title: Eribulin mesylate reduces tumor microenvironment abnormality by vascular remodeling in preclinical human breast cancer models.
abstract: Eribulin mesylate is a synthetic macrocyclic ketone analog of the marine sponge natural product halichondrin B and an inhibitor of microtubule dynamics. Some tubulin-binding drugs are known to have antivascular (antiangiogenesis or vascular-disrupting) activities that can target abnormal tumor vessels. Using dynamic contrast-enhanced MRI analyses, here we show that eribulin induces remodeling of tumor vasculature through a novel antivascular activity in MX-1 and MDA-MB-231 human breast cancer xenograft models. Vascular remodeling associated with improved perfusion was shown by Hoechst 33342 staining and by increased microvessel density together with decreased mean vascular areas and fewer branched vessels in tumor tissues, as determined by immunohistochemical staining for endothelial marker CD31. Quantitative RT-PCR analysis of normal host cells in the stroma of xenograft tumors showed that eribulin altered the expression of mouse (host) genes in angiogenesis signaling pathways controlling endothelial cell-pericyte interactions, and in the epithelial-mesenchymal transition pathway in the context of the tumor microenvironment. Eribulin also decreased hypoxia-associated protein expression of mouse (host) vascular endothelial growth factor by ELISA and human CA9 by immunohistochemical analysis. Prior treatment with eribulin enhanced the anti-tumor activity of capecitabine in the MDA-MB-231 xenograft model. These findings suggest that eribulin-induced remodeling of abnormal tumor vasculature leads to a more functional microenvironment that may reduce the aggressiveness of tumors due to elimination of inner tumor hypoxia. Because abnormal tumor microenvironments enhance both drug resistance and metastasis, the apparent ability of eribulin to reverse these aggressive characteristics may contribute to its clinical benefits.
authors: Biomarkers and Personalized Medicine Core Function Unit, Eisai Inc., Andover, Massachusetts, USA.
authors: Yasuhiro
authors: Y
authors: Funahashi
authors: Kiyoshi
authors: K
authors: Okamoto
authors: Yusuke
authors: Y
authors: Adachi
authors: Taro
authors: T
authors: Semba
authors: Mai
authors: M
authors: Uesugi
authors: Yoichi
authors: Y
authors: Ozawa
authors: Osamu
authors: O
authors: Tohyama
authors: Taisuke
authors: T
authors: Uehara
authors: Takayuki
authors: T
authors: Kimura
authors: Hideki
authors: H
authors: Watanabe
authors: Makoto
authors: M
authors: Asano
authors: Satoshi
authors: S
authors: Kawano
authors: Xavier
authors: X
authors: Tizon
authors: Paul J
authors: PJ
authors: McCracken
authors: Junji
authors: J
authors: Matsui
authors: Ken
authors: K
authors: Aoshima
authors: Kenichi
authors: K
authors: Nomoto
authors: Yoshiya
authors: Y
authors: Oda
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D000069287:Capecitabine; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D005260:Female; D005472:Fluorouracil / Q000031:analogs & derivatives / Q000494:pharmacology; D005663:Furans / Q000494:pharmacology*; D006801:Humans; D007659:Ketones / Q000494:pharmacology*; D008807:Mice, Inbred BALB C; D050257:Tubulin Modulators / Q000494:pharmacology*; D059016:Tumor Microenvironment / Q000187:drug effects*; D066253:Vascular Remodeling / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays; D000095662:Polyether Polyketides
chemical_list: D000069287:Capecitabine; D003841:Deoxycytidine; D005472:Fluorouracil; D005663:Furans; D007659:Ketones; D050257:Tubulin Modulators; C490954:eribulin; D000095662:Polyether Polyketides
keywords: Breast cancer; eribulin mesylate; tumor microenvironment; tumor vasculature; vascular remodeling