The EPH/Ephrin System in Gynecological Cancers: Focusing on the Roots of Carcinogenesis for Better Patient Management

Abstract

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.

Keywords: EPHs; cervical cancer; endometrial cancer; ephrins; ovarian cancer.

Figure 1

Structure of the erythropoietin-producing hepatocellular receptor (EPH)/ephrin molecules. Ephrin-A ligands are anchored to the plasma membrane by a glycosylphosphatidylinositol anchor, whereas ephrin-B ligands contain a transmembrane domain and a short cytoplasmatic tail. EPHs/ephrins, upon activation, exert their physiological as well as their tumor-promoting and tumor-suppressive functions through complex molecular pathways inside the cytoplasm. Forward signaling is conducted through EPH’s interaction with a number of different biomolecules and pathways, such as GTPases of the Rho and Ras family, focal adhesion kinase (FAK), and the pathways of the Janus kinase (JAK)-signal transducer and activator of transcription (STAT), as well as the phosphoinositide 3-kinase (PI3K). In backward signaling, upon the phosphorylation of ephrins, different proteins that contain Src Homology 2 (SH2) or PDZ domain, such as Grb4, interact with the ephrin and transmit the signal downstream [14]. Created with BioRender.com.

Figure 2

Key roles of the EPH/ephrin system in OC pathogenesis. Green font: EPHs/ephrins that promote each described process. Blue font: EPHs/ephrins that inhibit the specific action. Created with BioRender.com.

Figure 3

Members of the EPH/ephrin system promote various steps of EC tumorigenesis. Created with BioRender.com.