Enhanced SPARCL1 expression in cancer stem cells improves preclinical modeling of glioblastoma by promoting both tumor infiltration and angiogenesis.

Autor: Gagliardi F; Neural Stem Cell Biology Unit, Division of Neuroscience, San Raffaele Scientific Institute, Via Olgettina 58, Milan 20132, Italy; Department Neurosurgery and Gamma Knife Radiosurgery, San Raffaele Scientific Institute, Via Olgettina 60, Milan 20132, Italy., Narayanan A; Neural Stem Cell Biology Unit, Division of Neuroscience, San Raffaele Scientific Institute, Via Olgettina 58, Milan 20132, Italy., Gallotti AL; Neural Stem Cell Biology Unit, Division of Neuroscience, San Raffaele Scientific Institute, Via Olgettina 58, Milan 20132, Italy; Department Neurosurgery and Gamma Knife Radiosurgery, San Raffaele Scientific Institute, Via Olgettina 60, Milan 20132, Italy., Pieri V; Neural Stem Cell Biology Unit, Division of Neuroscience, San Raffaele Scientific Institute, Via Olgettina 58, Milan 20132, Italy; Neuroradiology Unit and CERMAC, Vita-Salute San Raffaele University and San Raffaele Scientific Institute, Milan 20132, Italy., Mazzoleni S; Neural Stem Cell Biology Unit, Division of Neuroscience, San Raffaele Scientific Institute, Via Olgettina 58, Milan 20132, Italy., Cominelli M; Department Molecular and Translational Medicine, Pathology Unit, University of Brescia, Brescia 25124, Italy., Rezzola S; Department Molecular and Translational Medicine, Experimental Oncology and Immunology, University of Brescia, Brescia 25124, Italy., Corsini M; Department Molecular and Translational Medicine, Experimental Oncology and Immunology, University of Brescia, Brescia 25124, Italy., Brugnara G; Neuroradiology Unit and CERMAC, Vita-Salute San Raffaele University and San Raffaele Scientific Institute, Milan 20132, Italy., Altabella L; Neuroradiology Unit and CERMAC, Vita-Salute San Raffaele University and San Raffaele Scientific Institute, Milan 20132, Italy., Politi LS; Neuroradiology Unit and CERMAC, Vita-Salute San Raffaele University and San Raffaele Scientific Institute, Milan 20132, Italy., Bacigaluppi M; Neuroimmunology Unit, Institute of Experimental Neurology (INSPE), Division of Neuroscience, San Raffaele Scientific Institute, Via Olgettina 58, Milan 20132, Italy., Falini A; Neuroradiology Unit and CERMAC, Vita-Salute San Raffaele University and San Raffaele Scientific Institute, Milan 20132, Italy., Castellano A; Neuroradiology Unit and CERMAC, Vita-Salute San Raffaele University and San Raffaele Scientific Institute, Milan 20132, Italy., Ronca R; Department Molecular and Translational Medicine, Experimental Oncology and Immunology, University of Brescia, Brescia 25124, Italy., Poliani PL; Department Molecular and Translational Medicine, Pathology Unit, University of Brescia, Brescia 25124, Italy., Mortini P; Department Neurosurgery and Gamma Knife Radiosurgery, San Raffaele Scientific Institute, Via Olgettina 60, Milan 20132, Italy., Galli R; Neural Stem Cell Biology Unit, Division of Neuroscience, San Raffaele Scientific Institute, Via Olgettina 58, Milan 20132, Italy. Electronic address: galli.rossella@hsr.it.
Jazyk: angličtina
Zdroj: Neurobiology of disease [Neurobiol Dis] 2020 Feb; Vol. 134, pp. 104705. Date of Electronic Publication: 2019 Dec 10.
DOI: 10.1016/j.nbd.2019.104705
Abstrakt: 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.
(Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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