EphA2: A Novel Target in Renal Cell Carcinoma
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Eph receptors and their ligands, ephrins, are known to play important roles in organ development (formation of tissue boundaries, neural crest cell migration, axon guidance) and angiogenesis. In particular, EphA2 has recently attracted interest in the field of cancer research. Many observations, including our own, have demonstrated that most cancers, such as renal cell carcinoma (RCC), overexpress the EphA2 protein. EphA2 overexpression/dysregulation is associated with carcinogenesis, metastasis, and poor clinical prognosis. Indeed EphA2 is not just a marker of metastatic potential, but its overexpression is directly linked to an aggressive tumor phenotype. As a consequence, EphA2 represents a potential target for therapeutic intervention in the setting of EphA2+ cancer histologies, with several agents being developed with clinical intent. Several strategies can be contemplated in this regard, including: (1) selected promotion of EphA2 degradation or to reduce EphA2 expression and signaling (via the application of agonistic antibody, ephrin-A1 Fc fusion protein, siRNA against EphA2, or protein tyrosine phosphatases (PTP) that regulate EphA2 expression or specific EphA2 kinase inhibitors); (2) antagonism of EphA2 receptor-ligand binding (by provision of mimetic peptides or EphA2 Fc fusion protein); and/or (3) vaccination against EphA2 (using specific peptide-, protein-, or gene-based methods) to elicit specific T-cell- or Ig-mediated immunity. In this chapter, we will discuss the basic immunobiology of tumor-associated EphA2 and potential therapeutic interventions directed against EphA2 that may yield clinical benefit in the setting of (renal cell) cancer.Keywords:
EPH receptor A2
Ephrin
EPH receptor A2
Ephrin
Receptor Protein-Tyrosine Kinases
Protein kinase domain
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The Eph Receptor Tyrosine Kinases form the largest subfamily of RTKs, with 14 receptors currently identified in mammals. Interaction of Ephs with their membrane bound ephrin ligands initiates bidirectional signalling pathways that regulate cell movements involved in axon guidance, vascular networking and the formation of embryonic tissue boundaries. While the complete range of physiological functions for Eph proteins is still emerging, elevated expression in discrete regions of the developing embryo and low levels in mature adult tissues are consistent with a critical role in embryogenesis. In addition to their role as guidance and adhesion molecules during normal development, Ephs and ephrins have been implicated in tumourigenesis, where they may perform similar functions during tumour invasion and metastasis. Hence, the overall aims of this thesis were to examine the role of the Eph-ephrin system during the early embryonic development of mice, and to investigate the effects of these genes on colon carcinogenesis. In order to define the functional role of Eph and ephrin proteins during early vertebrate development it was first necessary to elucidate the gene expression patterns. Expression of the EphA1 receptor and its high-affinity ligands, ephrin AI and ephrin A3, were characterised from 4.5 to 12.5 dpc using RNA in situ hybridisation and histological techniques. These results showed complex, dynamic patterns of expression for EphA1, ephrin A1 and ephrin A3 that imply novel functions for these genes during the earliest phases of development. The identification of receptors and ligands with overlapping or complementary expression was of particular interest, as it suggests the presence of authentic receptor-ligand pairs of in vivo functional significance. Although Ephs and ephrins are frequently overexpressed in a wide range of human malignancies, the molecular mechanisms underlying activation of expression in tumours have not yet been identified. Colorectal carcinoma is the most common cancer affecting humans and the Eph-ephrin system features extensively in the normal physiology and pathology of this organ. In order to investigate the relationship between the expression characteristics and the tumorigenic capacity of colon carcinomas, Quantitative PCR was used to develop an Eph-ephrin expression profile of cells, followed by Microarray Analysis to determine the broader expression characteristics. To complement these experiments, the generation of a transgenic mouse model of colon cancer that conditionally over-expresses the EphA1 receptor was also undertaken. This has enabled the identification of transcriptome variations commonly associated with changes in Eph-ephrin expression, which may contribute to the pathogenesis of cancer. The consensus class of gene expression changes identified in these experiments revealed biologically important features of tumourigenesis and metastasis, with particular emphasis on the Rho family of small GTPases. As colonic carcinomas demonstrate unpredictable metastatic behaviour associated with poor prognosis in humans, the identification of molecular derangements contributing to this behaviour may have profound clinical significance. Collectively, these results provide further evidence that the Eph-ephrin system functions as a key regulator of the cell-cell interactions that are critical to early vertebrate embryogenesis and make an important contribution to the developing theories that aim to understand the role of Eph and ephrin genes in the neoplastic process.
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The Eph receptor tyrosine kinases and ephrin ligands have been studied extensively for their roles in developmental processes. In recent years, Eph receptors and ephrins have been found to be integral players in cancer formation and progression. Among these are EphA2 and ephrinA1, which are involved in the development and maintenance of many different types of solid tumors. The function of EphA2 and ephrinA1 in tumorigenesis and tumor progression is complex and seems to be dependent on cell type and microenvironment. These variables affect the expression of the EphA2 and ephrinA1 proteins, the pathways through which they induce signaling, and the functional consequences of that signaling on the behavior of tumor cells and tumor-associated cells. This review will specifically focus on the roles that EphA2 and ephrinA1 play in the different cell types that contribute to the malignancy of solid tumors, with emphasis on the opportunities for therapeutic targeting.
EPH receptor A2
Ephrin
Receptor Protein-Tyrosine Kinases
Tumor progression
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Ephrin
EPH receptor A2
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Lung cancer (LC) is the leading cause of cancer death in the United States. Erythropoietin-producing hepatocellular receptors (EPHs) comprise the largest receptor tyrosine kinases (RTKs) family in mammals. EPHs along with their ligands, EPH-family receptor-interacting proteins (ephrins), have been found to be either up- or downregulated in LC cells, hence exhibiting a defining role in LC carcinogenesis and tumor progression. In their capacity as membrane-bound molecules, EPHs/ephrins may represent feasible targets in the context of precision cancer treatment. In order to investigate available therapeutics targeting the EPH/ephrin system in LC, a literature review was conducted, using the MEDLINE, LIVIVO, and Google Scholar databases. EPHA2 is the most well-studied EPH/ephrin target in LC treatment. The targeting of EPHA2, EPHA3, EPHA5, EPHA7, EPHB4, EPHB6, ephrin-A1, ephrin-A2, ephrin-B2, and ephrin-B3 in LC cells or xenograft models not only directly correlates with a profound LC suppression but also enriches the effects of well-established therapeutic regimens. However, the sole clinical trial incorporating a NSCLC patient could not describe objective anti-cancer effects after anti-EPHA2 antibody administration. Collectively, EPHs/ephrins seem to represent promising treatment targets in LC. However, large clinical trials still need to be performed, with a view to examining the effects of EPH/ephrin targeting in the clinical setting.
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4496 Eph receptors are the largest family of membrane bound receptor tyrosine kinases (RTKs) that have been implicated in various developmental processes as well as tumorigenesis. But the role of Eph kinases in tumor progression is controversial since on one hand it has been shown to inhibit or attenuate growth factors dependent MAPK activity and on the other hand, they are overexpressed and in some cases mutated in various types of tumors. However, in contrast to other RTKs, activation of Eph receptors fails to promote cell proliferation, or to transform rodent fibroblasts, indicating that Eph kinases may initiate signaling pathways that are distinct from those transmitted by other RTKs. We have previously reported that activation of EphA kinases by their ligand ephrinA1 inhibits the ras/Erk signaling cascade(Nature Cell Biology;3;p527). To characterize further regarding which EphA kinase/s are involved in this regulation, we established primary mouse embryonic fibroblasts (MEFs) from the EphA2 knock out (KO) mice. Here we show that disruption of EphA2 abolishes the inhibitory effect of ephrinA1 on Erk1/2 activity. More importantly, restoration of EphA2 expression rescued the inhibitory effect of ephrinA1 on Erk1/2 activity. In addition, deletion and site directed mutation analysis revealed that catalytic activity of kinase domain of EphA2 is required for Erk1/2 inhibition. Furthermore, we demonstrate that ephrinA1 is also capable of mediating EphA1 activation induced Erk1/2 inhibition. In summary, our data establishes that EphA1 and EphA2 are sufficient in mediating suppression of Erk1/2 activity in MEFs, and suggest that this activation of EphA kinases can be attractive targets for cancer therapy.
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Ephrin
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EPH receptor A2
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Eph receptor tyrosine kinases and their ligands, ephrins, are membrane proteins coordinating a wide range of biological functions both in developing embryos and in adult multicellular organisms. Numerous studies have implicated Eph receptors in the induction of opposing responses, including cell adhesion or repulsion, support or inhibition of cell proliferation and cell migration, and progression or suppression of multiple malignancies. Similar to other receptor tyrosine kinases, Eph receptors rely on their ability to catalyze tyrosine phosphorylation for signal transduction. Interestingly, however, Eph receptors also actively utilize three kinase-deficient receptor tyrosine kinases, EphB6, EphA10, and Ryk, in their signaling network. The accumulating evidence suggests that the unusual flexibility of the Eph family, allowing it to initiate antagonistic responses, might be partially explained by the influence of the kinase-dead participants and that the exact outcome of an Eph-mediated action is likely to be defined by the balance between the signaling of catalytically potent and catalytically null receptors. We discuss in this minireview the emerging functions of the kinase-dead EphB6, EphA10, and Ryk receptors both in normal biological responses and in malignancy, and analyze currently available information related to the molecular mechanisms of their action in the context of the Eph family.
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EPH receptor A2
Receptor Protein-Tyrosine Kinases
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Ephrin
EPH receptor A2
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