Blocking the adhesion cascade at the premetastatic niche for prevention of breast cancer metastasis.
Blocking the adhesion cascade at the premetastatic niche for prevention of breast cancer metastasis.
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DOI：
10.1038/mt.2015.45
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发表时间：
2015-06
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通讯作者：
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;D. Volk;D. Gorenstein;M. Cristofanilli;H. Rui;Takemi Tanaka
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作者：
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;D. Volk;D. Gorenstein;M. Cristofanilli;H. Rui;Takemi Tanaka
癌细胞在靶器官的抗剪切粘附和外渗是血行转移的关键步骤。我们发现，血管粘附分子E-选择素优先促进抗剪切粘附和跨内皮迁移的雌激素受体（ER）-/CD 44+雌激素非依赖性乳腺癌细胞，但不是ER+/CD 44-/lowhormone-dependent乳腺癌细胞。巧合的是，在ER-乳腺癌的转移性肺和脑病变中，CD 44+乳腺癌细胞丰富，这表明E-选择素支持ER-/CD 44+乳腺癌的血行转移。为了通过抑制CD 44+癌细胞与转移前小生境上表达E-选择素的血管的抗剪切粘附来预防血行转移，开发了E-选择素靶向适体（ESTA）。我们证明了单次静脉注射ESTA在同基因和异种强制乳腺癌转移模型中将转移减少到基线水平，而不重新定位转移部位。ESTA的作用在E-选择素基因敲除小鼠中不存在，表明E-选择素是ESTA的分子靶点。我们的数据突出了E-选择素拮抗剂在预防ER-/CD 44+乳腺癌血行转移中的潜在应用。
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-/lowhormone-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.