Blocking the adhesion cascade at the premetastatic niche for prevention of breast cancer metastasis

Shin Ae Kang, Nafis Hasan, Aman P. Mann, Wei Zheng, Lichao Zhao, Lynsie Morris, Weizhu Zhu, Yan D. Zhao, K. Stephen Suh, William C. Dooley, David Volk, David G. Gorenstein, Massimo Cristofanilli, Hallgeir Rui, Takemi Tanaka*

*Corresponding author for this work

Research output: Contribution to journalArticle

26 Scopus citations

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 languageEnglish (US)
Pages (from-to)1044-1054
Number of pages11
JournalMolecular Therapy
Volume23
Issue number6
DOIs
StatePublished - Jun 1 2015

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

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    Kang, S. A., Hasan, N., Mann, A. P., Zheng, W., Zhao, L., Morris, L., Zhu, W., Zhao, Y. D., Suh, K. S., Dooley, W. C., Volk, D., Gorenstein, D. G., Cristofanilli, M., Rui, H., & Tanaka, T. (2015). Blocking the adhesion cascade at the premetastatic niche for prevention of breast cancer metastasis. Molecular Therapy, 23(6), 1044-1054. https://doi.org/10.1038/mt.2015.45