Inhibition of endoglin exerts anti-tumor effects through the regulation of non-Smad TGF-β signaling in angiosarcoma

Abstract Angiosarcoma is a rare malignant tumor derived from endothelial cells, and its prognosis is poor because advanced angiosarcoma is often resistant to taxane therapy. Endoglin (CD105) acts as a coreceptor for transforming growth factor-β (TGF-β) signaling, and is overexpressed in tumor-associated endothelial cells and enhances tumor angiogenesis. Numerous clinical trials are testing the effectiveness of anti-endoglin antibodies in various types of malignancies. Here, we investigated the role of endoglin in the pathogenesis of angiosarcoma and whether endoglin inhibition results in anti-tumor activity. Endoglin was overexpressed in angiosarcoma and its inhibition was effective in promoting apoptosis and the suppression of migration, invasion, tube formation, and Warburg effect in angiosarcoma cells. Knockdown of endoglin activated caspase 3/7 that is essential for apoptosis, reduced survivin levels, and decreased paxillin and VE cadherin phosphorylation and MMP-2 and MMP-9 activities in angiosarcoma cells. Although endoglin is a coreceptor that regulates TGF-β signaling, the anti-tumor effect of endoglin in angiosarcoma was not based on Smad signaling regulation, but on non-Smad TGF-β signaling. Taken together, these results indicated that endoglin could be a novel therapeutic target for angiosarcoma.