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  • br EphB as a therapeutic target in cancer Eph receptors

    2020-10-29


    EphB4 as a therapeutic target in cancer Eph receptors and ephrins are promising new therapeutic targets in cancer. Various strategies have been employed to evaluate the interference of tumor-promoting effects or the enhancement of tumor suppressive effects. The inhibition of the Eph-ephrin system may be particularly useful for anti-angiogenic therapies. The EphB4/ephrinB2 bidirectional signaling has an established role in the formation of the vascular system, as evidenced by embryonic lethality in knockout mouse studies, which arise due to malformed vascular architecture [71].
    Tumor inhibitors targeting EphB4 EphB4 inhibitors have been studied over the past several years, with many different approaches used to test for inhibition of activity or competitive binding affinity as a novel therapeutic modality to treat malignancy. Several potent Eph kinase inhibitors were reported either based on high molecular weight compounds like death associated protein kinase [23], [93], [94], [95], which block the extracellular domain of the appropriate receptor, or on small organic molecules, which bind to the intramolecular ATP- binding pocket and inhibit EphB4 kinase activity [95].
    Conclusions and perspective For each type of target, there are some challenges: (1) the targets of protein- protein interactions at the surface of the EphB4- ephrinB2 complex are typically hard to perceive and difficult to inhibit using small molecules; (2) small molecule compounds targeting the ATP- binding site could block the activity of other kinases, and therefore, their selectivity tends to be low; (3) some Eph kinase inhibitors with anti-angiogenic activity might also block potential EphB4 tumor suppressive activities. Thus, despite the challenges presented by the complex biology of the Eph receptor/ephrin system, exciting possibilities exist for therapies exploiting these molecules. Multiple factors should be taken into consideration such as tumor type, stage, and tumor microenvironment. The optimizing strategies will require more details understanding of the signaling mechanisms via EphB4 in different tumor cells. Thus, a more in depth understanding of the structure, biogenesis, and mechanisms of EphB4 will provide invaluable information for functional studies and an increase in the efficiency of rational drug design.
    Conflict of interest
    Acknowledgements
    Introduction Preeclampsia is a specific hypertensive disorder that occurs during the second half of pregnancy and one of the leading causes of worldwide maternal-fetal morbidity and mortality [1], [2]. It is well known that preeclampsia is often associated with superficial trophoblast invasion, insufficient spiral artery remodeling and subsequent placental hypoxia, as well as ischemia/reperfusion injury [3], [4], [5]. Thus, researches on the mechanism of trophoblast invasion are of great value for early diagnosis and intervention of pregnant complications. Ephrins and their receptors (Ephs), identified in the late 1980s, are known as the largest family of receptor tyrosine kinases [6]. In mammals, the ephrins/Ephs system is composed of eight ephrin ligands (EFNA1-5, EFNB1-3) and fourteen Eph receptors (EPHA1–8, EPHA10, EPHB1–4, EPHB6) [7], [8]. Recent researches have demonstrated ephrins/Ephs signal pathway is essential during placentation [9]. Among them, EFNB2/EPHB4 at maternal-fetal interface has been identified to play a critical role in directing trophoblast invasion [10]. In our previous study, we have confirmed EPHB4 downregulated HTR8/SVneo functions in the pathogenesis of preeclampsia [11]. However, the regulatory mechanism for EPHB4 expression in trophoblast cells still remains to be elucidated. Homeobox morphoregulatory genes, first identified in Drosophila, encode for transcription factors-transcripamino acid DNA-binding motif and are mostly arranged in four parologous clusters (A, B, C, and D) [12]. Homeobox genes regulate organogenesis [13], vessel remodeling as it occurs during angiogenesis and atherosclerosis [14], as well as the development of the cardiovascular system during embryogenesis [15]. The special pattern of homeobox genes in vascular development implicated their essential roles in placentation. For example, previous studies have identified the role of HOXA11, HOXB6 and HOXC6 in the trophoblast differentiation process [16], [17]. In this study, through mining of public databases, we focused on HOXA9 gene. The HOXA9 gene exhibits three exons resulting in the production of two kinds of proteins. One HOXA9 protein (HA-9A) is uniquely expressed in fetal development and a distinct HOXA9 isoform (HA-9B) is expressed in various tissues of the fetal and adult organism [18]. Both proteins share a common exon encoding the homeodomain. Mouse bone marrow cells with HOXA9 overexpression induced stem cell expansion, invariably progressing to acute myeloid leukemia within 3–10 months [19]. Knockdown of HoxA9 in bone marrow cells induces an elevated apoptosis of primitive thymocytes and defects in erythroid, myeloid, and lymphoid hematopoiesis, contributing to a disorder of early T-cell development in mice [20]. Since HOXA9 plays an important role in controlling cancer cell biological behavior [21], we are convinced that it may work in modulating trophoblast functions, which share many striking similarities with the characteristics of malignant cells. Moreover, the regulation of HOXA9 on EPHB4 was demonstrated in endothelial cells [22]. Therefore, we sought to determine whether HOXA9 and EPHB4 have cooperating roles in regulating the trophoblast migration and invasion, which might involve in the pathogenesis of preeclampsia.