Fibulin‐7 is overexpressed in glioblastomas and modulates glioblastoma neovascularization through interaction with angiopoietin‐1

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.

Osterix-Cre marks distinct subsets of CD45- and CD45+ stromal populations in extra-skeletal tumors with pro-tumorigenic characteristics

“…Among the top upregulated genes in the TdT OSX single positive cells versus the double negative ( Table 1 ) we found several markers expressed by osteolinage cells, such as fibromodulin ( Fmod ), a binding protein regulating bone mineralization ( Gori et al, 2001 ) and also involved in TGF β signaling during cancer pathogenesis ( Pourhanifeh et al, 2019 ), Collagen 24a1 ( Col24a1 ), known to modulate collagen chain trimerization ( Koch et al, 2003 ; Matsuo et al, 2006 ), Frem1 , a protein involved in the formation and organization of basement membranes ( Vissers et al, 2011 ), and Msx1 , a transcription factor important in craniofacial bone development ( Orestes-Cardoso et al, 2002 ). TdT OSX single positive cells also expressed high levels of fibulin 7 ( Fbln7 ), a cell adhesion molecule overexpressed in glioblastoma by pericytes and involved in neovascularization ( de Vega et al, 2019 ; Ikeuchi et al, 2018 ). Such result confirmed the osteolineage nature of the TdT OSX + cells and indicated their tumor supporting role.…”

Identification of a prognosis‑associated signature associated with energy metabolism in triple‑negative breast cancer

“…However, it remains unclear regarding the association between the other genes and TNBC physiology, which require further study. Fibulin 7 has been previously reported to participate in the regulation of aberrant neovascularization by modulating the angiopoietin-1/angiopoietin-2-Tie2 axis (64). A previous study has shown that the cartilage intermediate layer protein gene is differentially expressed in differentiated thyroid carcinomas in comparison with normal thyroid tissues (65).…”

The “Janus Face” of Platelets in Cancer

“…Among them, those contained in α-granules play a pivotal role during platelet-cancer crosstalk (Table 2). Endostatin, TSP-1, angiostatin ↓ angiogenesis [107,108] Ang-1: angiopoietin-1; EGF: endothelial growth factor; MK: megakaryocytes; NK: natural kill cells; PAI-1: plasminogen activator inhibitor-1; PDGF-BB: Platelet-derived growth factor BB; TF: tumor necrosis factor; TSP-1: thrombospondin-1; VEGF Vascular endothelial growth factor.…”

“…In proteomic studies, α-granules also have been shown to contain a plethora of angiogenesis inhibitors, including endostatin, platelet factor-4, thrombospondin-1, α 2 -macroglobulin, plasminogen activator inhibitor-1 and angiostatin. Therefore, activated platelets can organize regulatory proteins in the α-granules in order to selectively address the release of pro-or anti-angiogenic factors, depending on which different sets of α-granules are segregated [107,108]. Although cancer cells might have the ability to provoke preferential release of pro-angiogenic mediators from platelet α-granules, in order to create a dynamic microenvironment favorable for their growth and survival [107], several experimental and clinical data point out that platelet secretion in the tumorigenic microenvironment might also be oriented towards an anti-angiogenic effect.…”

“…Therefore, activated platelets can organize regulatory proteins in the α-granules in order to selectively address the release of pro-or anti-angiogenic factors, depending on which different sets of α-granules are segregated [107,108]. Although cancer cells might have the ability to provoke preferential release of pro-angiogenic mediators from platelet α-granules, in order to create a dynamic microenvironment favorable for their growth and survival [107], several experimental and clinical data point out that platelet secretion in the tumorigenic microenvironment might also be oriented towards an anti-angiogenic effect. Such a hypothesis is supported by several findings: (i) significantly higher endostatin levels have been found in hepatocellular carcinoma patients, as well as in gastric cancer subjects [123,124]; (ii) increases in circulating thrombospondin-1 have been found to positively correlate with survival of patients with gynecological and non-small cell lung cancer [125,126]; and (iii) higher levels of angiostatin have been found in serum of prostate cancer patients [127], as well as in urine of patients with epithelial ovarian cancer [128].…”