Department of Pathology, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230036, Anhui, China;Intelligent Pathology Institute, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230036, Anhui, China.
Biomed Environ Sci. 2024 Aug 20;37(8):834-849. doi: 10.3967/bes2024.127.
Vasculogenic mimicry (VM) is a novel vasculogenic process integral to glioma stem cells (GSCs) in glioblastoma (GBM). However, the relationship between VM and ataxia-telangiectasia mutated (ATM) serine/threonine kinase activation, which confers chemoradiotherapy resistance, remains unclear.
We investigated VM formation and phosphorylated ATM (pATM) levels by CD31/GFAP-periodic acid-Schiff dual staining and immunohistochemical staining in 145 GBM specimens. Glioma stem-like cells (GSLCs) derived from the formatted spheres of U87 and U251 cell lines and their pATM level and VM formation ability were examined using western blot and three-dimensional culture. For the examination of the function of pATM in VM formation by GSLCs, ATM knockdown by shRNAs and deactivated ATM phosphorylation inhibitor KU55933 were studied.
VM and high pATM expression occurred in 38.5% and 41.8% of tumors, respectively, and were significantly associated with reduced progression-free and overall survival. Patients with VM-positive GBMs exhibited higher pATM levels ( = 0.425, = 0.01). The multivariate analysis established VM as an independent negative prognostic factor ( = 0.002). Furthermore, GSLCs expressed high levels of pATM and formed vascular-like networks . ATM inactivation or knockdown hindered VM-like network formation concomitant with the downregulation of pVEGFR-2, VE-cadherin, and laminin B2.
VM may predict a poor GBM prognosis and is associated with pATM expression. We propose that pATM promotes VM through extracellular matrix modulation and VE-Cadherin / pVEGFR-2 activation, thereby highlighting ATM activation as a potential target for enhancing anti-angiogenesis therapies for GBM.
血管生成拟态（VM）是胶质母细胞瘤（GBM）中神经胶质瘤干细胞（GSCs）的一种新的血管生成过程。然而，VM 与共济失调毛细血管扩张突变（ATM）丝氨酸/苏氨酸激酶激活之间的关系，该激酶赋予化学放射治疗耐药性，仍然不清楚。
我们通过 CD31/GFAP-过碘酸-Schiff 双重染色和免疫组织化学染色研究了 145 例 GBM 标本中的 VM 形成和磷酸化 ATM（pATM）水平。使用 Western blot 和三维培养研究了从 U87 和 U251 细胞系格式化球体中衍生的神经胶质瘤样干细胞（GSLCs）及其 pATM 水平和 VM 形成能力。为了研究 pATM 在 GSLCs 中 VM 形成中的功能，我们使用 shRNA 敲低 ATM 和失活的 ATM 磷酸化抑制剂 KU55933。
VM 和高 pATM 表达分别发生在 38.5%和 41.8%的肿瘤中，与无进展生存期和总生存期缩短显著相关。VM 阳性 GBM 患者表现出更高的 pATM 水平（ = 0.425， = 0.01）。多变量分析确立 VM 为独立的负预后因素（ = 0.002）。此外，GSLCs 表达高水平的 pATM 并形成血管样网络。ATM 失活或敲低阻碍了 VM 样网络的形成，同时下调了 pVEGFR-2、VE-钙粘蛋白和层粘连蛋白 B2。
VM 可能预测 GBM 预后不良，与 pATM 表达相关。我们提出 pATM 通过细胞外基质调节和 VE-Cadherin/pVEGFR-2 激活促进 VM，从而强调 ATM 激活作为增强 GBM 抗血管生成治疗的潜在靶点。
