Fibulin‐7 is overexpressed in glioblastomas and modulates glioblastoma neovascularization through interaction with angiopoietin‐1. Issue 8 (15th April 2019)

• Record Type: Journal Article
• Authors: de Vega, Susana; Kondo, Akihide; Suzuki, Mario; Arai, Hajime; Jiapaer, Shabierjiang; Sabit, Hemragul; Nakada, Mitsutoshi; Ikeuchi, Tomoko; Ishijima, Muneaki; Arikawa‐Hirasawa, Eri; Yamada, Yoshihiko; Okada, Yasunori
• Is Part Of: International journal of cancer. Volume 145:Issue 8(2019)
• Page Start: 2157
• Page End: 2169
• Publication Date: 2019-04-15
• Subjects: fibulin‐7 -- glioblastoma -- neovascularization -- angiopoietin‐1 -- vascular endothelial growth factor; Cancer -- Periodicals; Cancer -- Prevention -- Periodicals; 616.994
• DOI: 10.1002/ijc.32306
• Languages: English
• ISSNs: 0020-7136

Abstract

Abstract : Glioblastoma (GBM) is pathologically characterized by highly malignant neoplastic cells, focal necrosis and aberrant blood vessels composed of disorganized endothelial cells and pericytes. The recent cancer microarray database revealed upregulation of fibulin‐7 (Fbln7), a member of the fibulin family, but provided no information on the tissue localization or biological function. In the present study, we demonstrated that Fbln7 is markedly overexpressed by the GBM tissue among astrocytic tumors, and immunolocalized mainly to endothelial cells and pericytes of the glomeruloid and hypertrophied microvessels. The production of Fbln7 by endothelial cells and pericytes was confirmed in cultured human umbilical vein endothelial cells (HUVEC) and human brain vascular pericytes (HBVP) and vascular endothelial growth factor (VEGF) stimulated the Fbln7 expression in HUVEC. Fbln7 bound to angiopoietin‐1, but not angiopoietin‐2 or Tie2 receptor, through interaction between the N‐terminal portions of Fbln7 and angiopoietin‐1, and it blocked phosphorylation of Tie2 receptor in HUVEC. In a coculture assay using HUVEC and HBVP, multilayered and irregular‐shaped tube‐like structures of HUVEC were induced by treatment with a high concentration of VEGF. This was accompanied by Fbln7 overproduction by HUVEC and angiopoietin‐1 expression by HBVP. The production of aberrant VEGF‐induced tube‐like structures was attenuated by treatment with antibody or synthetic peptides specific to the Fbln7 N‐terminal domain or knockdown of Fbln7. These data demonstrate that Fbln7 is overexpressed by endothelial cells and pericytes of the abnormal microvessels in GBM, and suggest that Fbln7 may contribute to the aberrant vessel formation by modulation of the angiopoietin‐1/angiopoietin‐2‐Tie2 axis. Abstract : What's new? Matricellular protein fibulin‐7 has recently been suggested to play a role in glioblastoma, but its tissue localization and biological function remain to be clarified. Here, the authors show that fibulin‐7 is mainly overexpressed by endothelial cells and pericytes composing the aberrant microvasculature in glioblastoma. Fibulin‐7 selectively binds to angiopoietin‐1, leading to suppression of Tie2 activation in endothelial cells, and contributes to the formation of aberrant endothelial cell tubelike structures following stimulation with VEGF. The findings support a role of fibulin‐7 in aberrant blood vessel formation in glioblastoma through modulation of the angiopoietin1‐Tie2 axis.