolabeled liposomes, we postulated that this treatment might enhance the antitumor effect of Doxil (a liposomal anticancer agent) and facilitate recruitment of immune cells into the tumor. As expected, eribulin enhanced antitumor activity of Doxil in a post‐erlotinib treatment H1650 ( PE ‐H1650) xenograft model. Furthermore, infiltrating CD 11b‐positive immune cells were significantly increased in multiple eribulin‐treated xenografted tumors, and natural killer ( NK ) cell depletion reduced the antitumor effects of eribulin. These findings suggest a contribution of the immune cells for antitumor activities of eribulin. Taken together, our results suggest that vascular remodeling induced by eribulin acts as a microenvironment modulator and, consequently, this alteration enhanced the antitumor effects of eribulin.