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Fibulin‐7 is overexpressed in glioblastomas and modulates glioblastoma neovascularization through interaction with angiopoietin‐1
Author(s) -
Vega Susana,
Kondo Akihide,
Suzuki Mario,
Arai Hajime,
Jiapaer Shabierjiang,
Sabit Hemragul,
Nakada Mitsutoshi,
Ikeuchi Tomoko,
Ishijima Muneaki,
ArikawaHirasawa Eri,
Yamada Yoshihiko,
Okada Yasunori
Publication year - 2019
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.32306
Subject(s) - fibulin , angiogenesis , angiopoietin receptor , angiopoietin , neovascularization , cancer research , downregulation and upregulation , biology , umbilical vein , vascular endothelial growth factor a , vascular endothelial growth factor b , vascular endothelial growth factor , pericyte , microbiology and biotechnology , pathology , endothelial stem cell , medicine , extracellular matrix , gene , in vitro , biochemistry , vegf receptors
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.