Biological Role and Therapeutic Targeting of TGF-{beta}3 in Glioblastoma

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-β₁ and TGF-β₂ isoforms have been considered to act in a similar fashion without isoform-specific function in glioblastoma. A pathogenic role for TGF-β₃ in glioblastoma has not been defined yet. Here, we studied the expression and functional role of endogenous and exogenous TGF-β₃ in glioblastoma models. TGF-β₃ 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-β₁ or TGF-β₂ in most cell lines. Inhibition of TGF-β₃ 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-β₁ or TGF-β₂ mRNA expression or protein levels. Moreover, inhibition of TGF-β₃ expression reduces invasiveness in vitro. Interestingly, depletion of TGF-β₃ also attenuates signaling evoked by TGF-β₁ or TGF-β₂. In orthotopic syngeneic (SMA-560) and xenograft (LN-308) in vivo glioma models, expression of TGF-β₃ as well as of the downstream target, plasminogen-activator-inhibitor (PAI)-1, was reduced, while TGF-β₁ and TGF-β₂ levels were unaffected following systemic treatment with TGF-β₃-specific antisense oligonucleotides. We conclude that TGF-β₃ might function as a gatekeeper controlling downstream signaling despite high expression of TGF-β₁ and TGF-β₂ isoforms. Targeting TGF-β₃in vivo may represent a promising strategy interfering with aberrant TGF-β signaling in glioblastoma. Mol Cancer Ther; 16(6); 1177–86. ©2017 AACR.

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