Endoglin expression in metastatic breast cancer cells enhances their invasive phenotype
Endoglin expression in metastatic breast cancer cells enhances their invasive phenotype
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DOI：
10.1038/sj.onc.1211025
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发表时间：
2008-06-05
期刊：
影响因子：
8
通讯作者：
Mentlein, R.
中科院分区：
文献类型：
--
作者：
Oxmann, D.;Held-Feindt, J.;Mentlein, R.
内皮糖蛋白是一种细胞表面黏附蛋白，也是转化生长因子 -β（TGF -β）的共受体。它位于内皮细胞和少数其他细胞上，在某些肿瘤细胞中也有发现。源自MDA - MB - 231细胞系的脑转移性乳腺癌细胞与相应的亲本细胞相比，大量表达内皮糖蛋白。为了阐明这是否决定了它们的侵袭表型，我们将它们的生物学特性与内皮糖蛋白沉默的脑转移性细胞、低表达的亲本细胞以及转染了L - 和S - 内皮糖蛋白（传递或缺乏TGF -β信号的异构体）的细胞进行了比较。所有过表达L - 内皮糖蛋白的细胞都具有大量的侵袭伪足，内皮糖蛋白优先定位于此处。内皮糖蛋白的表达导致基质金属蛋白酶（MMP - 1和MMP - 19）水平升高以及纤溶酶原激活物抑制剂 - 1的下调。在博伊登小室和伤口愈合实验中，过表达内皮糖蛋白的细胞对TGF -β表现出相当高的迁移和趋化性。在乳腺癌细胞和分泌TGF -β的胶质瘤细胞之间的3D球体对抗实验中，高表达L - 内皮糖蛋白的细胞侵入胶质瘤球体，而低表达内皮糖蛋白的细胞在培养中解离；侵袭被TGF -β抗体阻断。与亲本细胞相比，过表达内皮糖蛋白的细胞深入侵入小鼠脑切片。因此，肿瘤细胞上的内皮糖蛋白表达通过形成侵袭伪足、细胞外蛋白水解、趋化性和迁移增强了它们的侵袭特性。
Endoglin is a cell-surface adhesion protein as well as a coreceptor for transforming growth factor-beta (TGF-beta). It is located on endothelial and few other cells, but also found on certain tumor cells. Brain metastatic breast tumor cells derived from the MDA-MB-231 cell line heavily express endoglin in contrast to the corresponding parental ones. To clarify whether this determines their invasive phenotype, we compared their biological properties with endoglin-silenced brain-metastatic cells, low-expressing parental cells and these transfected with L- and S-endoglins, isoforms transducing or lacking TGF-beta signals. All L-endoglin-overexpressing cells were characterized by numerous invadopodia where endoglin was preferentially localized. Endoglin-expression resulted in elevated levels of the matrix metalloproteinases (MMP-1 and MMP-19) and downregulation of the plasminogen activator inhibitor-1. In Boyden-chamber and wound-healing assays, endoglin-overexpressing cells showed a considerably higher migration and chemotaxis to TGF-beta. In 3D spheroid confrontation assays between breast tumor cells and TGF-beta-secreting glioma cells, high L-endoglin-expressing cells invaded into the glioma-spheroids whereas low-endoglin-expressing cells dissociated in the culture; invasion was blocked by TGF-beta antibodies. In contrast to parental cells, endoglin-overexpressing cells invaded deeply into mouse brain slices. Thus, endoglin expression on tumor cells enhances their invasive character by formation of invadopodia, extracellular proteolysis, chemotaxis and migration.