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Cellular and Molecular Biology

Angiogenin and plexin-B2 axis promotes glioblastoma progression by enhancing invasion, vascular association, proliferation and survival

Abstract

Background

Angiogenin is a multifunctional secreted ribonuclease that is upregulated in human cancers and downregulated or mutationally inactivated in neurodegenerative diseases. A role for angiogenin in glioblastoma was inferred from the inverse correlation of angiogenin expression with patient survival but had not been experimentally investigated.

Methods

Angiogenin knockout mice were generated and the effect of angiogenin deficiency on glioblastoma progression was examined. Angiogenin and plexin-B2 genes were knocked down in glioblastoma cells and the changes in cell proliferation, invasion and vascular association were examined. Monoclonal antibodies of angiogenin and small molecules were used to assess the therapeutic activity of the angiogenin-plexin-B2 pathway in both genetic and xenograft animal models.

Results

Deletion of Ang1 gene prolonged survival of PDGF-induced glioblastoma in mice in the Ink4a/Arf−/−:Pten−/− background, accompanied by decreased invasion, vascular association and proliferation. Angiogenin upregulated MMP9 and CD24 leading to enhanced invasion and vascular association. Inhibition of angiogenin or plexin-B2, either by shRNA, monoclonal antibody or small molecule inhibitor, decreases sphere formation of patient-derived glioma stem cells, reduces glioblastoma proliferation and invasion and inhibits glioblastoma growth in both genetic and xenograft animal models.

Conclusions

Angiogenin and its receptor, plexin-B2, are a pair of novel regulators that mediate invasion, vascular association and proliferation of glioblastoma cells. Inhibitors of the angiogenin-plexin-B2 axis have therapeutic potential against glioblastoma.

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Fig. 1: Ang1 deficiency enhanced survival and decreased progression of PDGF-induced GBM mice.
Fig. 2: ANG regulates self-renewal of GSCs and proliferation of GBM cells.
Fig. 3: ANG promotes GBM invasion through upregulation of MMP9.
Fig. 4: ANG enhances association GBM cells to vasculature through upregulation of CD24.
Fig. 5: PLXNB2 mediates formation GSC spheres, proliferation, apoptosis and invasion of GBM cells.
Fig. 6: Effect of PLXNB2 knockdown on xenograft growth of GBM cells in athymic mice.

Data availability

No datasets were generated or analysed during the current study. All data generated or analysed during this study are included in this published article and in its supplementary information files.

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Acknowledgements

We thank late Dr. Bert L. Vallee of Harvard Medical Scholl for support and guidance. We thank Dr. James F. Riordan of Harvard Medical Scholl for advice and discussion.

Funding

This work was supported in part by NIH grants R01CA105241, R01NS065237, R01HL135160 (G-FH), and Vertex Pharmaceuticals Inc.

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HY and G-FH developed the hypothesis, designed experiments, analysed the data and wrote the manuscript. HY, LY, SI, SL, NV, KAG, WY, HK, YJ, AJH and G-FH performed experiments. RS contributed to design and generation of Ang1 KO mice. HY, DJ, BC, EH and G-FH interpreted data. G-FH supervised the project. All authors reviewed and edited the manuscript.

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Correspondence to Guo-fu Hu.

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Yang, H., Yuan, L., Ibaragi, S. et al. Angiogenin and plexin-B2 axis promotes glioblastoma progression by enhancing invasion, vascular association, proliferation and survival. Br J Cancer 127, 422–435 (2022). https://doi.org/10.1038/s41416-022-01814-6

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  • DOI: https://doi.org/10.1038/s41416-022-01814-6

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