Endothelial cells create a stem cell niche in glioblastoma by providing NOTCH ligands that nurture self-renewal of cancer stem-like cells.
Endothelial cells create a stem cell niche in glioblastoma by providing NOTCH ligands that nurture self-renewal of cancer stem-like cells.
复制标题
DOI：
10.1158/0008-5472.can-10-4269
复制
发表时间：
2011-09-15
期刊：
影响因子：
11.2
通讯作者：
Fan X
中科院分区：
文献类型：
--
作者：
Zhu TS;Costello MA;Talsma CE;Flack CG;Crowley JG;Hamm LL;He X;Hervey-Jumper SL;Heth JA;Muraszko KM;DiMeco F;Vescovi AL;Fan X
胶质母细胞瘤（GBM）中内皮细胞的一个重要功能是创造一个小生境，帮助促进癌症干细胞样细胞（CSLC）的自我更新。然而，这种内皮功能的潜在分子机制尚不清楚。由于已经发现Notch信号传导的激活是GBM CSLC增殖所需的，我们假设GBM内皮可能提供Notch配体的来源。在这里，我们报告证实了这一概念的证据，Notch配体表达在内皮细胞相邻的巢蛋白和Notch受体阳性的癌细胞在原发性GBM。将人脑微血管内皮细胞（hBMEC）或Notch配体与GBM神经球共培养促进GBM细胞生长并增加CSLC自我更新。值得注意的是，RNAi介导的Notch配体在hBMEC中的敲低废除了它们在体外和体内诱导CSLC自我更新和GBM肿瘤生长的能力。因此，我们的研究结果证实，GBM CSLC中的Notch激活是由肿瘤微环境中肿瘤细胞及其周围内皮细胞之间的阿托他克林信号传导驱动的，这表明靶向CSLC及其小生境可能提供一种新的策略来耗尽CSLC并改善GBM治疗。
One important function of endothelial cells in glioblastoma (GBM) is to create a niche that helps promote self-renewal of cancer stem-like cells (CSLCs). However, the underlying molecular mechanism for this endothelial function is not known. Since activation of Notch signaling has been found to be required for propagation of GBM CSLCs, we hypothesized that the GBM endothelium may provide the source of Notch ligands. Here we report a corroboration of this concept with a demonstration that Notch ligands are expressed in endothelial cells adjacent to Nestin and Notch receptor-positive cancer cells in primary GBMs. Co-culturing human brain microvascular endothelial cells (hBMECs) or Notch ligand with GBM neurospheres promoted GBM cell growth and increased CSLC self-renewal. Notably, RNAi-mediated knockdown of Notch ligands in hBMECs abrogated their ability to induce CSLC self-renewal and GBM tumor growth, both in vitro and in vivo. Thus, our findings establish that Notch activation in GBM CSLCs is driven by juxtacrine signaling between tumor cells and their surrounding endothelial cells in the tumor microenvironment, suggesting that targeting both CSLCs and their niche may provide a novel strategy to deplete CSLCs and improve GBM treatment.