Eribulin mesylate reduces tumor microenvironment abnormality by vascular remodeling in preclinical human breast cancer models

• Published in: Cancer science Vol. 105; no. 10; pp. 1334 - 1342
• Main Authors: Funahashi, Yasuhiro, Okamoto, Kiyoshi, Adachi, Yusuke, Semba, Taro, Uesugi, Mai, Ozawa, Yoichi, Tohyama, Osamu, Uehara, Taisuke, Kimura, Takayuki, Watanabe, Hideki, Asano, Makoto, Kawano, Satoshi, Tizon, Xavier, McCracken, Paul J., Matsui, Junji, Aoshima, Ken, Nomoto, Kenichi, Oda, Yoshiya
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.10.2014; BlackWell Publishing Ltd
• Subjects: Angiogenesis; Animals; Apoptosis; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - pathology; Cancer therapies; Capecitabine; Cell cycle; Cell Line, Tumor; Deoxycytidine - analogs & derivatives; Deoxycytidine - pharmacology; Drug resistance; Endothelial cells; Enzyme-linked immunosorbent assay; eribulin mesylate; Female; Fluorouracil - analogs & derivatives; Fluorouracil - pharmacology; Furans - pharmacology; Gene expression; Humans; Hypoxia; Ketones - pharmacology; Laboratory animals; Magnetic resonance imaging; Mesenchyme; Metastases; Metastasis; Mice, Inbred BALB C; Microenvironments; Natural products; Original; Perfusion; Stroma; Tubulin; Tubulin Modulators - pharmacology; tumor microenvironment; Tumor Microenvironment - drug effects; tumor vasculature; Tumors; Vascular endothelial growth factor; vascular remodeling; Vascular Remodeling - drug effects; Xenograft Model Antitumor Assays; Xenografts; France; United States > US; Japan; eribulin mesylate; Breast cancer; tumor microenvironment; tumor vasculature; vascular remodeling
• ISSN: 1347-9032; 1349-7006; 1349-7006
• DOI: 10.1111/cas.12488

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. Eribulin mesylate, a nontaxane, synthetic microtubule‐dynamics inhibitor, induces tumor vascular remodeling and caused phenotypic changes of the abnormality of tumor microenvironment. This antivascular activity of eribulin (vascular remodeling) was novel, since it was different from known antivascular activity of other tubulin‐binding drugs (antiangiogenesis or vascular disrupting activities). Because vascular remodeling is a part of a longer‐term phenotypic change of the tumor microenvironment rather than a temporal “normalization” by the antiangiogenesis agent, eribulin may contribute to overcome the drug‐resistance and metastasis of malignant tumors, which prohibited long survival of cancer patients, based on this vascular remodeling activity.