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

doi:10.1038/mt.2015.45

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

Medicine, Hematology Oncology Division

Research output: Contribution to journal › Article › peer-review

48 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 language	English (US)
Pages (from-to)	1044-1054
Number of pages	11
Journal	Molecular Therapy
Volume	23
Issue number	6
DOIs	https://doi.org/10.1038/mt.2015.45
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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/mt.2015.45

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title = "Blocking the adhesion cascade at the premetastatic niche for prevention of breast cancer metastasis",

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.",

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AU - Zhao, Lichao

AU - Morris, Lynsie

AU - Zhu, Weizhu

AU - Zhao, Yan D.

AU - Suh, K. Stephen

AU - Dooley, William C.

AU - Volk, David

AU - Gorenstein, David G.

AU - Cristofanilli, Massimo

AU - Rui, Hallgeir

AU - Tanaka, Takemi

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

Abstract

Funding

ASJC Scopus subject areas

UN SDGs

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