A Tumor-Promoting Role For Soluble T Beta Riii In Glioblastoma

Purpose Members of the transforming growth factor (TGF)-beta 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-beta coreceptor also known as TGF-beta receptor III (T beta RIII), interacts with members of the TGF-beta superfamily and acts as membrane-associated or shed molecule. Shed, soluble T beta RIII (sT beta RIII) is produced upon ectodomain cleavage of the membrane-bound form. Elucidating the role of T beta RIII may improve our understanding of TGF-beta pathway activity in glioblastoma Methods Protein levels of T beta RIII were determined by immunohistochemical analyses and ex vivo single-cell gene expression profiling of glioblastoma tissue respectively. In vitro, T beta RIII 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 T beta RIII on TGF-beta signaling was investigated, and results were validated in a xenograft mouse glioma model Results Immunohistochemistry and ex vivo single-cell gene expression profiling of glioblastoma tissue showed that T beta RIII was expressed in the tumor tissue, predominantly in the vascular compartment. We confirmed this pattern of T beta RIII expression in vitro. Specifically, we detected sT beta RIII in glioblastoma-derived microvascular endothelial cells. ST beta RIII facilitated TGF-beta-induced Smad2 phosphorylation in vitro and overexpression of sT beta RIII in a xenograft mouse glioma model led to increased levels of Smad2 phosphorylation, increased tumor volume, and decreased survival Conclusions These data shed light on the potential tumor-promoting role of extracellular shed T beta RIII which may be released by glioblastoma endothelium with high sT beta RIII levels.