Department of Neurosurgery, University Hospital Wuerzburg, 97080 Wuerzburg, Germany.
Paul Flechsig Institute for Brain Research, University of Leipzig, 04103 Leipzig, Germany.
Int J Mol Sci. 2022 Mar 28;23(7):3726. doi: 10.3390/ijms23073726.
Targeting molecular alterations as an effective treatment for isocitrate dehydrogenase-wildtype glioblastoma (GBM) patients has not yet been established. Sterol-O-Acyl Transferase 1 (SOAT1), a key enzyme in the conversion of endoplasmic reticulum cholesterol to esters for storage in lipid droplets (LD), serves as a target for the orphan drug mitotane to treat adrenocortical carcinoma. Inhibition of SOAT1 also suppresses GBM growth. Here, we refined SOAT1-expression in GBM and -mutant astrocytoma, CNS WHO grade 4 (HGA), and assessed the distribution of LD in these tumors. Twenty-seven GBM and three HGA specimens were evaluated by multiple GFAP, Iba1, IDH1 R132H, and SOAT1 immunofluorescence labeling as well as Oil Red O staining. To a small extent SOAT1 was expressed by tumor cells in both tumor entities. In contrast, strong expression was observed in glioma-associated macrophages. Triple immunofluorescence labeling revealed, for the first time, evidence for SOAT1 colocalization with Iba1 and IDH1 R132H, respectively. Furthermore, a notable difference in the amount of LD between GBM and HGA was observed. Therefore, SOAT1 suppression might be a therapeutic option to target GBM and HGA growth and invasiveness. In addition, the high expression in cells related to neuroinflammation could be beneficial for a concomitant suppression of protumoral microglia/macrophages.
针对异柠檬酸脱氢酶野生型胶质母细胞瘤（GBM）患者的分子改变作为有效治疗方法尚未确立。甾醇-O-酰基转移酶 1（SOAT1）是内质网胆固醇转化为酯类以储存在脂滴（LD）中的关键酶，是治疗肾上腺皮质癌的孤儿药米托坦的靶标。SOAT1 的抑制也抑制了 GBM 的生长。在这里，我们在 GBM 和 -突变星形细胞瘤、中枢神经系统世界卫生组织 4 级（HGA）中精细地表达了 SOAT1，并评估了这些肿瘤中 LD 的分布。通过对 27 个 GBM 和 3 个 HGA 标本进行多次 GFAP、Iba1、IDH1 R132H 和 SOAT1 免疫荧光标记以及油红 O 染色进行评估。在这两种肿瘤实体中，SOAT1 在肿瘤细胞中均有少量表达。相比之下，在神经胶质瘤相关的巨噬细胞中观察到强烈的表达。三重免疫荧光标记首次显示了 SOAT1 与 Iba1 和 IDH1 R132H 分别共定位的证据。此外，还观察到 GBM 和 HGA 之间 LD 数量的显著差异。因此，抑制 SOAT1 可能是一种针对 GBM 和 HGA 生长和侵袭性的治疗选择。此外，与神经炎症相关的细胞中高表达可能有益于同时抑制促肿瘤性小胶质细胞/巨噬细胞。
