Glycoprotein nmb Is Exposed on the Surface of Dormant Breast Cancer Cells and Induces Stem Cell-like Properties
Glycoprotein nmb Is Exposed on the Surface of Dormant Breast Cancer Cells and Induces Stem Cell-like Properties
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DOI：
10.1158/0008-5472.can-18-0599
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发表时间：
2018-11-15
期刊：
影响因子：
11.2
通讯作者：
Kato, Mitsuyasu
中科院分区：
文献类型：
--
作者：
Chen, Chen;Okita, Yukari;Kato, Mitsuyasu
糖蛋白NMB(GPNMB)是一种I型跨膜蛋白，通过诱导上皮-间充质转化(EMT)参与乳腺癌的发生和恶性进展。虽然已知EMT不仅与癌症侵袭有关，而且与肿瘤干细胞(CSC)特性的获得有关，但GPNMB在获得CSC特性中的作用尚未阐明。为了解决这个问题，我们利用三维(3D)球体培养方法来检测乳腺癌细胞中GPNMB和CSC特性之间的相关性。三维球体培养诱导CSC基因和EMT诱导转录因子(EMT-TF)基因的表达高于2D单层培养。三维培养也能诱导球体中有限数量的细胞表面表达GPNMB，而二维培养不能。因此，我们从球体中分离出细胞表面-GPNMB(高)和-GPNMB(低)细胞。细胞表面-GPNMB(高)细胞高水平表达CSC基因和EMT-TF基因，球形率显著高于细胞表面-GPNMB(低)细胞，未检测到增殖标记基因。移植的乳腺肿瘤也得到了类似的结果。此外，野生型GPNMB，而不是缺乏致瘤活性的突变型GPNMB(YF)，可以诱导乳腺上皮细胞具有CSC样特性。这些发现表明，GPNMB暴露在休眠的乳腺癌细胞表面，其活性有助于获得干细胞样特性。意义：这些发现表明，GPNMB的细胞表面表达可以作为具有干细胞样特性的乳腺癌细胞的标志物和有前景的治疗靶点。(C)2018年AACR。
Glycoprotein nmb (GPNMB) is a type I transmembrane protein that contributes to the initiation and malignant progression of breast cancer through induction of epithelial-mesenchymal transition (EMT). Although it is known that EMT is associated with not only cancer invasion but also acquisition of cancer stem cell (CSC) properties, the function of GPNMB in this acquisition of CSC properties has yet to be elucidated. To address this issue, we utilized a three-dimensional (3D) sphere culture method to examine the correlation between GPNMB and CSC properties in breast cancer cells. Three-dimensional sphere cultures induced higher expression of CSC genes and EMT-inducing transcription factor (EMT-TF) genes than the 2D monolayer cultures. Three-dimensional culture also induced cell surface expression of GPNMB on limited numbers of cells in the spheres, whereas the 2D cultures did not. Therefore, we isolated cell surface-GPNMB(high) and -GPNMB(low) cells from the spheres. Cell surface-GPNMB(high) cells expressed high levels of CSC genes and EMT-TF genes, had significantly higher sphere-forming frequencies than the cell surface-GPNMB(low) cells, and showed no detectable levels of proliferation marker genes. Similar results were obtained from transplanted breast tumors. Furthermore, wild-type GPNMB, but not mutant GPNMB (YF), which lacks tumorigenic activity, induced CSC-like properties in breast epithelial cells. These findings suggest that GPNMB is exposed on the surface of dormant breast cancer cells and its activity contributes to the acquisition of stem cell-like properties.Significance: These findings suggest that cell surface expression of GPNMB could serve as a marker and promising therapeutic target of breast cancer cells with stem cell-like properties. (C) 2018 AACR.