Abstract
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.
Original language | English (US) |
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Pages (from-to) | 1044-1054 |
Number of pages | 11 |
Journal | Molecular Therapy |
Volume | 23 |
Issue number | 6 |
DOIs | |
State | Published - Jun 1 2015 |
Funding
This work was supported by the Department of Defense ( W81XWH-11-1-0238 ), the National Institutes of Health ( 1R01CA160271-01A1 ), the American Cancer Society ( IRG-08-060-04 ), and the Pennsylvania Breast Cancer Coalition to T.T., and U54CA151668 to D.G.G. The authors thank the Pathology and Imaging Core Facilities at the University of Oklahoma. D.G.G. is a founder of AM Biotechnologies, which has licensed thioaptamer selection technologies.
ASJC Scopus subject areas
- Molecular Medicine
- Molecular Biology
- Genetics
- Pharmacology
- Drug Discovery