Abstract 1413: Eribulin caused re-modeling of tumor vasculature altering gene expression profiling in angiogenesis and Epithelial Mesenchymal Transition (EMT) signaling pathway of host cells within human breast cancer cell (BCC) xenografts in nude mice.
Authors: Matsui Junji , Toyama Osamu , Ino Mitsuhiro , Semba Taro , Uesugi Mai , Muto Hiroki , Oestreicher Judith L. , Takahashi Kentaro , Matsuura Kentaro , Sato Yoshiaki , Uehara Taisuke , Kimura Takayuki , Watanabe Hideki , Ozawa Yoichi , Asano Makoto , Adachi Yusuke , Aoshima Ken , Funahashi Yasuhiro 
Published: August 2014

Objective: Eribulin mesylate (ERI) is a synthetic macrocyclic ketone analog of the marine sponge natural product halichondrin B and an inhibitor of microtubule dynamics. The objective of this study was to examine the effect of ERI on tumor vasculature with immunohistchemical (IHC) analysis and gene expression profiling (GEP) in normal host cells, such as endothelial cells and vascular mural cells within tumor microenvironments in human BCC xenograft models

Methods: Anti-tumor activity of ERI was examined at doses of 1.5 and 3.0 mg/kg, i.v. at day 1, in human BCC MX-1, MDA-MB-231 and MDA-MB-453 sc xenografts in nude mice. For IHC and GEP analysis, tumor tissues were collected at day 4 and day 8. IHC analysis was performed using mouse CD31 antibody to stain endothelial cells. Microvessel density (MVD) and vessel perimeter were determined by using Aperio Image Scope. GEP analysis for mouse host and human tumor cells within tumor tissues was done by using mouse and human TaqMan Low Density Arrays (TLDAs) consisting of a set of 92 genes related to angiogenesis, metastasis/EMT and cell differentiation signal pathways. Results shows % of non-treatment group (NT).

Results: ERI showed significant anti-tumor activity against all three human BCC xenografts in a dose dependent manner. IHC analysis showed that ERI altered morphology of tumor vasculature day 8 after treatments and increased number of vessels with small size of perimeter (&lt;300um), but decreased large size of vessels (&gt;300um) in both MX-1 and MDA-MB-231 xenograft models (p&lt;0.05 vs NT). ERI altered morphology of tumor vascular, which resembled normalized vasculature in two of triple negative (TN) breast cancer xenograft models. Next, GEP analysis revealed that in three human BCCs xenograft models, expression of endothelial (CD31, CD105) and pericyte markers (αSMA, NG2) were decreased in host cells 4 days after treatment of ERI (1.5mg/kg). ERI also decreased the expression of angiogenesis regulating genes (VEGF; 22.6%, Dll4; 30.4%, Notch4; 42.6%, Tie2; 63.4%) and genes in the EMT/metastasis pathway (TGFB1, ZEB1 and TWIST) in two of TN BCC (65.1%, 65.0%, 56.5% in MX-1 and 41.6%, 55.8%, 46.1% in MDA-MB-231, respectively) models compared to NT (p&lt;0.05), suggesting anti-EMT activity in host tissues within tumors.

Conclusions: ERI induced re-modeling of tumor vasculature in human BCC xenograft models. GEP related to angiogenesis and EMT/metastasis pathway was significantly affected with ERI treatment in host cells under tumor microenvironments. ERI might cause remodeling of tumor vasculature by regulating GEP in host cells. Further investigation may be warranted to examine if the activity of ERI against host cells in tumor tissues contributed to anti-tumor activity of ERI.

Citation Format: Junji Matsui, Osamu Toyama, Mitsuhiro Ino, Taro Semba, Mai Uesugi, Hiroki Muto, Judith L. Oestreicher, Kentaro Takahashi, Kentaro Matsuura, Yoshiaki Sato, Taisuke Uehara, Takayuki Kimura, Hideki Watanabe, Yoichi Ozawa, Makoto Asano, Yusuke Adachi, Ken Aoshima, Yasuhiro Funahashi. Eribulin caused re-modeling of tumor vasculature altering gene expression profiling in angiogenesis and Epithelial Mesenchymal Transition (EMT) signaling pathway of host cells within human breast cancer cell (BCC) xenografts in nude mice. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1413. doi:10.1158/1538-7445.AM2013-1413