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Parallel and anti-parallel signaling of an EphA2-ephrin interaction
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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, th...
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Glioblastoma (GBMs) is an aggressive type of brain tumour, driven by immature neural stem cell-like cells that promote tumour growth and underlie resistance to conventional therapy. The GBM stem cells (GSCs) can exist in quiescent or dormant states and infiltrate widely into surrounding brain tissues, currently incurable with only around one-year m...
Citations
... Next, the functional signalling receptor for PGRN covers EPHA2, which is mainly overexpressed in advanced grades of brain tumours, such as GBM [113]. Furthermore, the high expression of EPHA2 has been observed and confirmed within various types of GBM cell lines (e.g., LN-229, T98G, DBTRG-05M, U251MG, BTCOE 4795 and U87-MG) [114,115]. It was observed that the overexpression of EPHA2 is associated with low survival rates and tumour recurrence [115]. ...
... Furthermore, the high expression of EPHA2 has been observed and confirmed within various types of GBM cell lines (e.g., LN-229, T98G, DBTRG-05M, U251MG, BTCOE 4795 and U87-MG) [114,115]. It was observed that the overexpression of EPHA2 is associated with low survival rates and tumour recurrence [115]. At the cellular level, the deregulated expression of EPHA2 was linked to the promotion of tumour aggressiveness, invasion, and metastasis [116]. ...
Glioblastoma multiforme (GBM) represents the most common and aggressive malignant form of brain tumour in adults and is characterized by an extremely poor prognosis with dismal survival rates. Currently, expanding concepts concerning the pathophysiology of GBM are inextricably linked with neuroinflammatory phenomena. On account of this fact, the identification of novel pathomechanisms targeting neuroinflammation seems to be crucial in terms of yielding successful individual therapeutic strategies. In recent years, the pleiotropic growth factor progranulin (PGRN) has attracted significant attention in the neuroscience and oncological community regarding its neuroimmunomodulatory and oncogenic functions. This review of the literature summarizes and updates contemporary knowledge about PGRN, its associated receptors and signalling pathway involvement in GBM pathogenesis, indicating possible cellular and molecular mechanisms with potential diagnostic, prognostic and therapeutic targets in order to yield successful individual therapeutic strategies. After a review of the literature, we found that there are possible PGRN-targeted therapeutic approaches for implementation in GBM treatment algorithms both in preclinical and future clinical studies. Furthermore, PGRN-targeted therapies exerted their highest efficacy in combination with other established chemotherapeutic agents, such as temozolomide. The results of the analysis suggested that the possible implementation of routine determinations of PGRN and its associated receptors in tumour tissue and biofluids could serve as a diagnostic and prognostic biomarker of GBM. Furthermore, promising preclinical applications of PGRN-related findings should be investigated in clinical studies in order to create new diagnostic and therapeutic algorithms for GBM treatment.
... Similar expression of EPHA2 was observed with poor DFS in LGG and PAAD patients. Multiple investigations on breast cancer [27] , gastric cancer [28] , prostate cancer [36] , esophageal cancer [37] , colorectal cancer [38] , and glioma [39] have confirmed that EPHA2 overexpression is associated with a poor prognosis. Different outcomes regarding the prognostic value of EPHA2 level in multiple tumors were identified in the current investigation, which may have a larger sample size and different data sets. ...
Background: The tyrosine kinase ephrin type-A receptor 2（EPHA2）is remarkably elevated expressed in various tumors and plays a crucial role in cancer tumorigenesis and progression, while pan-cancer analyses (PCA) are currently lacking. This study was designed to analyze the expression status and prognostic significance of EPHA2 in pan-cancer.
Methods: By mining The Cancer Genome Atlas (TCGA) data, we performed a comprehensive and systematic characterization of EPHA2 across more than 10,000 samples of 33 types of cancer.
Results: EPHA2 expressions were substantially different in most of the normal control and tumor tissues and considerably associated with the prognosis of tumor patients. In addition, the missense mutation is more prevalent in EPHA2 genetic modification in malignancies. Moreover, a notable association has been developed between EPHA2 expressions and cancer-associated fibroblasts (CAFs) in most TCGA cancers. Furthermore, Functional enrichment analysis showed that the biological role of EPHA2 in tumors is mainly involved in some noticeably pro-oncogenic pathways, such as the Ras signaling pathway, PI3K-Akt signaling pathway, ErbB signaling pathway, MAPK signaling pathway, etc.
Conclusions: This study provides the first PCA with the extensive role of EPHA2 in various tumors, and EPHA2 is potentially involved in many cancer types and can be developed as candidates for cancer diagnosis, prognosis, and therapeutic biomarkers.
... This interaction between ephrin A1 and EphA2 receptor can drive different tumorigenic events such as cell proliferation, migration, and angiogenesis. These effects are the likely explanation for the observed overexpression of EphA2 receptor in different cancers [60]. ...
The development of novel target therapies based on the use of RNA interference (RNAi) and antisense oligonucleotides (ASOs) is growing in an exponential way, challenging the chance for the treatment of the genetic diseases and cancer by hitting selectively targeted RNA in a sequence-dependent manner. Multiple opportunities are taking shape, able to remove defective protein by silencing RNA (e.g., Inclisiran targets mRNA of protein PCSK9, permitting a longer half-life of LDL receptors in heterozygous familial hypercholesteremia), by arresting mRNA translation (i.e., Fomivirsen that binds to UL123-RNA and blocks the translation into IE2 protein in CMV-retinitis), or by reactivating modified functional protein (e.g., Eteplirsen able to restore a functional shorter dystrophin by skipping the exon 51 in Duchenne muscular dystrophy) or a not very functional protein. In this last case, the use of ASOs permits modifying the expression of specific proteins by modulating splicing of specific pre-RNAs (e.g., Nusinersen acts on the splicing of exon 7 in SMN2 mRNA normally not expressed; it is used for spinal muscular atrophy) or by downregulation of transcript levels (e.g., Inotersen acts on the transthryretin mRNA to reduce its expression; it is prescribed for the treatment of hereditary transthyretin amyloidosis) in order to restore the biochemical/physiological condition and ameliorate quality of life. In the era of precision medicine, recently, an experimental splice-modulating antisense oligonucleotide, Milasen, was designed and used to treat an 8-year-old girl affected by a rare, fatal, progressive form of neurodegenerative disease leading to death during adolescence. In this review, we summarize the main transcriptional therapeutic drugs approved to date for the treatment of genetic diseases by principal regulatory government agencies and recent clinical trials aimed at the treatment of cancer. Their mechanism of action, chemical structure, administration, and biomedical performance are predominantly discussed.
... 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. ...
Gliomas are one of the most lethal types of cancers accounting for ∼80% of all central nervous system (CNS) primary malignancies. Among gliomas, glioblastomas (GBM) are the most aggressive, characterized by a median patient survival of fewer than 15 months. Recent molecular characterization studies uncovered the genetic signatures and methylation status of gliomas and correlate these with clinical prognosis. The most relevant molecular characteristics for the new glioma classification are IDH mutation, chromosome 1p/19q deletion, histone mutations, and other genetic parameters such as ATRX loss, TP53, and TERT mutations, as well as DNA methylation levels. Similar to other solid tumors, glioma progression is impacted by the complex interactions between the tumor cells and immune cells within the tumor microenvironment. The immune system’s response to cancer can impact the glioma’s survival, proliferation, and invasiveness. Salient characteristics of gliomas include enhanced vascularization, stimulation of a hypoxic tumor microenvironment, increased oxidative stress, and an immune suppressive milieu. These processes promote the neuro-inflammatory tumor microenvironment which can lead to the loss of blood-brain barrier (BBB) integrity. The consequences of a compromised BBB are deleteriously exposing the brain to potentially harmful concentrations of substances from the peripheral circulation, adversely affecting neuronal signaling, and abnormal immune cell infiltration; all of which can lead to disruption of brain homeostasis. In this review, we first describe the unique features of inflammation in CNS tumors. We then discuss the mechanisms of tumor-initiating neuro-inflammatory microenvironment and its impact on tumor invasion and progression. Finally, we also discuss potential pharmacological interventions that can be used to target neuroinflammation in gliomas.
... [9][10][11] These 'shared' proteins (eg, ephrin A2 (EphA2), interleukin 13 receptor alpha 2, survivin (BIRC5), and epidermal growth factor receptor variant 3) are often expressed in non-malignant tissue during periods of high mitotic activity (eg, embryogenesis) or in immune-privileged sites but can also be aberrantly expressed in tumors (overexpression and different subcellular localization), where they provide a survival or growth advantage for malignant cells. [12][13][14][15] They are difficult to generate immune activity because the immune system recognizes these antigens as self-proteins, and high-affinity T cells are eliminated by clonal deletion as part of central tolerance. 16 EphA2 is one such shared antigen that belongs to the Eph subfamily of receptor tyrosine kinases. ...
Background
Oncolytic virotherapy (OV) is an immunotherapy that incorporates viral cancer cell lysis with engagement of the recruited immune response against cancer cells. Pediatric solid tumors are challenging targets because they contain both an inert immune environment and a quiet antigenic landscape, making them more resistant to conventional OV approaches. Further complicating this, herpes simplex virus suppresses host gene expression during virotherapy infection.
Methods
We therefore developed a multimodal oncolytic herpes simplex virus (oHSV) that expresses ephrin A2 (EphA2), a shared tumor-associated antigen (TAA) expressed by many tumors to improve immune-mediated antitumor activity. We verified the virus genotypically and phenotypically and then tested it in an oHSV-resistant orthotopic model (including immunophenotypic analysis), in flank and in T cell-deficient mouse models. We then assessed the antigen-expressing virus in an unrelated peripheral tumor model that also expresses the shared tumor antigen and evaluated functional T-cell response from the treated mice.
Results
Virus-based EphA2 expression induces a robust acquired antitumor immune responses in both an oHSV-resistant murine brain and peripheral tumor model. Our new multimodal oncolytic virus (1) improves survival in viroimmunotherapy resistant tumors, (2) alters both the infiltrating and peripheral T-cell populations capable of suppressing tumor growth on rechallenge, and (3) produces EphA2-specific CD8 effector-like populations.
Conclusions
Our results suggest that this flexible viral-based platform enables immune recognition of the shared TAA and improves the immune-therapeutic response, thus making it well suited for low-mutational load tumors.
... 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]. ...
... Expressed in GBM cells associated with blood vessels Regulate VEGFR2 expression Promote sprouting angiogenesis Inhibition of EphA2 and VEGFR2 abolished microvessel growth [72] Upon physiological angiogenic stimulation, ECs and pericytes dynamically remodel, with striking changes in their cellular interactions, based on active proteolytic degradation of the basement membrane and weakening of endothelial junctions (VE-cadherin, occludin). ECs might ultimately specialize in either tip or stalk cells, involving a finely-tuned choreography of DLL-4 (Delta-like 4)/NOTCH and VEGF/VEFGR2 signaling [73]. ...
Glioblastoma, a subset of aggressive brain tumors, deploy several means to increase blood vessel supply dedicated to the tumor mass. This includes typical program borrowed from embryonic development, such as vasculogenesis and sprouting angiogenesis, as well as unconventional processes, including co-option, vascular mimicry, and transdifferentiation, in which tumor cells are pro-actively engaged. However, these neo-generated vascular networks are morphologically and functionally abnormal, suggesting that the vascularization processes are rather inefficient in the tumor ecosystem. In this review, we reiterate the specificities of each neovascularization modality in glioblastoma, and, how they can be hampered mechanistically in the perspective of anti-cancer therapies.
... 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. ...
Glioblastoma multiforme (GBM) is the most common and aggressive malignant primary brain tumor in adults. Current treatment options typically consist of surgery followed by chemotherapy or more frequently radiotherapy, however, median patient survival remains at just over 1 year. Therefore, the need for novel curative therapies for GBM is vital. Characterization of GBM cells has contributed to identify several molecules as targets for immunotherapy-based treatments such as EGFR/EGFRvIII, IL13Rα2, B7-H3, and CSPG4. Cytotoxic T lymphocytes collected from a patient can be genetically modified to express a chimeric antigen receptor (CAR) specific for an identified tumor antigen (TA). These CAR T cells can then be re-administered to the patient to identify and eliminate cancer cells. The impressive clinical responses to TA-specific CAR T cell-based therapies in patients with hematological malignancies have generated a lot of interest in the application of this strategy with solid tumors including GBM. Several clinical trials are evaluating TA-specific CAR T cells to treat GBM. Unfortunately, the efficacy of CAR T cells against solid tumors has been limited due to several factors. These include the immunosuppressive tumor microenvironment, inadequate trafficking and infiltration of CAR T cells and their lack of persistence and activity. In particular, GBM has specific limitations to overcome including acquired resistance to therapy, limited diffusion across the blood brain barrier and risks of central nervous system toxicity. Here we review current CAR T cell-based approaches for the treatment of GBM and summarize the mechanisms being explored in pre-clinical, as well as clinical studies to improve their anti-tumor activity.
... 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. ...
... 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]. ...
... 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. ...
Glioblastoma (GBM) is the most aggressive tumor type whose resistance to conventional treatment is mediated, in part, by the angiogenic process. New treatments involving the application of nanoformulations composed of encapsulated drugs coupled to peptide motifs that direct drugs to specific targets triggered in angiogenesis have been developed to reach and modulate different phases of this process. We performed a systematic review with the search criterion (Glioblastoma OR Glioma) AND (Therapy OR Therapeutic) AND (Nanoparticle) AND (Antiangiogenic OR Angiogenesis OR Anti-angiogenic) in Pubmed, Scopus, and Cochrane databases, in which 312 articles were identified; of these, only 27 articles were included after selection and analysis of eligibility according to the inclusion and exclusion criteria. The data of the articles were analyzed in five contexts: the characteristics of the tumor cells; the animal models used to induce GBM for antiangiogenic treatment; the composition of nanoformulations and their physical and chemical characteristics; the therapeutic anti-angiogenic process; and methods for assessing the effects on antiangiogenic markers caused by therapies. The articles included in the review were heterogeneous and varied in practically all aspects related to nanoformulations and models. However, there was slight variance in the antiangiogenic effect analysis. CD31 was extensively used as a marker, which does not provide a view of the effects on the most diverse aspects involved in angiogenesis. Therefore, the present review highlighted the need for standardization between the different approaches of antiangiogenic therapy for the GBM model that allows a more effective meta-analysis and that helps in future translational studies.
... We chose to study this interaction, as VEGFR2 is sometimes expressed in the same cells as EGFR and EPHA2 (55)(56)(57). Moreover, EPHA2 is also involved in angiogenesis, and its activity is at least partly dependent on VEGFR2 (68)(69)(70). ...
Receptor tyrosine kinases (RTKs) are single-pass membrane proteins that control vital cell processes such as cell growth, survival, and differentiation. There is a growing body of evidence that RTKs from different subfamilies can interact and that these diverse interactions can have important biological consequences. However, these heterointeractions are often ignored, and their strengths are unknown. In this work, we studied the heterointeractions of nine RTK pairs, epidermal growth factor receptor (EGFR)- EPH receptor A2 (EPHA2), EGFR-vascular endothelial growth factor receptor 2 (VEGFR2), EPHA2-VEGFR2, EPHA2-fibroblast growth factor receptor 1 (FGFR1), EPHA2-FGFR2, EPHA2-FGFR3, VEGFR2-FGFR1, VEGFR2-FGFR2, and VEGFR2-FGFR3, using a FRET-based method. Surprisingly, we found that RTK heterodimerization and homodimerization strengths can be similar, underscoring the significance of RTK heterointeractions in signaling. We discuss how these heterointeractions can contribute to the complexity of RTK signal transduction, and we highlight the utility of quantitative FRET for probing multiple interactions in the plasma membrane.
