Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, Milan, Italy.
Department of Neurosurgery, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.
Clin Cancer Res. 2019 Jan 1;25(1):266-276. doi: 10.1158/1078-0432.CCR-18-1941. Epub 2018 Oct 4.
Glioblastoma (GBM) is the most common primary brain tumor. The identification of blood biomarkers reflecting the tumor status represents a major unmet need for optimal clinical management of patients with GBM. Their high number in body fluids, their stability, and the presence of many tumor-associated proteins and RNAs make extracellular vesicles potentially optimal biomarkers. Here, we investigated the potential role of plasma extracellular vesicles from patients with GBM for diagnosis and follow-up after treatment and as a prognostic tool.
Plasma from healthy controls ( = 33), patients with GBM ( = 43), and patients with different central nervous system malignancies ( = 25) were collected. Extracellular vesicles were isolated by ultracentrifugation and characterized in terms of morphology by transmission electron microscopy, concentration, and size by nanoparticle tracking analysis, and protein composition by mass spectrometry. An orthotopic mouse model of human GBM confirmed human plasma extracellular vesicle quantifications. Associations between plasma extracellular vesicle concentration and clinicopathologic features of patients with GBM were analyzed. All statistical tests were two-sided.
GBM releases heterogeneous extracellular vesicles detectable in plasma. Plasma extracellular vesicle concentration was higher in GBM compared with healthy controls ( < 0.001), brain metastases ( < 0.001), and extra-axial brain tumors ( < 0.001). After surgery, a significant drop in plasma extracellular vesicle concentration was measured ( < 0.001). Plasma extracellular vesicle concentration was also increased in GBM-bearing mice ( < 0.001). Proteomic profiling revealed a GBM-distinctive signature.
Higher extracellular vesicle plasma levels may assist in GBM clinical diagnosis: their reduction after GBM resection, their rise at recurrence, and their protein cargo might provide indications about tumor, therapy response, and monitoring.
胶质母细胞瘤（GBM）是最常见的原发性脑肿瘤。鉴定反映肿瘤状态的血液生物标志物代表了对 GBM 患者进行最佳临床管理的主要未满足需求。它们在体液中的数量多、稳定性高，并且存在许多与肿瘤相关的蛋白质和 RNA，使细胞外囊泡成为潜在的最佳生物标志物。在这里，我们研究了 GBM 患者血浆细胞外囊泡在诊断、治疗后随访以及作为预后工具的潜在作用。
收集了健康对照者（=33 人）、GBM 患者（=43 人）和不同中枢神经系统恶性肿瘤患者（=25 人）的血浆。通过超速离心分离细胞外囊泡，并通过透射电子显微镜观察其形态、纳米颗粒跟踪分析测量其浓度和大小、质谱法测量其蛋白质组成进行表征。建立了人 GBM 的原位小鼠模型，以确认人血浆细胞外囊泡的定量。分析了 GBM 患者血浆细胞外囊泡浓度与临床病理特征之间的关系。所有统计检验均为双侧检验。
GBM 释放可在血浆中检测到的异质细胞外囊泡。与健康对照组（<0.001）、脑转移瘤（<0.001）和脑外轴肿瘤（<0.001）相比，GBM 患者的血浆细胞外囊泡浓度更高。手术后，测量到血浆细胞外囊泡浓度显著下降（<0.001）。荷瘤小鼠的血浆细胞外囊泡浓度也升高（<0.001）。蛋白质组学分析显示了 GBM 独特的特征。
较高的细胞外囊泡血浆水平可能有助于 GBM 的临床诊断：GBM 切除后其水平降低、复发时升高以及其蛋白 cargo 可能提供关于肿瘤、治疗反应和监测的信息。
