Biological Role and Therapeutic Targeting of TGF-ß3 in Glioblastoma.

ABSTRACT

Transforming growth factor (TGF)-ß contributes to the malignant phenotype of glioblastoma by promoting invasiveness and angiogenesis and creating an immunosuppressive microenvironment. So far, TGF-ß1 and TGF-ß2 isoforms have been considered to act in a similar fashion without isoform-specific function in glioblastoma. A pathogenic role for TGF-ß3 in glioblastoma has not been defined yet. Here, we studied the expression and functional role of endogenous and exogenous TGF-ß3 in glioblastoma models. TGF-ß3 mRNA is expressed in human and murine long-term glioma cell lines as well as in human glioma-initiating cell cultures with expression levels lower than TGF-ß1 or TGF-ß2 in most cell lines. Inhibition of TGF-ß3 mRNA 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 affecting TGF-ß1 or TGF-ß2 mRNA expression or protein levels. Moreover, inhibition of TGF-ß3 expression reduces invasiveness in vitro Interestingly, depletion of TGF-ß3 also attenuates signaling evoked by TGF-ß1 or TGF-ß2 In orthotopic syngeneic (SMA-560) and xenograft (LN-308) in vivo glioma models, expression of TGF-ß3 as well as of the downstream target, plasminogen-activator-inhibitor (PAI)-1, was reduced, while TGF-ß1 and TGF-ß2 levels were unaffected following systemic treatment with TGF-ß3 -specific antisense oligonucleotides. We conclude that TGF-ß3 might function as a gatekeeper controlling downstream signaling despite high expression of TGF-ß1 and TGF-ß2 isoforms. Targeting TGF-ß3in vivo may represent a promising strategy interfering with aberrant TGF-ß signaling in glioblastoma. Mol Cancer Ther; 16(6); 1177-86. ©2017 AACR.