Endoglin and TGF-β signaling in glioblastoma

Microvascular proliferation is a key feature of glioblastoma and neovascularization has been implicated in tumor progression. Glioblastomas use pro-angiogenic factors such as vascular endothelial growth factor (VEGF) for new blood vessel formation. Yet, anti-VEGF therapy does not prolong overall survival so that alternative angiogenic pathways may need to be explored as drug targets. Both glioma cells and glioma-associated endothelial cells produce TGF-beta superfamily ligands which bind TGF-beta receptors (TGF-beta R). The TGF-beta R type III endoglin (CD105), is a marker of proliferating endothelium that has already been studied as a potential therapeutic target. We studied endoglin expression in glioblastoma tissue and in glioma-associated endothelial cells in a cohort of 52 newly diagnosed and 10 recurrent glioblastoma patients by immunohistochemistry and by ex vivo single-cell gene expression profiling of 6 tumors. Endoglin protein levels were similar in tumor stroma and endothelium and correlated within tumors. Similarly, endoglin mRNA determined by ex vivo single-cell gene expression profiling was expressed in both compartments. There was positive correlation between endoglin and proteins of TGF-beta superfamily signaling. No prognostic role of endoglin expression in either compartment was identified. Endoglin gene silencing in T98G glioma cells and in human cerebral microvascular endothelial cells (hCMEC) did not affect constitutive or exogenous TGF-beta superfamily ligand-dependent signaling, except for a minor facilitation of pSmad1/5 signaling in hCMEC. These observations challenge the notion that endoglin might become a promising therapeutic target in glioblastoma.

Automated summary

Microvascular proliferation is a key feature of glioblastoma, and alternative angiogenic pathways may need to be explored as drug targets as anti-VEGF therapy does not prolong overall survival. Endoglin, a marker of proliferating endothelium, was found to have similar protein levels in tumor stroma and endothelium, correlated with proteins of TGF-beta superfamily signaling, but did not show a prognostic role in glioblastoma. Silencing the endoglin gene in glioma cells and human cerebral microvascular endothelial cells did not significantly affect TGF-beta superfamily ligand-dependent signaling, challenging the notion of endoglin as a promising therapeutic target in glioblastoma.