Abstract
Glioma is a devastating cancer with a rich vascular network. No anti-angiogenic treatment is available for prolonging the overall survival of glioma patients. Recent studies have demonstrated that the endothelial differentiation of glioma stem cells (GSCs) into glioma-derived endothelial cells (GDECs) may be a novel target for anti-angiogenic therapy in glioma; however, the underlying mechanisms of this process remain unknown. Here, we report that wingless-related integration site (WNT) family member 5A (WNT5A) plays significant roles in GSC endothelial differentiation and GDECs angiogenesis. WNT5A is preferentially secreted by GDECs, and inhibition of WNT5A suppresses angiogenesis and tumorigenesis in GDECs. Silencing of WNT5A in GDECs also disrupts the impact of GDECs on stimulating GSC endothelial differentiation. Frizzled-4 is a receptor that mediates the effect of WNT5A on GSC endothelial differentiation and angiogenesis of GDECs via GSK3β/β-catenin/epithelial-mesenchymal transition signalling. The shWNT5A@cRGD-DDD liposomes, targeting WNT5A, exert anti-angiogenic effects in vivo. In this study, we identified that WNT5A has a dual functional role in modulating the endothelial differentiation of GSCs and angiogenesis of GDECs, indicating that WNT5A is a potential target for anti-angiogenesis-based therapeutics in glioma.
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Acknowledgements
Xinlin Sun received funding from the Natural Science Foundation of China (No. 81772652). Jihui Wang received funding from the Natural Science Foundation of China (No. 81802481), Natural Science Foundation of Guangdong Province (No. 2018A030310423), China Postdoctoral Science Foundation funded project (No. 2020M672737) and President Foundation of ZhuJiang Hospital, Southern Medical University (No. jzjj2018rc04). Taoliang Chen received funding from the President Foundation of ZhuJiang Hospital, Southern Medical University (No. yjjj2019qn14) and Guangzhou Science and Technology Planning Project (No. 202102020015)
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XLS conceived the project. JHW and YL designed experiments. TLC, FBZ and JL write the manuscript. TLC, JL, ZLH, YFZ and SKD performed the experiments. FBZ performed the bioinformatics analyses. XLS, JHW and YL edited the manuscript. All authors read and approved the final manuscript.
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Chen, T., Zhang, F., Liu, J. et al. Dual role of WNT5A in promoting endothelial differentiation of glioma stem cells and angiogenesis of glioma derived endothelial cells. Oncogene 40, 5081–5094 (2021). https://doi.org/10.1038/s41388-021-01922-2
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DOI: https://doi.org/10.1038/s41388-021-01922-2
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