Roles of EphA2 Receptor in Angiogenesis Signaling Pathway of Glioblastoma Multiforme

Abstract

Glioblastoma multiforme (GBM) is one of the most common primary brain tumours in adults, accounting for almost 65% of all cases. Among solid tumours, GBM is characterised by strong angiogenesis, including the highest degree of vascular proliferation and endothelial cell hyperplasia. Despite numerous improvements in existing treatment approaches, the prognosis of GBM patients remains poor, with a mean survival of only 14.6 months. Growing evidence has shown significant overexpression of the ephrin type-A receptor 2 (EphA2) receptor in various malignancies, including GBM, as well as a correlation to poor prognoses. It is believed that EphA2 receptors play important roles in mediating GBM tumourigenesis, including invasion, metastasis, and angiogenesis. Despite the clinical and pathological importance of tumour-associated vasculature, the underlying mechanism involving EphA2 is poorly known. Here, we have summarised the current knowledge in the field regarding EphA2 receptors’ roles in the angiogenesis of GBM.

CAR T Cell-Based Immunotherapy for the Treatment of Glioblastoma

“…Erythropoietin-producing hepatocellular carcinoma A2 (EphA2) belongs to the Eph family of receptor tyrosine kinases (RTKs); it plays a role in a wide variety of functions in malignant cells, such as tumorigenesis, invasion, angiogenesis and metastasis ( Wykosky and Debinski, 2008 ; Baharuddin et al, 2018 ). Therefore, targeting EphA2 could prevent tumor progression and recurrence.…”

Tumor Vessels Fuel the Fire in Glioblastoma

“…Angiogenesis can be defined as the formation of new blood vessels from pre-existing ones, and involves proliferation, migration, and differentiation of vascular ECs. Angiogenesis is a tightly tuned process regulated by a balance between pro-angiogenic and inhibiting factors ( Table 1 ) [ 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 ]. Among the broad range of angiogenic stimuli, a lack of oxygen is one of the more potent triggers, which mainly operates via the activation of the hypoxia-inducible factor (HIF-1) transcription factor and commands the expression of VEGF [ 59 ].…”

Antiangiogenic Targets for Glioblastoma Therapy from a Pre-Clinical Approach, Using Nanoformulations

“…The study by Wang [55] used a heparin-based polymer conjugated with cRGD and SWLAYPGAVSYR (SWL; S = serine, W = tryptophan, L = leucine, A = alanine, Y = tyrosine, P = proline, and V = valine) peptides to promote selective affinity for the overexpressed integrin and EphA2 tyrosine kinase receptor, respectively, reaching 56% simultaneous inhibition of endothelial-lined blood vessels and 82% vasculogenic mimicry. VEGFR-2 plays a key role in vasculogenic mimicry formation, neovascularization, and tumor initiation by glioma stem-like cells [99], and EphA2 and its receptors are significantly involved in blood vessel formation and remodeling during the vascular development of cancers [25]. EphA2 may regulate vessel sprouting during developmental angiogenesis independently via inhibition at both the gene and protein levels of VEGFR-2, without affecting VEGF expression by GBM cells [25].…”

“…VEGFR-2 plays a key role in vasculogenic mimicry formation, neovascularization, and tumor initiation by glioma stem-like cells [99], and EphA2 and its receptors are significantly involved in blood vessel formation and remodeling during the vascular development of cancers [25]. EphA2 may regulate vessel sprouting during developmental angiogenesis independently via inhibition at both the gene and protein levels of VEGFR-2, without affecting VEGF expression by GBM cells [25]. The study by Zhang [45] modified the surface of liposomes with a thiolated cyclic pentapeptide derivative containing RGD conjugated with DSPE-PEG2000-maleimide, aiming at a nanoformulation capable of crossing the BBB and target GBM neovasculature.…”

“…All these growth factors in intercellular communication form several fronts of action that, in a dependent or independent manner, favor the formation of new blood vessels from pre-existing vessels [ 8 , 9 , 10 ]. Throughout the links of growth factors with the receptors present in endothelial cells that make up blood vessels, there is the activation of receptors, which are mostly transmembrane kinase proteins that, when activated, trigger a series of intracellular reactions to stimulate endothelial cell migration, proliferation, and differentiation as well as modulate vascular support cells [ 23 , 24 , 25 ]. For this migratory process to occur, it is necessary to have basement membrane degradation of the brain parenchyma extracellular matrix (ECM) through the stimulation of matrix metalloproteinases (MMPs) [ 11 , 26 ].…”