Abstract:Angiopoietins signal through TIE receptors to control both developmental and homeostatic processes that can go awry in genetic diseases and cancer. This SnapShot illustrates key elements of angiopoietin signaling in normal and disease contexts.
“…Here, the imaging data imply that the Tie2 signal originates from tumor vasculature or at least through a tumor vasculature-associated cell lineage. This finding is consistent with the known data documenting expression of Tie2 in vessels 18 and its modulation by VEGF 4 , 5 . Fig.…”
Oncological use of anti-angiogenic VEGF inhibitors has been limited by the lack of informative biomarkers. Previously we reported circulating Tie2 as a vascular response biomarker for bevacizumab-treated ovarian cancer patients. Using advanced MRI and circulating biomarkers we have extended these findings in metastatic colorectal cancer (n = 70). Bevacizumab (10 mg/kg) was administered to elicit a biomarker response, followed by FOLFOX6-bevacizumab until disease progression. Bevacizumab induced a correlation between Tie2 and the tumor vascular imaging biomarker, Ktrans (R:−0.21 to 0.47) implying that Tie2 originated from the tumor vasculature. Tie2 trajectories were independently associated with pre-treatment tumor vascular characteristics, tumor response, progression free survival (HR for progression = 3.01, p = 0.00014; median PFS 248 vs. 348 days p = 0.0008) and the modeling of progressive disease (p < 0.0001), suggesting that Tie2 should be monitored clinically to optimize VEGF inhibitor use. A vascular response is defined as a 30% reduction in Tie2; vascular progression as a 40% increase in Tie2 above the nadir. Tie2 is the first, validated, tumor vascular response biomarker for VEGFi.
“…Here, the imaging data imply that the Tie2 signal originates from tumor vasculature or at least through a tumor vasculature-associated cell lineage. This finding is consistent with the known data documenting expression of Tie2 in vessels 18 and its modulation by VEGF 4 , 5 . Fig.…”
Oncological use of anti-angiogenic VEGF inhibitors has been limited by the lack of informative biomarkers. Previously we reported circulating Tie2 as a vascular response biomarker for bevacizumab-treated ovarian cancer patients. Using advanced MRI and circulating biomarkers we have extended these findings in metastatic colorectal cancer (n = 70). Bevacizumab (10 mg/kg) was administered to elicit a biomarker response, followed by FOLFOX6-bevacizumab until disease progression. Bevacizumab induced a correlation between Tie2 and the tumor vascular imaging biomarker, Ktrans (R:−0.21 to 0.47) implying that Tie2 originated from the tumor vasculature. Tie2 trajectories were independently associated with pre-treatment tumor vascular characteristics, tumor response, progression free survival (HR for progression = 3.01, p = 0.00014; median PFS 248 vs. 348 days p = 0.0008) and the modeling of progressive disease (p < 0.0001), suggesting that Tie2 should be monitored clinically to optimize VEGF inhibitor use. A vascular response is defined as a 30% reduction in Tie2; vascular progression as a 40% increase in Tie2 above the nadir. Tie2 is the first, validated, tumor vascular response biomarker for VEGFi.
“…Since the first clinical use of a VEGF antagonist for cancer and vascular eye disease more than a decade ago (1), there has been rapid development of new drugs targeting the VEGF-VEGFR2 and Angpt-TIE2 pathways (2). In the Angpt-Tie2 pathway the major ligands are ANGPT1, which is a strong Tie2 agonist, and ANGPT2, which acts as a context-dependent antagonist of Tie2 (3,4). One of the key distinctions between these two ligands is that ANGPT1 self-clusters into higher order oligomers, and this is critical to induce Tie2 activation (5,6).…”
Vascular leak is a key driver of organ injury in diseases such as Acute Respiratory Distress Syndrome caused by viruses, including COVID-19. Strategies that reduce enhanced permeability and vascular inflammation are promising therapeutic targets. Activation of the Angiopoietin-1 (Angpt1)-Tie2 tyrosine kinase signaling pathway is an important regulator of vascular quiescence. Here we describe the design and construction of a new soluble ANGPT1 mimetic that is a potent activator of endothelial Tie2 in vitro and in vivo. Using a chimeric fusion strategy, we replaced the extracellular matrix (ECM) binding and oligomerization domain of ANGPT1 with a heptameric scaffold derived from the C-terminus of serum complement protein C4-binding protein α (C4BP). We refer to this new fusion protein biologic as C4BP-ANG1, which forms a stable heptamer and induces TIE2 phosphorylation in cultured cells, and in the lung following i.v. injection of mice. Injection of C4BP-ANG1 ameliorates VEGF-and lipopolysaccharideinduced vascular leakage, in keeping with the known functions of Angpt1-Tie2 in maintaining quiescent vascular stability, and therefore is a promising candidate treatment for inflammatory endothelial dysfunction.
“…These include angiopoietin‐1 (Ang1) and angiopoietin‐2 (Ang2), both of which bind to the endothelial cell‐specific receptor Tie2 . Ang2 is produced by endothelial cells and binds to Tie2 on endothelial cells, stimulating them to differentiate into invading tip cells that promote sprouting and filopodia formation . Conversely, Ang1, which is synthesized by pericytes and other cells including glioma cells, binds to Tie2 on the endothelial cells and stabilizes the newly formed blood vessels by recruiting pericytes to the endothelium .…”
Section: Introductionmentioning
confidence: 99%
“…9 Ang2 is produced by endothelial cells and binds to Tie2 on endothelial cells, stimulating them to differentiate into invading tip cells that promote sprouting and filopodia formation. 10 Conversely, Ang1, which is synthesized by pericytes and other cells including glioma cells, binds to Tie2 on the endothelial cells and stabilizes the newly formed blood vessels by recruiting pericytes to the endothelium. 9 Therefore, the Ang1-Tie2 and Ang2-Tie2 signaling pathways play antagonizing roles in angiogenesis, and their imbalance may be implicated in the development of abnormal neovascularization in GBM.…”
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.
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