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Ephrin Receptors and Cancer
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Ephrin Receptors and Cancer

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: closed (30 April 2022) | Viewed by 17905

Special Issue Editor

Prof. Dr. Stamatios E. Theocharis

E-Mail Website
Guest Editor
First Department of Pathology, Medical School, National and Kapodistrian University of Athens, Goudi, Athens, Greece
Interests: apoptosis; metabolism; cytopathology; pathology; molecular pathology; immunohistochemistry
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

The family of receptor tyrosine kinases (RTKs), ephrin receptors (EPHs), comprises 14 cell-bound members divided into two classes, A and B, based on their sequence similarity and binding affinity to their ligands, ephrins. In a similar manner, ephrins are also cell-bound proteins and include ephrin-A and ephrin-B classes. Nine class A EPHs (EPHA1-EPHA8, EPHA10) and five class B EPHs (EPHB1-EPHB4, EPHB6) preferentially bind five ephrin-A and three ephrin-B classes. The EPH/ephrin system is involved into key regulatory processes of human physiology: it highlights axon guidance and synaptic plasticity in the nervous system, as well as angiogenesis, vascular remodeling, and homeostasis of various tissues. In addition, this cell–cell communication system is implicated in several pathologic processes, including neurodegenerative disorders, viral infections, and cancer. Indeed, its deregulation affects tumor growth, progression, metastasis, and neovascularization by disrupting critical signaling transduction pathways. EPHs’ and ephrins’ aberrant expression characterizes not only the tumor cells but also the tumor microenvironment, where endothelial cells have mostly been investigated; this makes the EPH/ephrin system an appealing candidate for targeted intervention. EPHs’ upregulation in the pathogenesis of malignant transformation has been reported, suggesting their use as potential biomarkers and drug targets for various cancer types.

Prof. Stamatios E. Theocharis
Guest Editor

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Keywords

  • ephrin receptors
  • ephrins
  • cancer
  • pathogenesis
  • biomarkers
  • treatment

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Published Papers (5 papers)

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Review

19 pages, 1549 KiB  
Review
The EPH/Ephrin System in Bone and Soft Tissue Sarcomas’ Pathogenesis and Therapy: New Advancements and a Literature Review
by Argyris C. Hadjimichael, Alexandros Pergaris, Angelos Kaspiris, Athanasios F. Foukas, Stefania Kokkali, Gerasimos Tsourouflis and Stamatios Theocharis
Int. J. Mol. Sci. 2022, 23(9), 5171; https://doi.org/10.3390/ijms23095171 - 5 May 2022
Cited by 10 | Viewed by 2269
Abstract
Musculoskeletal sarcomas represent rare heterogenous malignancies of mesenchymal origin that can be divided in two distinct subtypes, bone and soft tissue sarcomas. Current treatment options combine the surgical excision of local tumors and multidrug chemotherapy to prevent metastatic widespread disease. Due to the [...] Read more.
Musculoskeletal sarcomas represent rare heterogenous malignancies of mesenchymal origin that can be divided in two distinct subtypes, bone and soft tissue sarcomas. Current treatment options combine the surgical excision of local tumors and multidrug chemotherapy to prevent metastatic widespread disease. Due to the grim prognosis that usually accompanies such tumors, researchers have attempted to shed light on the molecular pathways implicated in their pathogenesis in order to develop novel, innovative, personalized therapeutic strategies. Erythropoietin-producing human hepatocellular receptors (EPHs) are tyrosine-kinase transmembrane receptors that, along with their ligands, ephrins, participate in both tumor-suppressive or tumor-promoting signaling pathways in bone and soft tissue sarcomas. The EPH/ephrin axis orchestrates cancerous processes such as cell–cell and cell–substrate adhesion and enhances the remodeling of the intracellular cytoskeleton to stimulate the motility and invasiveness of sarcoma cells. The purpose of our study was to review published PubMed literature to extract results from in vitro, in vivo and clinical trials indicative of the role of EPH/ephrin signaling in bone and soft tissue sarcomas. Based on these reports, significant interactions between the EPH/ephrin signaling pathway and a plethora of normal and abnormal cascades contribute to molecular mechanisms enhancing malignancy during sarcoma progression. In addition, EPHs and ephrins are prospective candidates for diagnostic, monitoring and therapeutic purposes in the clinical setting against bone and soft tissue sarcomas. Full article
(This article belongs to the Special Issue Ephrin Receptors and Cancer)
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13 pages, 1035 KiB  
Review
Utilizing Exosomal-EPHs/Ephrins as Biomarkers and as a Potential Platform for Targeted Delivery of Therapeutic Exosomes
by Dimitrios Goutas, Alexandros Pergaris, Nikolaos Goutas and Stamatios Theocharis
Int. J. Mol. Sci. 2022, 23(7), 3551; https://doi.org/10.3390/ijms23073551 - 24 Mar 2022
Cited by 11 | Viewed by 2735
Abstract
Exosomes are cell-secreted nanoparticles containing various molecules including small vesicles, microRNAs (miRNAs), messenger RNAs or bioactive proteins which are thought to be of paramount importance for intercellular communication. The unique effects of exosomes in terms of cell penetration capacity, decreased immunogenicity and inherent [...] Read more.
Exosomes are cell-secreted nanoparticles containing various molecules including small vesicles, microRNAs (miRNAs), messenger RNAs or bioactive proteins which are thought to be of paramount importance for intercellular communication. The unique effects of exosomes in terms of cell penetration capacity, decreased immunogenicity and inherent stability, along with their key role in mediating information exchange among tumor cells and their surrounding tumor microenvironment (TME), render them a promising platform for drug targeted delivery. Compared to synthetic drugs, exosomes boast a plethora of advantages, including higher biocompatibility, lower toxicity and increased ability of tissue infiltration. Nevertheless, the use of artificial exosomes can be limited in practice, partly due to their poor targeting ability and partly due to their limited efficacy. Therefore, efforts have been made to engineer stem cell-derived exosomes in order to increase selectiveness and effectivity, which can then become loaded with various active substances depending on the therapeutic approach followed. Erythropoietin-producing human hepatocellular receptors (EPHs), along with their ligands, the EPH family receptor interacting proteins (ephrins), have been extensively investigated for their key roles in both physiology and cancer pathogenesis. EPHs/ephrins exhibit both tumorigenic and tumor suppressing properties, with their targeting representing a promising, novel therapeutic approach in cancer patients’ management. In our review, the use of ephrin-loaded exosomes as a potential therapeutic targeted delivery system in cancer will be discussed. Full article
(This article belongs to the Special Issue Ephrin Receptors and Cancer)
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16 pages, 1858 KiB  
Review
The EPH/Ephrin System in Colorectal Cancer
by Stavros P. Papadakos, Leonidas Petrogiannopoulos, Alexandros Pergaris and Stamatios Theocharis
Int. J. Mol. Sci. 2022, 23(5), 2761; https://doi.org/10.3390/ijms23052761 - 2 Mar 2022
Cited by 15 | Viewed by 4257
Abstract
The EPH/ephrin system constitutes a bidirectional signaling pathway comprised of a family of tyrosine kinase receptors in tandem with their plasma membrane-bound ligand (ephrins). Its significance in a wide variety of physiologic and pathologic processes has been recognized during the past decades. In [...] Read more.
The EPH/ephrin system constitutes a bidirectional signaling pathway comprised of a family of tyrosine kinase receptors in tandem with their plasma membrane-bound ligand (ephrins). Its significance in a wide variety of physiologic and pathologic processes has been recognized during the past decades. In carcinogenesis, EPH/ephrins coordinate a wide spectrum of pathologic processes, such as angiogenesis, vessel infiltration, and metastasis. Despite the recent advances in colorectal cancer (CRC) diagnosis and treatment, it remains a leading cause of death globally, accounting for 9.2% of all cancer deaths. A growing body of literature has been published lately revitalizing our scientific interest towards the role of EPH/ephrins in pathogenesis and the treatment of CRC. The aim of the present review is to present the recent CRC data which might lead to clinical practice changes in the future. Full article
(This article belongs to the Special Issue Ephrin Receptors and Cancer)
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17 pages, 2939 KiB  
Review
EphrinB2–EphB4 Signaling in Neurooncological Disease
by Andras Piffko, Christian Uhl, Peter Vajkoczy, Marcus Czabanka and Thomas Broggini
Int. J. Mol. Sci. 2022, 23(3), 1679; https://doi.org/10.3390/ijms23031679 - 31 Jan 2022
Cited by 9 | Viewed by 4223
Abstract
EphrinB2–EphB4 signaling is critical during embryogenesis for cardiovascular formation and neuronal guidance. Intriguingly, critical expression patterns have been discovered in cancer pathologies over the last two decades. Multiple connections to tumor migration, growth, angiogenesis, apoptosis, and metastasis have been identified in vitro and [...] Read more.
EphrinB2–EphB4 signaling is critical during embryogenesis for cardiovascular formation and neuronal guidance. Intriguingly, critical expression patterns have been discovered in cancer pathologies over the last two decades. Multiple connections to tumor migration, growth, angiogenesis, apoptosis, and metastasis have been identified in vitro and in vivo. However, the molecular signaling pathways are manifold and signaling of the EphB4 receptor or the ephrinB2 ligand is cancer type specific. Here we explore the impact of these signaling pathways in neurooncological disease, including glioma, brain metastasis, and spinal bone metastasis. We identify potential downstream pathways that mediate cancer suppression or progression and seek to understand it´s role in antiangiogenic therapy resistance in glioma. Despite the Janus-faced functions of ephrinB2–EphB4 signaling in cancer Eph signaling remains a promising clinical target. Full article
(This article belongs to the Special Issue Ephrin Receptors and Cancer)
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38 pages, 2329 KiB  
Review
The Clinical Impact of the EPH/Ephrin System in Cancer: Unwinding the Thread
by Alexandros Pergaris, Eugene Danas, Dimitrios Goutas, Alexandros G. Sykaras, Angelos Soranidis and Stamatios Theocharis
Int. J. Mol. Sci. 2021, 22(16), 8412; https://doi.org/10.3390/ijms22168412 - 5 Aug 2021
Cited by 34 | Viewed by 3037
Abstract
Erythropoietin-producing human hepatocellular receptors (EPHs) compose the largest known subfamily of receptor tyrosine kinases (RTKs). They bind and interact with the EPH family receptor interacting proteins (ephrins). EPHs/ephrins are implicated in a variety of physiological processes, as well as in cancer pathogenesis. With [...] Read more.
Erythropoietin-producing human hepatocellular receptors (EPHs) compose the largest known subfamily of receptor tyrosine kinases (RTKs). They bind and interact with the EPH family receptor interacting proteins (ephrins). EPHs/ephrins are implicated in a variety of physiological processes, as well as in cancer pathogenesis. With neoplastic disease remaining a leading cause of death world-wide, the development of novel biomarkers aiding in the field of diagnosis, prognosis, and disease monitoring is of utmost importance. A multitude of studies have proven the association between the expression of members of the EPH/ephrin system and various clinicopathological parameters, including disease stage, tumor histologic grade, and patients’ overall survival. Besides their utilization in timely disease detection and assessment of outcome, EPHs/ephrins could also represent possible novel therapeutic targets. The aim of the current review of the literature was to present the existing data regarding the association between EPH/ephrin system expression and the clinical characteristics of malignant tumors. Full article
(This article belongs to the Special Issue Ephrin Receptors and Cancer)
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