Abstract
PurposeMembers of the transforming growth factor (TGF)-β superfamily play a key role in the regulation of the malignant phenotype of glioblastoma by promoting invasiveness, angiogenesis, immunosuppression, and maintaining stem cell-like properties. Betaglycan, a TGF-β coreceptor also known as TGF-β receptor III (TβRIII), interacts with members of the TGF-β superfamily and acts as membrane-associated or shed molecule. Shed, soluble TβRIII (sTβRIII) is produced upon ectodomain cleavage of the membrane-bound form. Elucidating the role of TβRIII may improve our understanding of TGF-β pathway activity in glioblastomaMethodsProtein levels of TβRIII were determined by immunohistochemical analyses and ex vivo single-cell gene expression profiling of glioblastoma tissue respectively. In vitro, TβRIII levels were assessed investigating long-term glioma cell lines (LTCs), cultured human brain-derived microvascular endothelial cells (hCMECs), glioblastoma-derived microvascular endothelial cells, and glioma-initiating cell lines (GICs). The impact of TβRIII on TGF-β signaling was investigated, and results were validated in a xenograft mouse glioma modelResultsImmunohistochemistry and ex vivo single-cell gene expression profiling of glioblastoma tissue showed that TβRIII was expressed in the tumor tissue, predominantly in the vascular compartment. We confirmed this pattern of TβRIII expression in vitro. Specifically, we detected sTβRIII in glioblastoma-derived microvascular endothelial cells. STβRIII facilitated TGF-β-induced Smad2 phosphorylation in vitro and overexpression of sTβRIII in a xenograft mouse glioma model led to increased levels of Smad2 phosphorylation, increased tumor volume, and decreased survivalConclusionsThese data shed light on the potential tumor-promoting role of extracellular shed TβRIII which may be released by glioblastoma endothelium with high sTβRIII levels.
Highlights
Glioblastoma is one of the most common malignant intrinsic brain tumors [1]
Given the putative central role of transforming growth factor (TGF)-β superfamily signaling in glioblastoma, the present study focused on the role of TGF-β receptor III (TβRIII) in the regulation of TGF-β pathway activity in this disease
Expression ratios relative to the respective control are depicted. f TβRIII protein levels in whole cell lysates of LN-229 cells were detected by immunoblot following the treatments described in e. g and h Shed TβRIII levels in LN-229 glioma cell supernatants following the treatments as described in e were determined by Enzyme‐linked immunosorbent assay (ELISA) (g) and by immunoblot (h), ponceau S staining is shown as loading control in h of soluble TβRIII (sTβRIII) reduced pSmad1/5 levels in LN-229 cells stimulated with bone morphogenetic proteins (BMP)-4 (Fig. 4c, left panel, lanes 3 versus 6), whereas baseline and TGF-β2-or BMP-4-evoked pSmad1/5 levels were increased in ZH-161 cells overexpressing sTβRIII (Fig. 4c, right panel, lanes 3 versus 6)
Summary
Glioblastoma is one of the most common malignant intrinsic brain tumors [1]. Prominent biological features of glioblastoma include excessive migratory, invasive and angiogenic potential, and suppression of anti-tumor immune surveillance. TGF-β signaling has been proposed to be a key regulator in glioma vasculature [6] and the maintenance of stem cell-like properties and tumorigenic activity of GIC [7, 8]. TβRI, known as activin receptor-like kinases (ALK), and TβRII form heteromeric complexes upon binding of TGF-β family ligands [10]. TGF-β receptors may directly interact with or phosphorylate non-Smad proteins initiating parallel signaling that cooperates with the Smad pathway in downstream responses [12]. The role of TβRIII is complex and difficult to predict as the balance of cell surface and shed TβRIII, which is called soluble TβRIII (sTβRIII), may differentially regulate TGF-β superfamily signaling [13, 18]. Given the putative central role of TGF-β superfamily signaling in glioblastoma, the present study focused on the role of TβRIII in the regulation of TGF-β pathway activity in this disease.
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