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.