KUMC-Molecular Medicine Laboratory, Department of Medicine, The University of Kansas Medical Center, Kansas city, KS 66160, USA.
J Neurooncol. 2012 Jul;108(3):423-34. doi: 10.1007/s11060-012-0852-1. Epub 2012 Apr 8.
Cancer stem cells (CSCs) are believed to be the regenerative pool of cells responsible for repopulating tumors. Gaining knowledge about the signaling characteristics of CSCs is important for understanding the biology of tumors and developing novel anti-cancer therapies. We have identified a subpopulation of cells positive for CD133 (a CSC marker) from human primary malignant peripheral nerve sheath tumor (MPNST) cells which were absent in non-malignant Schwann cells. CD133 was also found to be expressed in human tissue samples and mouse MPNST cells. CD133+ cells were capable of forming spheres in non-adherent/serum-free conditions. The activation levels of Ras and its downstream effectors such as ERK, JNK, PI3K, p38K, and RalA were significantly increased in this population. Moreover, the CD133+ cells showed enhanced invasiveness which was linked to the increased expression of β-Catenin and Snail, two important proteins involved in the epithelial to mesenchymal transition, and Paxilin, a focal adhesion protein. Among other important characteristics of the CD133+ population, endoplasmic reticulum stress marker IRE1α was decreased, implying the potential sensitivity of CD133+ to the accumulation of unfolded proteins. Apoptotic indicators seemed to be unchanged in CD133+ cells when compared to the wild (unsorted) cells. Finally, in order to test the possibility of targeting CD133+ MPNST cells with Ras pathway pharmacological inhibitors, we exposed these cells to an ERK inhibitor. The wild population was more sensitive to inhibition of proliferation by this inhibitor as compared with the CD133+ cells supporting previous studies observing enhanced chemoresistance of these cells.
癌症干细胞（CSC）被认为是负责肿瘤再增殖的细胞再生池。了解 CSC 的信号特征对于理解肿瘤生物学和开发新的抗癌疗法非常重要。我们从人原发性恶性外周神经鞘瘤（MPNST）细胞中鉴定出了一小部分 CD133（CSC 标志物）阳性的细胞，而这些细胞在非恶性施万细胞中不存在。CD133 也在人类组织样本和小鼠 MPNST 细胞中表达。CD133+细胞能够在非贴附和无血清条件下形成球体。该群体中 Ras 及其下游效应物（如 ERK、JNK、PI3K、p38K 和 RalA）的激活水平显著增加。此外，CD133+细胞表现出增强的侵袭性，这与β-Catenin 和 Snail 的表达增加有关，β-Catenin 和 Snail 是参与上皮间质转化的两个重要蛋白，以及 Paxilin，一种焦点粘附蛋白。在 CD133+群体的其他重要特征中，内质网应激标志物 IRE1α 减少，这意味着 CD133+细胞对未折叠蛋白积累的潜在敏感性。与野生（未分选）细胞相比，CD133+细胞中的凋亡指标似乎没有变化。最后，为了测试用 Ras 通路药理学抑制剂靶向 CD133+MPNST 细胞的可能性，我们将这些细胞暴露于 ERK 抑制剂中。与 CD133+细胞相比，野生细胞对这种抑制剂抑制增殖的敏感性更高，这支持了先前观察到这些细胞增强化疗耐药性的研究。
