Inhibition of Endoglin Exerts Antitumor 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 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 antitumor 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 vascular endothelial cadherin phosphorylation and matrix metalloproteinase 2 and matrix metalloproteinase 9 activities in angiosarcoma cells. Although endoglin is a coreceptor that regulates TGF-β signaling, the antitumor 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.

• Authors: Ryoko Sakamoto, Ikko Kajihara, Hitomi Miyauchi, Saki Maeda-Otsuka, Saori Yamada-Kanazawa, Soichiro Sawamura, Hisashi Kanemaru, Katsunari Makino, Jun Aoi, Takamitsu Makino, Satoshi Fukushima, Mamiko Masuzawa, Mikio Masuzawa, Yasuyuki Amoh, Daichi Hoshina, Riichiro Abe, Hironobu Ihn
• Journal: The Journal of investigative dermatology (J Invest Dermatol) Vol. 140 Issue 10 Pg. 2060-2072.e6 (10 2020) ISSN: 1523-1747 [Electronic] United States
• PMID: 32142796 (Publication Type: Journal Article)
• Copyright: Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Endoglin
• Receptors, Transforming Growth Factor beta
• Transforming Growth Factor beta
• Matrix Metalloproteinases

Topics

• Cell Line, Tumor
• Endoglin (antagonists & inhibitors, physiology)
• Hemangiosarcoma (drug therapy, etiology, pathology)
• Humans
• Matrix Metalloproteinases (physiology)
• Receptors, Transforming Growth Factor beta (analysis)
• Signal Transduction (drug effects, physiology)
• Transforming Growth Factor beta (physiology)