PO.TB10.02 · 肿瘤生物学
胶质母细胞瘤中的β淀粉样蛋白积累由血管重塑和APP加工通路驱动
Amyloid-beta accumulation in glioblastoma is driven by vascular remodeling and APP-processing pathways
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：胶质母细胞瘤（GBM）是一种预后不良的侵袭性脑肿瘤。鉴定用于靶向治疗的生物标志物仍是GBM治疗中的一大挑战。近期，我们证明经典上与神经退行性疾病相关的肽段β淀粉样蛋白（Abeta）会在GBM肿瘤中积累。本研究旨在探究GBM组织中Abeta积累的潜在机制。
方法：进行免疫组化分析和共聚焦成像以评估Abeta在人GBM组织切片中的定位。分别使用胶质纤维酸性蛋白（GFAP）、离子钙结合衔接分子1（Iba1）和CD31作为星形胶质细胞、小胶质细胞和血管的标志物。进行蛋白质印迹分析以评估Abeta和淀粉样前体蛋白（APP）的表达，以及参与Abeta生成的基质金属蛋白酶2和9（MMP-2和MMP-9）、早老素-1、nicastrin蛋白和血管内皮生长因子（VEGF）的表达。进行Pearson相关分析以评估Abeta、VEGF、MMP-2/9、早老素-1和nicastrin之间的关系。
结果：共聚焦成像显示Abeta在血管和高度血管化的肿瘤区域中大量积累，同时在小胶质细胞中强烈积累，在胶质瘤细胞中积累程度较轻。蛋白质印迹分析显示Abeta水平与VEGF、MMP-2和早老素-1等因子之间存在强相关性，表明存在驱动Abeta积累的复杂调控相互作用。
结论：这些发现表明GBM中的Abeta积累与肿瘤血管化和小胶质细胞参与密切相关。与VEGF、MMP-2和早老素-1的强相关性提示血管重塑和蛋白水解加工均促进了Abeta的堆积。本研究由以下资助支持：NIH基金1R15CA287203和1R16GM153522。
查看英文原文 English abstract
Background: Glioblastoma (GBM) is an aggressive brain tumor with a poor prognosis.Identifying biomarkers for targeted therapies remains a major challenge in GBM treatment.Recently, we demonstrated that amyloid-beta (Abeta), a peptide classically associated with neurodegenerative diseases, accumulates in GBM tumors. This study aims to investigate the mechanism underlying Abeta accumulation in GBM tissues.
Methods: Immunohistochemical analysis and confocal imaging were performed to assessAbeta localization in human GBM tissue sections. Glial fibrillary acidic protein (GFAP), ionizedcalcium-binding adaptor molecule 1 (Iba1), and CD31 were used as markers of astrocytes, microglia, and blood vessels, respectively. Western blot analysis was performed toevaluate the expression of Abeta and amyloid precursor protein (APP), along with matrixmetalloproteinases 2 and 9 (MMP-2 and MMP-9), presenilin-1, nicastrin proteins involved inAbeta production and vascular endothelial growth factor (VEGF). Pearson correlation analysis was conducted to assess relationships among Abeta, VEGF, MMP-2/9, presenilin-1, and nicastrin.
Results: Confocal imaging revealed robust Abeta accumulation in blood vessels and in tumor regions with high vascularization, as well as strong Abeta accumulation in microglia and, to alesser extent, in glioma cells. Western blot analysis showed strong correlations betweenAbeta levels and factors such as VEGF, MMP-2, and presenilin-1, indicating complex regulatory interactions driving Abeta accumulation.
Conclusion : These findings demonstrate that Abeta accumulation in GBM is closely linked to tumor vascularization and microglial involvement. The strong correlations with VEGF, MMP-2, and presenilin-1 suggest that both vascular remodeling and proteolytic processing contribute to Abeta buildup.This study was supported by: NIH Grants 1R15CA287203 and 1R16GM153522
利益披露 Disclosure
F. Y. Narvaez Irizarry, None..
A. M. Bermudez Adorno, None..
L. Kucheryavykh, None.