title: Biological Role and Therapeutic Targeting of TGF-β3in Glioblastoma.
abstract: Transforming growth factor (TGF)-β contributes to the malignant phenotype of glioblastoma by promoting invasiveness and angiogenesis and creating an immunosuppressive microenvironment. So far, TGF-β1and TGF-β2isoforms have been considered to act in a similar fashion without isoform-specific function in glioblastoma. A pathogenic role for TGF-β3in glioblastoma has not been defined yet. Here, we studied the expression and functional role of endogenous and exogenous TGF-β3in glioblastoma models.TGF-β3mRNA is expressed in human and murine long-term glioma cell lines as well as in human glioma-initiating cell cultures with expression levels lower thanTGF-β1orTGF-β2in most cell lines. Inhibition ofTGF-β3mRNA expression by ISTH2020 or ISTH2023, two different isoform-specific phosphorothioate locked nucleic acid (LNA)-modified antisense oligonucleotide gapmers, blocks downstream SMAD2 and SMAD1/5 phosphorylation in human LN-308 cells, without affectingTGF-β1orTGF-β2mRNA expression or protein levels. Moreover, inhibition ofTGF-β3expression reduces invasivenessin vitroInterestingly, depletion ofTGF-β3also attenuates signaling evoked by TGF-β1or TGF-β2In orthotopic syngeneic (SMA-560) and xenograft (LN-308)in vivoglioma models, expression ofTGF-β3as well as of the downstream target,plasminogen-activator-inhibitor (PAI)-1, was reduced, whileTGF-β1andTGF-β2levels were unaffected following systemic treatment withTGF-β3-specific antisense oligonucleotides. We conclude that TGF-β3might function as a gatekeeper controlling downstream signaling despite high expression of TGF-β1and TGF-β2isoforms. Targeting TGF-β3in vivomay represent a promising strategy interfering with aberrant TGF-β signaling in glioblastoma.Mol Cancer Ther; 16(6); 1177-86. ©2017 AACR.
authors.affiliation: Laboratory of Molecular Neuro-Oncology, Department of Neurology, University Hospital and University of Zurich, Switzerland. katharina.seystahl@usz.ch.
authors.forename: Katharina
authors.initials: K
authors.lastname: Seystahl
authors.affiliation: Laboratory of Molecular Neuro-Oncology, Department of Neurology, University Hospital and University of Zurich, Switzerland.
authors.forename: Alexandros
authors.initials: A
authors.lastname: Papachristodoulou
authors.affiliation: Laboratory of Molecular Neuro-Oncology, Department of Neurology, University Hospital and University of Zurich, Switzerland.
authors.forename: Isabel
authors.initials: I
authors.lastname: Burghardt
authors.affiliation: Laboratory of Molecular Neuro-Oncology, Department of Neurology, University Hospital and University of Zurich, Switzerland.
authors.forename: Hannah
authors.initials: H
authors.lastname: Schneider
authors.affiliation: Laboratory of Molecular Neuro-Oncology, Department of Neurology, University Hospital and University of Zurich, Switzerland.|Isarna Therapeutics GmbH, Munich, Germany.
authors.forename: Kathy
authors.initials: K
authors.lastname: Hasenbach
authors.affiliation: Isarna Therapeutics GmbH, Munich, Germany.
authors.forename: Michel
authors.initials: M
authors.lastname: Janicot
authors.affiliation: Laboratory of Molecular Neuro-Oncology, Department of Neurology, University Hospital and University of Zurich, Switzerland.
authors.forename: Patrick
authors.initials: P
authors.lastname: Roth
authors.affiliation: Laboratory of Molecular Neuro-Oncology, Department of Neurology, University Hospital and University of Zurich, Switzerland.
authors.forename: Michael
authors.initials: M
authors.lastname: Weller
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D015870:Gene Expression; D020868:Gene Silencing; D005909:Glioblastoma / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality; D064593:Heterografts; D006801:Humans; D051379:Mice; D016376:Oligonucleotides, Antisense / Q000235:genetics; D010766:Phosphorylation; D011379:Prognosis; D020033:Protein Isoforms; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051899:Smad2 Protein / Q000235:genetics / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism; D053781:Transforming Growth Factor beta2 / Q000235:genetics / Q000378:metabolism; D053782:Transforming Growth Factor beta3 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*
chemical_list: D016376:Oligonucleotides, Antisense; D020033:Protein Isoforms; D012333:RNA, Messenger; C497782:SMAD2 protein, human; D051899:Smad2 Protein; D053773:Transforming Growth Factor beta1; D053781:Transforming Growth Factor beta2; D053782:Transforming Growth Factor beta3