Galunisertib inhibits glioma vasculogenic mimicry formation induced by astrocytes.

Abstract

Gliomas are among the most lethal primary brain tumors found in humans. In high-grade gliomas, vasculogenic mimicry is often detected and has been correlated with prognosis, thus suggesting its potential as a therapeutic target. Vasculogenic mimicry mainly forms vascular-like channels independent of endothelial cells; however, little is known about the relationship between astrocytes and vasculogenic mimicry. In our study, we demonstrated that the presence of astrocytes promoted vasculogenic mimicry. With suspension microarray technology and in vitro tube formation assays, we identified that astrocytes relied on TGF-β1 to enhance vasculogenic mimicry. We also found that vasculogenic mimicry was inhibited by galunisertib, a promising TGF-β1 inhibitor currently being studied in an ongoing trial in glioma patients. The inhibition was partially attributed to a decrease in autophagy after galunisertib treatment. Moreover, we observed a decrease in VE-cadherin and smooth muscle actin-α expression, as well as down-regulation of Akt and Flk phosphorylation in galunisertib-treated glioma cells. By comparing tumor weight and volume in a xenograft model, we acquired promising results to support our theory. This study expands our understanding of the role of astrocytes in gliomas and demonstrates that galunisertib inhibits glioma vasculogenic mimicry induced by astrocytes.

• Authors: Chao Zhang, Wenliang Chen, Xin Zhang, Bin Huang, Aanjing Chen, Ying He, Jian Wang, Xingang Li
• Journal: Scientific reports (Sci Rep) Vol. 6 Pg. 23056 (Mar 15 2016) ISSN: 2045-2322 [Electronic] England
• PMID: 26976322 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, CD
• Cadherins
• Pyrazoles
• Quinolines
• Transforming Growth Factor beta1
• cadherin 5
• LY-2157299
• Vascular Endothelial Growth Factor Receptor-2
• Proto-Oncogene Proteins c-akt

Topics

• Animals
• Antigens, CD (metabolism)
• Astrocytes (cytology, drug effects, metabolism)
• Autophagy (drug effects, genetics)
• Blotting, Western
• Cadherins (metabolism)
• Cell Line, Tumor
• Cells, Cultured
• Coculture Techniques
• Gene Expression Regulation, Neoplastic (drug effects)
• Glioma (blood supply, genetics, metabolism)
• Humans
• Mice, Inbred BALB C
• Mice, Nude
• Neovascularization, Pathologic (genetics, metabolism, prevention & control)
• Phosphorylation (drug effects)
• Proto-Oncogene Proteins c-akt (metabolism)
• Pyrazoles (pharmacology)
• Quinolines (pharmacology)
• Reverse Transcriptase Polymerase Chain Reaction
• Transforming Growth Factor beta1 (antagonists & inhibitors, genetics, metabolism)
• Tumor Burden (drug effects, genetics)
• Vascular Endothelial Growth Factor Receptor-2 (metabolism)
• Xenograft Model Antitumor Assays