Glioblastoma (GBM) is the most malignant brain tumor of adults and is characterized by extensive cell dissemination within the brain parenchyma and enhanced angiogenesis. Effective preclinical modeling of these key features suffers from several shortcomings. Aim of this study was to determine whether modulating the expression of extracellular matrix (ECM) modifiers in proneural (PN) and mesenchymal (MES) cancer stem cells (CSCs) and in conventional glioma cell lines (GCLs) might improve tumor invasion and vascularization. To this end, we selected secreted, acidic and rich in cysteine-like 1 (SPARCL1) as a potential mediator of ECM remodeling in GBM. SPARCL1 transcript and protein expression was assessed in PN and MES CSCs as well as GCLs, in their xenografts and in patient-derived specimens by qPCR, WB and IHC. SPARCL1 expression was then enforced in both CSCs and GCLs by lentiviral-based transduction. The effect of SPARCL1 gain-of-function on microvascular proliferation, microglia activation and advanced imaging features was tested in intracranial xenografts by IHC and MRI and validated by chorioallantoic membrane (CAM) assays. SPARCL1 expression significantly enhanced the infiltrative and neoangiogenic features of PN and MES CSC/GCL-induced tumors, with the concomitant activation of inflammatory responses associated with the tumor microenvironment, thus resulting in experimental GBMs that reproduced both the parenchymal infiltration and the increased microvascular density, typical of GBM. Overall, these results indicate that SPARCL1 overexpression might be instrumental for the generation of CSC-derived preclinical models of GBM in which the main pathognomonic hallmarks of GBMs are retrievable, making them suitable for effective preclinical testing of therapeutics.

中文翻译：

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通过促进肿瘤浸润和血管生成，癌症干细胞中增强的SPARCL1表达改善了胶质母细胞瘤的临床前模型。

胶质母细胞瘤（GBM）是成人最恶性的脑肿瘤，其特征是在脑实质内广泛的细胞扩散和增强的血管生成。这些关键特征的有效临床前建模存在几个缺点。这项研究的目的是确定调节细胞外基质（PN）和间充质（MES）癌症干细胞（CSC）和常规神经胶质瘤细胞系（GCL）中细胞外基质（ECM）修饰子的表达是否可以改善肿瘤的侵袭和血管形成。为此，我们选择了分泌的，酸性且富含半胱氨酸样1（SPARCL1）作为GBM中ECM重塑的潜在介质。通过qPCR，WB和IHC对PN和MES CSC以及GCL，异种移植物和患者标本中的SPARCL1转录和蛋白表达进行了评估。然后，通过基于慢病毒的转导，在CSC和GCL中都增强了SPARCL1的表达。通过IHC和MRI在颅内异种移植物中测试了SPARCL1功能获得对微血管增殖，小胶质细胞活化和高级成像功能的影响，并通过绒膜尿囊膜（CAM）分析进行了验证。SPARCL1的表达显着增强了PN和MES CSC / GCL诱导的肿瘤的浸润和新血管生成特征，并伴随了与肿瘤微环境相关的炎症反应的激活，从而导致实验性GBM既重现了实质浸润，又增加了微血管密度， GBM的典型。全面的，