Blocking the adhesion cascade at the premetastatic niche for prevention of breast cancer metastasis. Mol Ther 2015 Jun;23(6):1044-1054
Date
03/31/2015Pubmed ID
25815697Pubmed Central ID
PMC4817749DOI
10.1038/mt.2015.45Scopus ID
2-s2.0-84930178523 (requires institutional sign-in at Scopus site) 48 CitationsAbstract
Shear-resistant adhesion and extravasation of disseminated cancer cells at the target organ is a crucial step in hematogenous metastasis. We found that the vascular adhesion molecule E-selectin preferentially promoted the shear-resistant adhesion and transendothelial migration of the estrogen receptor (ER)(-)/CD44(+) hormone-independent breast cancer cells, but not of the ER(+)/CD44(-/low) hormone-dependent breast cancer cells. Coincidentally, CD44(+) breast cancer cells were abundant in metastatic lung and brain lesions in ER(-) breast cancer, suggesting that E-selectin supports hematogenous metastasis of ER(-)/CD44(+) breast cancer. In an attempt to prevent hematogenous metastasis through the inhibition of a shear-resistant adhesion of CD44(+) cancer cells to E-selectin-expressing blood vessels on the premetastatic niche, an E-selectin targeted aptamer (ESTA) was developed. We demonstrated that a single intravenous injection of ESTA reduced metastases to a baseline level in both syngeneic and xenogeneic forced breast cancer metastasis models without relocating the site of metastasis. The effect of ESTA was absent in E-selectin knockout mice, suggesting that E-selectin is a molecular target of ESTA. Our data highlight the potential application of an E-selectin antagonist for the prevention of hematogenous metastasis of ER(-)/CD44(+) breast cancer.
Author List
Kang SA, Hasan N, Mann AP, Zheng W, Zhao L, Morris L, Zhu W, Zhao YD, Suh KS, Dooley WC, Volk D, Gorenstein DG, Cristofanilli M, Rui H, Tanaka TMESH terms used to index this publication - Major topics in bold
AnimalsAptamers, Nucleotide
Breast Neoplasms
Cell Adhesion
Cell Line, Tumor
E-Selectin
Endothelial Cells
Female
Gene Expression Regulation, Neoplastic
Genetic Therapy
Humans
MCF-7 Cells
Mice
Mice, Inbred BALB C
Neoplasm Metastasis
Receptors, Estrogen
Transendothelial and Transepithelial Migration
