Departments of Neurosurgery and Experimental Pathology, New York Medical College, Valhalla, NY 10595, USA.
Anticancer Res. 2010 Dec;30(12):4915-20.
Glioblastoma multiforme (GBM), a grade IV glioma, appears to harbor therapy-resistant cancer stem cells (CSCs) that are the major cause of recurrence. All-trans retinoic acid (ATRA), a derivative of retinoid, is capable of differentiating a variety of stem cells, as well as normal neural progenitor cells, and down-regulates expression of the stem cell marker nestin. This study investigated the effects of ATRA on differentiation, proliferation, self-renewal, and signaling pathways of CSCs in GBM. CSCs differentiated into glial and neuronal lineages at low concentrations of ATRA (10 μM). Proliferation and self renewal of neurospheres were reduced following ATRA, although ATRA induced apopotsis at higher (40 μM) concentrations. Analysis of mitogen-activated protein kinase signaling pathways, specifically extracellular signal-regulated kinases (ERK1/2), showed that ATRA-induced alterations in ERK1/2 were associated with regulation of differentiation, proliferation and apoptosis. These results emphasize that low doses of ATRA may have therapeutic potential by differentiating GBM CSCs and rendering them sensitive to targeted therapy.
多形性胶质母细胞瘤（GBM）是一种 4 级神经胶质瘤，似乎存在对治疗有抗性的肿瘤干细胞（CSC），这些 CSC 是肿瘤复发的主要原因。全反式视黄酸（ATRA）是维 A 酸的衍生物，能够诱导多种干细胞，包括正常神经祖细胞的分化，并下调干细胞标志物巢蛋白的表达。本研究探讨了 ATRA 对 GBM 中 CSC 的分化、增殖、自我更新和信号通路的影响。在低浓度 ATRA（10 μM）的作用下，CSC 分化为神经胶质和神经元谱系。ATRA 降低了神经球的增殖和自我更新能力，尽管在更高浓度（40 μM）时 ATRA 诱导了细胞凋亡。对丝裂原活化蛋白激酶信号通路的分析，特别是细胞外信号调节激酶（ERK1/2），表明 ATRA 诱导的 ERK1/2 改变与分化、增殖和凋亡的调节有关。这些结果强调了低剂量 ATRA 通过诱导 GBM CSC 分化并使其对靶向治疗敏感，可能具有治疗潜力。
