Hailing Yang1,2, Liang Yuan1,3, Soichiro Ibaragi4, Shuping Li1,4, Robert Shapiro4, Nil Vanli1,5, Kevin A Goncalves1,2, Wenhao Yu1,4, Hiroko Kishikawa1,4, Yuxiang Jiang1, Alexander J Hu1,3, Daniel Jay2,3,6, Brent Cochran2,3,6, Eric C Holland7, Guo-Fu Hu8,9,10,11,12. 1. Division of Hematology and Oncology, Department of Medicine, Tufts Medical Center, Boston, MA, USA. 2. Program in Cellular and Molecular Physiology, Graduate School of Biomedical Sciences, Tufts University, Boston, MA, USA. 3. Program in Cell, Molecular, and Developmental Biology, Graduate School of Biomedical Sciences, Tufts University, Boston, MA, USA. 4. Department of Pathology, Harvard Medical School, Boston, MA, USA. 5. Program in Biochemistry, Graduate School of Biomedical Sciences, Tufts University, Boston, MA, USA. 6. Department of Developmental, Molecular and Chemical Biology, Tufts University School of Medicine, Boston, MA, USA. 7. Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. 8. Division of Hematology and Oncology, Department of Medicine, Tufts Medical Center, Boston, MA, USA. guo-fu.hu@tufts.edu. 9. Program in Cellular and Molecular Physiology, Graduate School of Biomedical Sciences, Tufts University, Boston, MA, USA. guo-fu.hu@tufts.edu. 10. Program in Cell, Molecular, and Developmental Biology, Graduate School of Biomedical Sciences, Tufts University, Boston, MA, USA. guo-fu.hu@tufts.edu. 11. Department of Pathology, Harvard Medical School, Boston, MA, USA. guo-fu.hu@tufts.edu. 12. Program in Biochemistry, Graduate School of Biomedical Sciences, Tufts University, Boston, MA, USA. guo-fu.hu@tufts.edu.
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.
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.
Authors: Alexander Pietras; Amanda M Katz; Elin J Ekström; Boyoung Wee; John J Halliday; Kenneth L Pitter; Jillian L Werbeck; Nduka M Amankulor; Jason T Huse; Eric C Holland Journal: Cell Stem Cell Date: 2014-03-06 Impact factor: 24.633
Authors: Yong Huang; Rut Tejero; Vivian K Lee; Concetta Brusco; Theodore Hannah; Taylor B Bertucci; Chrystian Junqueira Alves; Igor Katsyv; Michael Kluge; Ramsey Foty; Bin Zhang; Caroline C Friedel; Guohao Dai; Hongyan Zou; Roland H Friedel Journal: Commun Biol Date: 2021-01-29