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Dual role of WNT5A in promoting endothelial differentiation of glioma stem cells and angiogenesis of glioma derived endothelial cells

Oncogene volume 40, pages 5081–5094 (2021)Cite this article

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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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Fig. 1: WNT5A is preferentially secreted by the GDECs.
Fig. 2: Silencing of WNT5a inhibits proangiogenic features and tumorgenicity of GDECs.
Fig. 3: WNT5A promotes the endothelial trans-differentiation of GSCs.
Fig. 4: FZD4 is a receptor for autocrine WNT5A in GDECs.
Fig. 5: WNT5A modulates the proangiogenic features of GDECs and the endothelial transdifferentiation of GSCs via the FZD4/GSK3β/β-catenin/EMT pathway.
Fig. 6: WNT5A regulates the tumorgenicity of GDECs via the FZD4/GSK3β/β-catenin/EMT pathway.
Fig. 7: WNT5A is an available target for anti-angiogenesis in glioma.
Fig. 8: A schematic model of WNT5A-mediated signalling pathway regulating endothelial differentiation of GSCs and angiogenesis of GDECs.

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References

  1. Ostrom QT, Cioffi G, Gittleman H, Patil N, Waite K, Kruchko C, et al. CBTRUS statistical report: primary brain and other central nervous system tumors diagnosed in the United States in 2012-2016. Neuro Oncol. 2019;21:v1–v100.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Wen PY, Kesari S. Malignant gliomas in adults. N. Engl J Med. 2008;359:492–507.

    Article  CAS  PubMed  Google Scholar 

  3. Zeng Y, Fu BM. Resistance mechanisms of anti-angiogenic therapy and exosomes-mediated revascularization in cancer. Front Cell Dev Biol. 2020;8:610661.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Mooi J, Chionh F, Savas P, Da Gama Duarte J, Chong G, Brown S, et al. Dual anti-angiogenesis agents bevacizumab plus trebananib, without chemotherapy, in first-line treatment of metastatic colorectal cancer: results of a phase II study. Clin Cancer Res. 2021;27:2159–67.

    Article  CAS  PubMed  Google Scholar 

  5. Chen Y, Guo L, Li X, Liu R, Ren C, Du S. Reduced-dose bevacizumab vs. standard-dose bevacizumab in recurrent high-grade glioma: which one is better? A meta-analysis. Clin Neurol Neurosurg. 2020;198:106239.

    Article  PubMed  Google Scholar 

  6. Wu HB, Yang S, Weng HY, Chen Q, Zhao XL, Fu WJ, et al. Autophagy-induced KDR/VEGFR-2 activation promotes the formation of vasculogenic mimicry by glioma stem cells. Autophagy. 2017;13:1528–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Piao Y, Liang J, Holmes L, Henry V, Sulman E, de Groot JF. Acquired resistance to anti-VEGF therapy in glioblastoma is associated with a mesenchymal transition. Clin Cancer Res. 2013;19:4392–403.

    Article  CAS  PubMed  Google Scholar 

  8. Suvà ML, Tirosh I. The glioma stem cell model in the era of single-cell genomics. Cancer Cell. 2020;37:630–6.

    Article  PubMed  CAS  Google Scholar 

  9. Zhang L, Yu H, Yuan Y, Yu JS, Lou Z, Xue Y, et al. The necessity for standardization of glioma stem cell culture: a systematic review. Stem Cell Res Ther. 2020;11:84.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Wang R, Chadalavada K, Wilshire J, Kowalik U, Hovinga KE, Geber A, et al. Glioblastoma stem-like cells give rise to tumour endothelium. Nature. 2010;468:829–33.

    Article  CAS  PubMed  Google Scholar 

  11. Carlson JC, Cantu-Gutierrez M, Lozzi B, Huang-Hobbs E, Turner WD, Tepe B, et al. Identification of diverse tumor endothelial cell populations in malignant glioma. Neuro Oncol. 2020;23:932–44.

    Article  PubMed Central  Google Scholar 

  12. Kamino M, Kishida M, Kibe T, Ikoma K, Iijima M, Hirano H, et al. Wnt-5a signaling is correlated with infiltrative activity in human glioma by inducing cellular migration and MMP-2. Cancer Sci. 2011;102:540–8.

    Article  CAS  PubMed  Google Scholar 

  13. Habu M, Koyama H, Kishida M, Kamino M, Iijima M, Fuchigami T, et al. Ryk is essential for Wnt-5a-dependent invasiveness in human glioma. J Biochem. 2014;156:29–38.

    Article  CAS  PubMed  Google Scholar 

  14. Yu JM, Jun ES, Jung JS, Suh SY, Han JY, Kim JY, et al. Role of Wnt5a in the proliferation of human glioblastoma cells. Cancer Lett. 2007;257:172–81.

    Article  CAS  PubMed  Google Scholar 

  15. Zhang Y, Wu Z, Li L, Xie M. miR-30a inhibits glioma progression and stem cell-like properties by repression of Wnt5a. Oncol Rep. 2017;38:1156–62.

    Article  CAS  PubMed  Google Scholar 

  16. Yang DH, Yoon JY, Lee SH, Bryja V, Andersson ER, Arenas E, et al. Wnt5a is required for endothelial differentiation of embryonic stem cells and vascularization via pathways involving both Wnt/beta-catenin and protein kinase Calpha. Circ Res. 2009;104:372–9.

    Article  CAS  PubMed  Google Scholar 

  17. Masckauchán TN, Agalliu D, Vorontchikhina M, Ahn A, Parmalee NL, Li CM, et al. Wnt5a signaling induces proliferation and survival of endothelial cells in vitro and expression of MMP-1 and Tie-2. Mol Biol Cell. 2006;17:5163–72.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Yang X, Zhao S, Yuan H, Shi R, Gu W, Gu Z, et al. Knockdown of Ror2 suppresses TNF‑α‑induced inflammation and apoptosis in vascular endothelial cells. Mol Med Rep. 2020;22:2981–9.

    CAS  PubMed  Google Scholar 

  19. Shi YN, Zhu N, Liu C, Wu HT, Gui YU, Liao DF. et al. Wnt5a and its signaling pathway in angiogenesis. Clin Chim Acta. 2017;471:263–9.

    Article  CAS  PubMed  Google Scholar 

  20. Cheng CW, Yeh JC, Fan TP, Smith SK, Charnock-Jones DS. Wnt5a-mediated non-canonical Wnt signalling regulates human endothelial cell proliferation and migration. Biochemical Biophysical Res Commun. 2008;365:285–90.

    Article  CAS  Google Scholar 

  21. Yang X, Zhao S, Yuan H, Shi R, Gu W, Gu Z, et al. Knockdown of Ror2 suppresses TNF‑α‑induced inflammation and apoptosis in vascular endothelial cells. Mol Med Rep. 2020;22:2981–9.

    CAS  PubMed  Google Scholar 

  22. Ekström EJ, Bergenfelz C, von Bülow V, Serifler F, Carlemalm E, Jönsson G, et al. WNT5A induces release of exosomes containing pro-angiogenic and immunosuppressive factors from malignant melanoma cells. Mol Cancer. 2014;13:88.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Hu B, Wang Q, Wang YA, Hua S, Sauve CG, Ong D, et al. Epigenetic activation of WNT5A drives glioblastoma stem cell differentiation and invasive growth. Cell. 2016;167:1281–.e18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Chen T, Chen J, Zhu Y, Li Y, Wang Y, Chen H, et al. CD163, a novel therapeutic target, regulates the proliferation and stemness of glioma cells via casein kinase 2. Oncogene. 2019;38:1183–99.

  25. Liu J, Zhang Y, Chen T, Chen H, He H, Jin T, et al. Environmentally self-adaptative nanocarriers suppress glioma proliferation and stemness via codelivery of shCD163 and doxorubicin. ACS Appl Mater Interfaces. 2020;12:52354–69.

    Article  CAS  PubMed  Google Scholar 

  26. Yu X, Xia J, Cao Y, Tang L, Tang X, Li Z. SNHG1 represses the anti-cancer roles of baicalein in cervical cancer through regulating miR-3127-5p/FZD4/Wnt/β-catenin signaling. Exp Biol Med. 2021;246:20–30.

    Article  CAS  Google Scholar 

  27. Han S, Sun J, Yang L, Qi M. Role of NDP- and FZD4-related novel mutations identified in patients with FEVR in Norrin/β-catenin signaling pathway. Biomed Res Int. 2020;2020:7681926.

    PubMed  PubMed Central  Google Scholar 

  28. Emami KH, Nguyen C, Ma H, Kim DH, Jeong KW, Eguchi M, et al. A small molecule inhibitor of beta-catenin/CREB-binding protein transcription. Proc Natl Acad Sci USA. 2004;101:12682–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Yin J, Kim SS, Choi E, Oh YT, Lin W, Kim TH, et al. ARS2/MAGL signaling in glioblastoma stem cells promotes self-renewal and M2-like polarization of tumor-associated macrophages. Nat Commun. 2020;11:2978.

  30. Li X, Lv F, Li F, Du M, Liang Y, Ju S, et al. LINC01089 inhibits tumorigenesis and epithelial-mesenchymal transition of non-small cell lung cancer via the miR-27a/SFRP1/Wnt/β-catenin axis. Front Oncol. 2020;10:532581.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Sun L, Shi C, Liu S, Zhang E, Yan L, Ji C, et al. Overexpression of NuSAP1 is predictive of an unfavourable prognosis and promotes proliferation and invasion of triple-negative breast cancer cells via the Wnt/β-catenin/EMT signalling axis. Gene. 2020;747:144657.

    Article  CAS  PubMed  Google Scholar 

  32. Sun Z, Liu B, Liu ZH, Song W, Wang D, Chen BY, et al. Notochordal-cell-derived exosomes induced by compressive load inhibit angiogenesis via the miR-140-5p/Wnt/β-catenin axis. Mol Ther Nucleic Acids. 2020;22:1092–106.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Ma L, Zhao X, Liu Y, Wu J, Yang X, Jin Q. Dihydroartemisinin attenuates osteoarthritis by inhibiting abnormal bone remodeling and angiogenesis in subchondral bone. Int J Mol Med. 2021;47:04855.

    PubMed Central  Google Scholar 

  34. Ricci-Vitiani L, Pallini R, Biffoni M, Todaro M, Invernici G, Cenci T, et al. Tumour vascularization via endothelial differentiation of glioblastoma stem-like cells. Nature. 2010;468:824–8.

    Article  CAS  PubMed  Google Scholar 

  35. Mei X, Chen YS, Chen FR, Xi SY, Chen ZP. Glioblastoma stem cell differentiation into endothelial cells evidenced through live-cell imaging. Neuro Oncol. 2017;19:1109–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Deshors P, Toulas C, Arnauduc F, Malric L, Siegfried A, Nicaise Y, et al. Ionizing radiation induces endothelial transdifferentiation of glioblastoma stem-like cells through the Tie2 signaling pathway. Cell Death Dis. 2019;10:816.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Hardee ME, Zagzag D. Mechanisms of glioma-associated neovascularization. Am J Pathol. 2012;181:1126–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Plate K, Scholz A, Dumont D. Tumor angiogenesis and anti-angiogenic therapy in malignant gliomas revisited. Acta Neuropathologica. 2012;124:763–75.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Hu B, Wang Q, Wang YA, Hua S, Sauve CG, Ong D, et al. Epigenetic activation of WNT5A drives glioblastoma stem cell differentiation and invasive growth. Cell. 2016;167:1281–.e18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Liu Z, Qi L, Li Y, Zhao X, Sun B. VEGFR2 regulates endothelial differentiation of colon cancer cells. BMC Cancer. 2017;17:593.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Han Y, Gong T, Zhang C, Dissanayaka WL. HIF-1α stabilization enhances angio-/vasculogenic properties of SHED. J Dent Res. 2020;99:804–12.

    Article  CAS  PubMed  Google Scholar 

  42. Zhang X, Dong S, Xu F. Structural and druggability landscape of frizzled G protein-coupled receptors. Trends Biochemical Sci. 2018;43:1033–46.

    Article  CAS  Google Scholar 

  43. Frenquelli M, Tonon G. WNT signaling in hematological malignancies. Front Oncol. 2020;10:615190.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Junge HJ, Yang S, Burton JB, Paes K, Shu X, French DM, et al. TSPAN12 regulates retinal vascular development by promoting Norrin- but not Wnt-induced FZD4/beta-catenin signaling. Cell. 2009;139:299–311.

    Article  CAS  PubMed  Google Scholar 

  45. Jiang X, Liu J, Li S, Jia B, Huang Z, Shen J, et al. CCL18-induced LINC00319 promotes proliferation and metastasis in oral squamous cell carcinoma via the miR-199a-5p/FZD4 axis. Cell Death Dis. 2020;11:777.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Li ZT, Zhang X, Wang DW, Xu J, Kou KJ, Wang ZW, et al. Overexpressed lncRNA GATA6-AS1 inhibits LNM and EMT via FZD4 through the Wnt/β-catenin signaling pathway in GC. Mol Ther Nucleic Acids. 2020;19:827–40.

    Article  CAS  PubMed  Google Scholar 

  47. Yang Y, Sun Y, Wu Y, Tang D, Ding X, Xu W, et al. Downregulation of miR-3127-5p promotes epithelial-mesenchymal transition via FZD4 regulation of Wnt/β-catenin signaling in non-small-cell lung cancer. Mol Carcinog. 2018;57:842–53.

    Article  CAS  PubMed  Google Scholar 

  48. Wei Y, Zhang F, Zhang T, Zhang Y, Chen H, Wang F, et al. LDLRAD2 overexpression predicts poor prognosis and promotes metastasis by activating Wnt/β-catenin/EMT signaling cascade in gastric cancer. Aging. 2019;11:8951–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Zhang Yi-kun, Wang Hua, Guo Yu-wei, Yue Yang. Novel role of Snail 1 in promoting tumor neoangiogenesis. Biosci Rep. 2019;39:BSR20182161.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Abdulkhalek S, Geen OD, Brodhagen L, Haxho F, Alghamdi F, Allison S, et al. Transcriptional factor snail controls tumor neovascularization, growth and metastasis in mouse model of human ovarian carcinoma. Clin Transl Med. 2014;3:28.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Akhtar N. Hijacking a morphogenesis proteinase for cancer cell invasion. Dev Cell. 2018;47:135–7.

    Article  CAS  PubMed  Google Scholar 

  52. Yu L, Lu S, Tian J, Ma J, Li J, Wang H, et al. TWIST expression in hypopharyngeal cancer and the mechanism of TWIST-induced promotion of metastasis. Oncol Rep. 2012;27:416–22.

    Article  CAS  PubMed  Google Scholar 

  53. Kemper K, Sprick MR, de Bree M, Scopelliti A, Vermeulen L, Hoek M, et al. The AC133 epitope, but not the CD133 protein, is lost upon cancer stem cell differentiation. Cancer Res. 2010;70:719–29.

    Article  CAS  PubMed  Google Scholar 

  54. Ying M, Wang S, Sang Y, Sun P, Lal B, Goodwin CR, et al. Regulation of glioblastoma stem cells by retinoic acid: role for Notch pathway inhibition. Oncogene. 2011;30:3454–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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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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  1. These authors contributed equally: Taoliang Chen, Fabing Zhang, Jie Liu.

Authors and Affiliations

  1. The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Guangzhou, China

    Taoliang Chen, Fabing Zhang, Jie Liu, Zhilin Huang, Yaofeng Zheng, Shaokang Deng, Yang Liu, Jihui Wang & Xinlin Sun

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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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Correspondence to Yang Liu, Jihui Wang or Xinlin Sun.

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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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