Anti-Angiogenic Therapies in the Management of Glioblastoma

Jessica D. Schulte; Manish K. Aghi; Jennie W. Taylor

Disclosures

Chin Clin Oncol. 2021;10(4):37 

In This Article

Mechanisms of Angiogenesis

Angiogenesis in gliomas involves various mechanisms: co-option of preexisting vessels;[8] de novo angiogenesis through extension of nearby vessels;[9] differentiation of bone marrow-derived endothelial progenitors;[10] multiplication of vessels through splitting of existing vessels (also known as intussusception);[11] and vascular mimicry by glioma stem cells that form luminal cylinders resembling vessels.[12–15]

Angiogenesis is regulated by intricate and overlapping signaling pathways, which involve both hypoxia-dependent and -independent processes. In hypoxic environments, hypoxia inducible factor 1 subunit alpha (HIF-1α) is upregulated, driving expression of pro-angiogenic genes such as vascular endothelial growth factor (VEGF). VEGF protein binds to its receptor VEGFR and activates additional growth factors that mediate endothelial sprouting, migration, and endovascular permeability. Hypoxia also induces matrix metalloproteinase (MMP) production that mediates stromal disintegration and endothelial migration.[16,17] Angiopoietin 1 (ANG1) and ANG2 have a complicated interplay, but work together to help formalize these primitive vessels. ANG1 protein stabilizes vessels by facilitating cell interactions that support vasculature integrity.[18] The role of ANG2 depends on the presence or absence of VEGF. When VEGF is present, ANG2 acts via tyrosine kinase with immunoglobulin-like and EGF-like 1 (TIE1) receptors to promote angiogenesis and stimulate the migration and differentiation of endothelial cells, through Notch and ephrin-A2 signaling, respectively.[19–22] When VEGF is absent, ANG2 acts via TIE2 receptors to destabilize blood vessels, causing endothelial apoptosis and vessel regression.[19] In low nutrient environments, VEGF can be upregulated through peroxisome-proliferator-activated receptor-γ coactivator-1α (PGC-1-α) independently of hypoxia.[23] In addition, several different gene mutations that are common in gliomas, including platelet-derived growth factor (PDGF), epithelial growth factor receptor (EGFR), p53 (TP53), RB transcriptional corepressor 1 (RB1), von Hippel-Lindau tumor suppressor (VHL) and phosphate and tensin homolog (PTEN), all stabilize HIF-1α causing subsequent upregulation of VEGF.[24,25]

In addition to VEGF-related actions on angiogenesis, stromal cell-derived factor 1 protein (SDF-1, also known as C-X-C motif chemokine ligand 2, CXCL2), and its receptor CXCR4 (C-X-C motif chemokine receptor 4), also recruit bone marrow-derived progenitors from the circulation into the tumor that subsequently differentiate into endothelial cells and pericytes.[26–28] Other growth factor pathways including fibroblast growth factor (FGF), phosphoinositide 3-kinase (PIK3), PDGF, and transforming growth factor β1 (TGFβ1), mediate angiogenesis through a combination of mechanisms that regulate VEGF expression, stimulate endothelial cell proliferation, and regulate expression of proteases implicated in vessel dissolution and migration.[29–32] As these processes unfold, the tumor vasculature manifests as irregular, poorly constructed, and poorly connected vessels.[33] This disorganized and leaky system creates spatiotemporal heterogeneity in tumor oxygenation that may impact the development and expansion of the tumor's genetic subclone populations.

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