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

Differential Expression and Clinical Significance of Transforming Growth Factor-Beta Isoforms in GBM Tumors

“…Although we did not assess the possibility for TGF-β 3 to be used as a prognostic biomaker or target, analysis of the TCGA data by Seystahl and collaborators revealed that low expression of this isoform was associated with a better prognosis in GBM of the neural subtype whereas it bore no significant effect in proneural, mesenchymal, or classical GBM subtypes. Moreover, their study corroborated that oligonucleotide-based specific inhibition of TGF-β 3 significantly reduced invasiveness in vitro as well as in vivo [ 33 ].…”

Upregulation of allograft inflammatory factor‑1 expression and secretion by macrophages stimulated with aldosterone promotes renal fibroblasts to a profibrotic phenotype

“…Aberrant TGF-β signaling is considered as a hallmark of certain diseases. Three isoforms of TGF-β exist, including TGF-β1, TGF-β2 and TGF-β3, and targeting TGF-β3 represents a promising strategy interfering with aberrant TGF-β signaling in glioblastoma ( 58 ). TGF-β has also been implicated as an important mediator of renal fibrosis ( 59 ), and thus, the concentration of TGF-β was detected in the current study.…”

Intratumoral Heterogeneity and Longitudinal Changes in Gene Expression Predict Differential Drug Sensitivity in Newly Diagnosed and Recurrent Glioblastoma

“…For example, isogenic GSCs "IT726R2" and "IT726R3"originating from different regions of ndGB #726 showed significant differences (p = 5.08 × 10 −12 ) in the number of cells required for generating clonal self-renewing spheres ( Figure 5A). Furthermore, there were also profound differences in the steady-state levels of several proteins implicated as therapeutic targets in GB such as glioma promoting factor TGFβ [41,42], TMZ-resistance factor MGMT [43], stemness marker CD133/Prominin-1 [44] or the marker of Proneural subtype PDFGRα [45] ( Figure 5). These results provide evidence that GSCs recapitulate interregional divergence at the cellular and molecular level.…”