The EphA2 and cancer connection: potential for immune-based interventions

London, Max; Gallo, Eugenio

doi:10.1007/s11033-020-05767-y

Cited by 11 publications

(18 citation statements)

References 98 publications

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“…Lack of chemerin also leads to the reduction of pro-inflammatory cytokines, like TNFα, in the serum suggesting a feedback loop between the two ( 179 ). Another component that modulates TNFα-induced remodeling is the erythropoietin-producing human hepatocellular receptor (EphA), which is a receptor tyrosine kinase that mediates cell-adhesion and leukocyte homing in atherosclerosis by promoting ICAM1 and VCAM1 expression on ECs ( 181 ). EphA2-deficient Apoe −/− mice which were fed a WD for 12 weeks developed smaller innominate artery and carotid sinus plaque size compared to Apoe −/− control animals ( 182 ).…”

Section: Cytokinesmentioning

confidence: 99%

Inflammatory Mediators in Atherosclerotic Vascular Remodeling

Evans

Yerly

Vorst

et al. 2022

Front. Cardiovasc. Med.

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Atherosclerotic vascular disease remains the most common cause of ischemia, myocardial infarction, and stroke. Vascular function is determined by structural and functional properties of the arterial vessel wall, which consists of three layers, namely the adventitia, media, and intima. Key cells in shaping the vascular wall architecture and warranting proper vessel function are vascular smooth muscle cells in the arterial media and endothelial cells lining the intima. Pathological alterations of this vessel wall architecture called vascular remodeling can lead to insufficient vascular function and subsequent ischemia and organ damage. One major pathomechanism driving this detrimental vascular remodeling is atherosclerosis, which is initiated by endothelial dysfunction allowing the accumulation of intimal lipids and leukocytes. Inflammatory mediators such as cytokines, chemokines, and modified lipids further drive vascular remodeling ultimately leading to thrombus formation and/or vessel occlusion which can cause major cardiovascular events. Although it is clear that vascular wall remodeling is an elementary mechanism of atherosclerotic vascular disease, the diverse underlying pathomechanisms and its consequences are still insufficiently understood.

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Section: Cytokinesmentioning

confidence: 99%

Inflammatory Mediators in Atherosclerotic Vascular Remodeling

Evans

Yerly

Vorst

et al. 2022

Front. Cardiovasc. Med.

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“…Recent studies have shown that EphA2 can promote the growth and invasion of a variety of cancer cells. 28–30 This membrane protein has a similar expression level in pure exosomes and serum. We have previously shown the diagnostic value of Exo-EphA2 combined with CA 19–9 and CA 242 in PC, but to the best of our knowledge, the effect of Exo-EphA2 on the prognosis of PC remains unclear.…”

Section: Discussionmentioning

confidence: 96%

Serum Exosomal EphA2 is a Prognostic Biomarker in Patients with Pancreatic Cancer

Qian¹,

Li²,

Feng³

et al. 2021

CMAR

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Background Pancreatic cancer (PC) is one of the worst prognoses amongst all malignant diseases. It is therefore of great significance to identify biomarkers with predictive clinical value for the prognosis and recurrence of PC. Methods In our study, enzyme-linked immunosorbent assays (ELISA) were used to detect the expression of Exo-EphA2 in the serum of PC patients and controls. Kaplan–Meier curve and Cox regression analyses were used to evaluate the prognostic value of Exo-EphA2 expression in patients with primary and recurrent PC. Results The level of serum Exo-EphA2 was significantly higher in the PC group when compared to that of the control group. High expression of Exo-EphA2 in PC was associated with shorter overall survival (OS) and proved to be a significant negative prognostic factor in the multivariate analysis (HR = 1.04, 95% CI: 1.00–1.09, P <0.001). Additionally, we found that the level of serum Exo-EphA2 in recurrent PC patients (first recurrence < 12 months) was positively correlated with the level of Exo-EphA2 at primary diagnosis. Multivariate analysis showed that a high expression of Exo-EphA2 in recurrent PC was associated with shorter recurrence-free survival (RFS) (HR = 1.41, 95% CI: 1.10–1.70, P < 0.001). Conclusion High expression of serum Exo-EphA2 represents a novel biomarker for a poor prognosis in PC patients.

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“…The upregulation of EPHA2 is associated with poor prognosis, increased metastatic potential and reduced survival in breast cancer patients 23 - 26 . High expression of EPHA2 is an indicator of high tumor cell aggressiveness.…”

Section: Introductionmentioning

confidence: 99%

Exosomal EPHA2 derived from highly metastatic breast cancer cells promotes angiogenesis by activating the AMPK signaling pathway through Ephrin A1-EPHA2 forward signaling

Han¹,

Zhang²,

Tian³

et al. 2022

Theranostics

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Rationale: Angiogenesis is a fundamental process of tumorigenesis, growth, invasion and metastatic spread. Extracellular vesicles, especially exosomes, released by primary tumors promote angiogenesis and cancer progression. However, the mechanism underlying the pro-angiogenic potency of cancer cell-derived exosomes remains poorly understood. Methods: Exosomes were isolated from breast cancer cells with high metastatic potential (HM) and low metastatic potential (LM). The pro-angiogenic effects of these exosomes were evaluated by in vitro tube formation assays, wound healing assays, rat arterial ring budding assays and in vivo Matrigel plug assays. Subsequently, RNA sequencing, shRNA-mediated gene knockdown, overexpression of different EPHA2 mutants, and small-molecule inhibitors were used to analyze the angiogenesis-promoting effect of exosomal EPHA2 and its potential downstream mechanism. Finally, xenograft tumor models were established using tumor cells expressing different levels of EPHA2 to mimic the secretion of exosomes by tumor cells in vivo, and the metastasis of cancer cells were monitored using the IVIS Spectrum imaging system and Computed Tomography. Results: Herein, we demonstrated that exosomes produced by HM breast cancer cells can promote angiogenesis and metastasis. EPHA2 was rich in HM-derived exosomes and conferred the pro-angiogenic effect. Exosomal EPHA2 can be transferred from HM breast cancer cells to endothelial cells. Moreover, it can stimulate the migration and tube-forming abilities of endothelial cells in vitro and promote angiogenesis and tumor metastasis in vivo. Mechanistically, exosomal EPHA2 activates the AMPK signaling via the ligand Ephrin A1-dependent canonical forward signaling pathway. Moreover, inhibition of the AMPK signaling impairs exosomal EPHA2-mediated pro-angiogenic effects. Conclusion: Our findings identify a novel mechanism of exosomal EPHA2-mediated intercellular communication from breast cancer cells to endothelial cells in the tumor microenvironment to provoke angiogenesis and metastasis. Targeting the exosomal EPHA2-AMPK signaling may serve as a potential strategy for breast cancer therapy.

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The EphA2 and cancer connection: potential for immune-based interventions

Cited by 11 publications

References 98 publications

Inflammatory Mediators in Atherosclerotic Vascular Remodeling

Inflammatory Mediators in Atherosclerotic Vascular Remodeling

Serum Exosomal EphA2 is a Prognostic Biomarker in Patients with Pancreatic Cancer

Exosomal EPHA2 derived from highly metastatic breast cancer cells promotes angiogenesis by activating the AMPK signaling pathway through Ephrin A1-EPHA2 forward signaling

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