Department of Neurosurgery, University Hospital of Zurich, University of Zurich, CH‑8091 Zurich, Switzerland.
Neurosurgical Institute, The Seventh Medical Center of PLA Army General Hospital, Beijing 100700, P.R. China.
Oncol Rep. 2020 May;43(5):1479-1490. doi: 10.3892/or.2020.7525. Epub 2020 Feb 28.
Glioblastoma (GBM) is the most prevalent and lethal primary intrinsic brain cancer. The disease is essentially incurable, with glioblastomas characterized by resistance to both chemotherapy and radiotherapy, as well as by rapid tumor progression, all of which are mainly ascribed to glioma stem‑like cells (GSLCs). In the present study, an improved model that is more similar to clinical GBM was constructed. Twenty clinical glioma samples were collected to obtain primary low‑grade tumor cells. The cells were either maintained in serum‑free medium as primary glioma‑based cells (PGBCs) or cultured in the same medium with CHIR99021 as GSLCs. Then, the molecular and ultrastructural differences between the two cell groups were determined. Furthermore, the proliferation and migration of the GSLCs were examined and the potential mechanisms were investigated. Finally, temozolomide resistance in vitro and in the mouse model was assessed to study the properties of the induced GSLCs. The primary low‑grade tumor cells extracted from surgical samples were enriched with GSLC properties, with high expression levels of CD133 and Nestin in 100 nM CHIR99021. The GSLCs exhibited high proliferation and migration. Furthermore, the expression of the PI3K/AKT signaling pathway and that of related genes and proteins were significantly enhanced by CHIR99021. The animal study also revealed high levels of STAT3, mTOR, NF‑κB, and VEGF in the GSLC‑transplanted mice. CHIR99021 could stably enhance GSLC properties in patient‑derived glioma samples. It may provide a useful model for further study, helping to understand the pathogenesis of therapeutic resistance and to screen drug candidates.
胶质母细胞瘤（GBM）是最常见和最致命的原发性内在脑癌。这种疾病基本上是无法治愈的，胶质母细胞瘤的特征是对化疗和放疗均有抗性，以及肿瘤快速进展，所有这些主要归因于神经胶质瘤干细胞（GSLCs）。在本研究中，构建了一种更类似于临床 GBM 的改良模型。收集了 20 例临床胶质瘤样本以获得原发性低级别肿瘤细胞。将这些细胞维持在无血清培养基中作为原发性基于神经胶质瘤的细胞（PGBCs），或者在含有 CHIR99021 的相同培养基中培养作为 GSLCs。然后，确定了这两个细胞群之间的分子和超微结构差异。此外，还检查了 GSLC 的增殖和迁移，并研究了潜在的机制。最后，评估了体外和小鼠模型中的替莫唑胺耐药性，以研究诱导的 GSLC 的特性。从手术样本中提取的原发性低级别肿瘤细胞具有 GSLC 特性，在 100 nM CHIR99021 中高表达 CD133 和 Nestin。GSLCs 表现出高增殖和迁移能力。此外，CHIR99021 显著增强了 PI3K/AKT 信号通路以及相关基因和蛋白的表达。动物研究还表明，在 GSLC 移植小鼠中 STAT3、mTOR、NF-κB 和 VEGF 水平较高。CHIR99021 可以稳定增强患者来源的神经胶质瘤样本中的 GSLC 特性。它可能为进一步的研究提供有用的模型，有助于了解治疗耐药性的发病机制并筛选药物候选物。
