Involvement of the chemokine receptor CXCR4 and its ligand stromal cell-derived factor 1alpha in breast cancer cell migration through human brain microvascular endothelial cells.
Involvement of the chemokine receptor CXCR4 and its ligand stromal cell-derived factor 1alpha in breast cancer cell migration through human brain microvascular endothelial cells.
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DOI：
10.1158/1541-7786.327.2.6
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发表时间：
2004-06
期刊：
影响因子：
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通讯作者：
Byeong‐Chel Lee;Tae-Hee Lee;S. Avraham;H. Avraham
中科院分区：
文献类型：
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作者：
Byeong‐Chel Lee;Tae-Hee Lee;S. Avraham;H. Avraham
在这项研究中，我们已经确定了乳腺癌细胞中CXCR 4介导的信号通路及其在乳腺癌细胞侵袭和迁移中的作用。基质细胞衍生因子1 α（SDF-1 α; CXCL 12）刺激乳腺癌细胞导致磷酸肌醇3-激酶（PI-3 K）活化、AKT磷酸化和FKHRL 1转录因子活化。此外，SDF-1 α诱导黏着斑激酶（FAK）的活化以及乳腺癌细胞的迁移。与正常上皮细胞相比，SDF-1 α（CXCR 4的配体）在显微切割的人乳腺上皮癌细胞中的表达约高2倍。免疫组化分析表明，SDF-1 α的表达在原发性乳腺肿瘤细胞中始终高于正常乳腺上皮细胞。此外，SDF-1 α通过增加血管通透性诱导血管不稳定，导致乳腺肿瘤细胞穿透人脑微血管内皮细胞（HBMEC）。值得注意的是，PI-3 K抑制剂Wortmannin和Ca（2+）抑制剂BAPTA/AM抑制了乳腺癌细胞的迁移，表明SDF-1 α诱导的跨内皮乳腺癌细胞迁移是通过PI-3 K/AKT通路和Ca（2+）介导的信号转导的激活介导的。用抗CXCR 4抗体阻断CXCR 4/SDF 1信号通路也降低了乳腺癌细胞的跨内皮迁移以及血管通透性。这项研究的重点是乳腺癌细胞和脑微血管内皮细胞中高度相关的信号通路之间的新的相互作用，并可能提供深入了解CXCR 4/SDF-1 α介导的乳腺癌转移到大脑的分子机制。
In this study, we have characterized the signaling pathways mediated by CXCR4 in breast cancer cells and its role in breast cancer cell invasion and migration. Stromal cell-derived factor 1alpha (SDF-1alpha; CXCL12) stimulation of breast cancer cells resulted in phosphoinositide 3-kinase (PI-3K) activation, AKT phosphorylation, and activation of the FKHRL1 transcription factor. In addition, SDF-1alpha induced activation of the focal adhesion kinase (FAK) as well as the migration of breast cancer cells. Expression of SDF-1alpha, the ligand of CXCR4, was about 2-fold higher in microdissected human breast epithelial cancer cells as compared with normal epithelial cells. Immunohistochemical analysis indicated that SDF-1alpha expression is consistently higher in primary breast tumor cells than in normal breast epithelial cells. Furthermore, SDF-1alpha induced blood vessel instability, through increased vascular permeability, resulting in the penetration of breast tumor cells through the human brain microvascular endothelial cells (HBMEC). Notably, the migration of breast cancer cells was inhibited by the PI-3K inhibitor, Wortmannin, and the Ca(2+) inhibitor BAPTA/AM, indicating that transendothelial breast cancer cell migration induced by SDF-1alpha is mediated by activation of the PI-3K/AKT pathway and Ca(2+)-mediated signaling. Blockade of the CXCR4/SDF1 signaling pathway with anti-CXCR4 antibody also decreased transendothelial breast cancer cell migration as well as vascular permeability. This study focuses on novel interactions between highly relevant signaling pathways in breast cancer cells and brain microvascular endothelial cells and may provide insights into the molecular mechanisms of CXCR4/SDF-1alpha-mediated breast cancer metastasis to the brain.