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Pancreatic ductal adenocarcinoma (PDAC) is a major concern for health care systems worldwide, since its mortality remains unaltered despite the surge in cutting-edge science. The EPH/ephrin signaling system was first investigated in the 1980s. EPH/ephrins have been shown to exert bidirectional signaling and cell-to-cell communication, influencing cellular morphology, adhesion, migration and invasion. Recent studies have highlighted the critical role of the EPH/ephrin system in various physiologic processes, including cellular proliferation, survival, synaptic plasticity and angiogenesis. Thus, it has become evident that the EPH/ephrin signaling system may have compelling effects on cell homeostasis that contribute to carcinogenesis. In particular, the EPH/ephrins have an impact on pancreatic morphogenesis and development, whereas several EPHs and ephrins are altered in PDAC. Several clinical and preclinical studies have attempted to elucidate the effects of the EPH/ephrin pathway, with multilayered effects on PDAC development. These studies have highlighted its highly promising role in the diagnosis, prognosis and therapeutic management of PDAC. The aim of this review is to explore the obscure aspects of the EPH/ephrin system concerning the development, physiology and homeostasis of the pancreas.

Breast cancer (BC) is the most common malignant tumor in women. Erythropoietin-producing hepatocellular receptors (EPHs), receptor tyrosine kinases binding the membrane-bound proteins ephrins, are differentially expressed in BC, and correlate with carcinogenesis and tumor progression. With a view to examining available therapeutics targeting the EPH/ephrin system in BC, a literature review was conducted, using the MEDLINE, LIVIVO, and Google Scholar databases. EPHA2 is the most studied EPH/ephrin target in BC treatment. The targeting of EPHA2, EPHA10, EPHB4, ephrin-A2, ephrin-A4, as well as ephrin-B2 in BC cells or xenograft models is associated with apoptosis induction, tumor regression, anticancer immune response activation, and impaired cell motility. In conclusion, EPHs/ephrins seem to represent promising future treatment targets in BC.

During orthodontic tooth movement, mechanically induced remodeling occurs in the alveolar bone due to the action of orthodontic forces. The number of factors identified to be involved in mechanically induced bone remodeling is growing steadily. With the uncovering of the functions of neuronal guidance molecules (NGMs) for skeletal development as well as for bone homeostasis, NGMs are now also among the potentially significant factors for the regulation of bone remodeling during orthodontic tooth movement. This narrative review attempts to summarize the functions of NGMs in bone homeostasis and provides insight into the currently sparse literature on the functions of these molecules during orthodontic tooth movement. Presently, four families of NGMs are known: Netrins, Slits, Semaphorins, ephrins and Eph receptors. A search of electronic databases revealed roles in bone homeostasis for representatives from all four NGM families. Functions during orthodontic tooth movement, however, were only identified for Semaphorins, ephrins and Eph receptors. For these, crucial prerequisites for participation in the regulation of orthodontically induced bone remodeling, such as expression in cells of the periodontal ligament and in the alveolar bone, as well as mechanical inducibility, were shown, which suggests that the importance of NGMs in orthodontic tooth movement may be underappreciated to date and further research might be warranted.

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.

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.

Gynecological cancers represent some of the most common types of malignancy worldwide. Erythropoietin-producing hepatocellular receptors (EPHs) comprise the largest subfamily of receptor tyrosine kinases, binding membrane-bound proteins called ephrins. EPHs/ephrins exhibit widespread expression in different cell types, playing an important role in carcinogenesis. The aim of the current review was to examine the dysregulation of the EPH/ephrin system in gynecological cancer, clarifying its role in ovarian, endometrial, and cervical carcinogenesis. In order to identify relevant studies, a literature review was conducted using the MEDLINE and LIVIVO databases. The search terms ephrin , ephrin receptor , ovarian cancer , endometrial cancer , and cervical cancer were employed and we were able to identify 57 studies focused on gynecological cancer and published between 2001 and 2021. All researched ephrins seemed to be upregulated in gynecological cancer, whereas EPHs showed either significant overexpression or extensive loss of expression in gynecological tumors, depending on the particular receptor. EPHA2, the most extensively studied EPH in ovarian cancer, exhibited overexpression both in ovarian carcinoma cell lines and patient tissue samples, while EPHB4 was found to be upregulated in endometrial cancer in a series of studies. EPHs/ephrins were shown to exert their role in different stages of gynecological cancer and to influence various clinicopathological parameters. The analysis of patients' gynecological cancer tissue samples, most importantly, revealed the significant role of the EPH/ephrin system in the development and progression of gynecological cancer, as well as overall patient survival. In conclusion, the EPH/ephrin system represents a large family of biomolecules with promising applications in the fields of diagnosis, prognosis, disease monitoring, and treatment of gynecological cancer, with an established important clinical impact.

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.

Eph receptors are the largest family of receptor tyrosine kinases and by interactions with ephrin ligands mediate a myriad of processes from embryonic development to adult tissue homeostasis. The interaction of Eph receptors, especially at their transmembrane (TM) domains is key to understanding their mechanism of signal transduction across cellular membranes. We review the structural and functional aspects of EphA1/A2 association and the techniques used to investigate their TM domains: NMR, molecular modelling/dynamics simulations and fluorescence. We also introduce transmembrane peptides, which can be used to alter Eph receptor signaling and we provide a perspective for future studies.

Retinal diseases are the leading cause of irreversible blindness. They affect people of all ages, from newborns in retinopathy of prematurity, through age-independent diabetic retinopathy and complications of retinal detachment, to age-related macular degeneration (AMD), which occurs mainly in the elderly. Generally speaking, the causes of all problems are disturbances in blood supply, hypoxia, the formation of abnormal blood vessels, and fibrosis. Although the detailed mechanisms underlying them are varied, the common point is the involvement of Eph receptors and ephrins in their pathogenesis. In our study, we briefly discussed the pathophysiology of the most common retinal diseases (diabetic retinopathy, retinopathy of prematurity, proliferative vitreoretinopathy, and choroidal neovascularization) and collected available research results on the role of Eph and ephrins. We also discussed the safety aspect of the use of drugs acting on Eph and ephrin for ophthalmic indications.

Eph receptors and their ephrin ligands are important guidance molecules during neurological and vascular development. In recent years, it has become clear that the Eph protein family remains functional in adult physiology. A subset of Ephs and ephrins is highly expressed by endothelial cells. As endothelial cells form the first barrier between the blood and surrounding tissues, maintenance of a healthy endothelium is crucial for tissue homeostasis. This review gives an overview of the current insights of the role of ephrin ligands and receptors in endothelial function and leukocyte recruitment in the (patho)physiology of adult vascular biology.