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BioMed Research International
Volume 2018, Article ID 7390104, 23 pages
https://doi.org/10.1155/2018/7390104
Review Article

Differential Expression Patterns of Eph Receptors and Ephrin Ligands in Human Cancers

Department of Basic Medical Sciences, Western University of Health Sciences, Pomona, CA 91766, USA

Correspondence should be addressed to Raj P. Kandpal; ude.unretsew@lapdnakr

Received 29 September 2017; Revised 11 January 2018; Accepted 22 January 2018; Published 28 February 2018

Academic Editor: Pasquale De Bonis

Copyright © 2018 Chung-Ting Jimmy Kou and Raj P. Kandpal. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Eph receptors constitute the largest family of receptor tyrosine kinases, which are activated by ephrin ligands that either are anchored to the membrane or contain a transmembrane domain. These molecules play important roles in the development of multicellular organisms, and the physiological functions of these receptor-ligand pairs have been extensively documented in axon guidance, neuronal development, vascular patterning, and inflammation during tissue injury. The recognition that aberrant regulation and expression of these molecules lead to alterations in proliferative, migratory, and invasive potential of a variety of human cancers has made them potential targets for cancer therapeutics. We present here the involvement of Eph receptors and ephrin ligands in lung carcinoma, breast carcinoma, prostate carcinoma, colorectal carcinoma, glioblastoma, and medulloblastoma. The aberrations in their abundances are described in the context of multiple signaling pathways, and differential expression is suggested as the mechanism underlying tumorigenesis.

1. Introduction

The discovery of oncogenes and tumor suppressors in 1970s and subsequent advances in 1980s illuminated the mechanisms responsible for regulating the growth and proliferation of normal cells. The activation of protooncogenes and inactivation of tumor suppressors are frequently observed in cancer cells. In most cases, tumor cells display alterations in morphology, cell-cell interactions, membrane properties, cytoskeletal structure, protein secretion, and gene expression. Furthermore, transformed cells also exhibit loss of contact inhibition, self-sufficiency of growth signals, and escape from replicative senescence [14].

The growth and consequent metastasis of tumor cells are largely dependent on neovascularization [5], which is regulated by many different cellular signals including axon guidance molecules. Axon guiding signal molecules consist of Eph/ephrin, Semaphorins/plexins, VEGF/VEGFR, chemokines/chemokine receptors, netrins/DCC, Slit/Robo, and Notch/Delta [6]. In fact, altered abundance and regulation of these proteins have been associated with a variety of human cancers. We have focused here on Eph/ephrin molecules and their roles in tumorigenesis.

2. Structure of Eph Receptors and Ephrin Ligands

Eph receptors are important for development and tissue organization in multicellular organisms. These transmembrane (TM) proteins are activated by binding to ephrin ligands. Fourteen Eph receptors encoded in the human genome are divided into A and B classes. EphA receptors consist of nine members (EphA1–EphA8 and EphA10), which are activated by five different ephrin-A ligands. Five EphB receptors (EphB1–EphB4 and EphB6) bind to three ephrin-B ligands [7]. Although interactions of Eph receptors with their cognate class of ephrin ligands are well documented, interclass binding between Eph receptors and ephrin ligands has also been reported.

The native structure of Eph receptors displays an ephrin-binding domain, a cysteine-rich region, two fibronectin type III repeats, a transmembrane segment with conserved tyrosine residues, a kinase domain, a sterileα motif (SAM) protein-protein interaction domain, and a C-terminal PDZ-binding motif [1719]. The arrangement of these domains and motifs in Eph receptors is schematically represented in Figure 1. These domains and regions contribute to the 3D topology of the protein and facilitate its interaction with other proteins within the cellular signaling network. Phosphorylated amino acid residues in the activated Eph receptors mediate these interactions. However, EphA10 and EphB6 lack kinase activity due to altered sequence of the conserved regions within the kinase domain [20].

Figure 1: Domains in Eph Receptors. The cytoplasmic and extracellular portions of the receptor are separated by the membrane bilayer. The extracellular region of Eph receptors contains a ligand binding domain, a cysteine-rich domain, and two fibronectin type III repeats. The intracellular region is composed of a tyrosine domain, a sterile motif (SAM), and a PDZ domain. The domains have been drawn in different shapes and colors, and individual domains are labeled with their designations. Phosphorylated residues are indicated.

Eph receptors are activated by binding of ephrin ligands to the ephrin-binding domain in the receptor. The Eph binding domain of the ephrin ligand is attached to the plasma membrane by a linker segment of variable length [17]. The two classes of ligands are distinguished by the presence of GPI anchor in ephrin-A ligands and a transmembrane segment in ephrin-B ligands [21]. The structural features of the two classes of ephrins are illustrated in Figure 2.

Figure 2: Structure of Ephrin Ligands. The GPI anchor and transmembrane domains of ephrin-A and ephrin-B are shown. Both classes have Eph binding domain on the extracellular side. Ephrin-B contains a cytoplasmic domain and a PDZ domain.

3. Physiological Roles of Eph Receptors and Ephrin Ligands

The spatial organizations of Eph receptors and ephrin ligands require the presence of these molecules on the surface of two interacting cells of the same or different types. Thus, physical contact is necessary for initiating forward and/or reverse signaling in different cell types. Such contact-mediated physiological functions of these receptor-ligand pairs have been extensively documented for axon guidance, neuronal development, vascular patterning, and wound healing as described below.

3.1. Axon Guidance

Axons in the nervous system extend over long distances to reach their targets, and this process is facilitated by Eph receptors and ephrins. Attraction or repulsion of growth cones, which are large actin-supported extensions of a growing neurite, modulate axonal spread [112]. Interactions of ephrin-As with TrkB and p75 neurotrophin receptor lead to axon pathfinding and elongation via reverse signaling [113]. Ephrin-Bs recruit cytoskeleton regulators for axon guidance, dendrite morphogenesis, and postsynapse maturation [113]. While several other important molecules such as Zic2, neuropilin-1 (NRP1), and NrCAM are involved in guiding retinal ganglion axons, induction of EphB receptors by Zic2 transcription factor substantiate the central role of Eph/ephrin signaling in axon guidance during neurogenesis [114119].

3.2. Neural Development

Neural progenitor cell proliferation, neuroblast migration, neuron survival, and neuronal plasticity also depend on Eph-ephrin interactions. The activation of EphB1, EphB2, EphB3, and EphA4 by ephrin ligands leads to migration of neuroblasts in the subventricular zone of the lateral ventricles in the adult mammalian brain [120]. Ephrin-A5 is required for the survival of newborn neurons in adult mice hippocampus, proliferation of cells in the hippocampal dentate gyrus, and the regulation of vasculature within the hippocampus [121]. Eph/ephrins also act as negative modulators in the nervous system as shown by the involvement of EphA7 and ephrin-A2 on progenitor cell proliferation in mice [122], influence of ephrin-B3 [123], and EphB3 [124] in the adult subventricular zone, and regulation of hippocampus neural progenitor growth by ephrin-A2/A3-mediated activation of EphA7 [125]. Thus, activation of Eph receptors by ephrins is critical for the maintenance, proliferation, and inhibition of neural progenitors during neurogenesis.

3.3. Vascular Development

EphB4 and ephrin-B2 are known for their roles in dorsal aorta and cardinal veins. The endothelial cells in the artery are marked by ephrin-B2, while EphB4 marks venous endothelial cells [126]. The interaction of ephrin-B2 in artery and Eph receptor in veins is indicative of their roles in defining boundaries between veins and arteries [127]. These observations are also confirmed by zebra fish model of vascular development [128] and mouse retinal system [129, 130].

The lymphatic vasculature, a branched network of blind-ended capillaries and collecting lymph vessels [131], requires EphB4 and ephrin-B2 to develop vascular valves to regulate unidirectional flow within the lymphatics [132]. Involvement of ephrin-B2 has been confirmed by its ability to induce VEGFR3 internalization [129] as well as lymphatic system remodeling [102, 133]. Ephrin-B2 is also necessary for blood vessel network stabilization [134, 135].

3.4. Tissue Injury

The healing of injured or inflamed vessels occurs by platelet plug formation and coagulation of extravasated blood. This process involves signaling pathways that facilitate the recruitment of inflammatory cells and proliferation of fibroblasts and epithelial cells. Eph/ephrin proteins partake in tissue healing as regulators of angiogenesis [19] and cell migration [136]. Eph/ephrin regulation has also been observed in renal ischemic injury [137]. Upregulation of Eph/ephrin expression in hypoxic mouse skin flap models supports the hypothesis of Eph/ephrin involvement in ischemic tissue injury repair [138]. Similarly, remodeling events following optic nerve injury in EphB3 null rodents resulted in decreased axon sprouting due to impaired interaction between macrophages and retinal ganglion cell axons [139]. Lastly, immunochemistry data showed EphB3 overexpression in invading fibroblasts and ephrin-B2 expression in astrocytes during spinal cord injury [140]. EphA4 has been implicated in the formation of astrocytic gliosis and scar formation following spinal injury in rodents and nonhuman primates [141, 142]. These observations indicate Eph/ephrin involvement in the events that follow tissue injury.

4. Eph/Ephrin Signaling System

Eph receptors constitute the largest family of receptor tyrosine kinases (RTK). Several features of the Eph-ephrin family distinguish it from other RTK families. RTK are activated by binding to soluble ligands, but Eph RTK bind to ephrin ligands attached to the plasma membrane of an opposing cell. Activated RTK exist as dimers, and activated Eph-ephrin signaling system exists as higher order clusters [143, 144]. The formation of multimeric structures by high affinity binding between Eph and ephrins may lead to repulsion of cells [144]. The repulsion between two cells is attributed to the cleavage of the ephrin ligand as demonstrated by the association of ADAM10 metalloprotease with EphA3 and cleavage of ephrin-A5 following its binding with EphA3 [145]. Alternatively, endocytosis of Eph-ephrin complexes by Rac-mediated actin cytoskeletal reorganization can also cause contact-mediated repulsion [146, 147]. Lastly, ephrins have the potential to elicit reverse signaling within ephrin-bearing cells [148, 149]. Although the physiological relevance of Eph-ephrin clustering is not clearly understood, it appears to determine the strength of kinase activity and the cellular response [145].

Trans-interaction between Eph receptors and ephrin ligands on opposite cells activates forward and reverse signaling. Coexpressions of EphA receptors and ephrins in their cis-interactions lead to inhibition of trans-interaction signaling [148, 150, 151]. Figure 3 summarizes the generic transactivation processes in forward signaling mediated by Eph receptors and reverse signaling mediated by ephrin ligands [113]. The figure also illustrates cis-inhibition caused by coexpression of Eph receptors and ephrin ligands in the same cell. While forward signaling involves Rho GTPases, reverse signaling is mediated by Src kinases as described below. A heterotetrameric structure is formed after binding of ephrin ligands to the glycosylated ligand binding domain of the Eph receptor, leading to the activation of the tyrosine kinase domain and subsequent phosphorylation of specific tyrosine residues [143, 152]. Activated Eph receptors recruit phosphotyrosine-binding adapters to activate Rho GTPases such as RhoA, Cdc42, and Rac for actin cytoskeleton remodeling [16]. Rho GTPases function as molecular switches that cycle between an inactive (GDP-bound) and an active (GTP-bound) state. Guanine nucleotide exchange factors (GEF) and GTPase-activating proteins (GAP) regulate the relative abundance of active and inactive Rho proteins [153]. Reverse signaling in ephrin-bearing cells begins with clustering of the ligand to promote the recruitment and activation of Src family kinases which phosphorylate specific tyrosine residues of the ligand’s cytoplasmic domain [154]. The phosphorylated ligand provides a docking site for Grb4 and alters cytoskeletal dynamics by a variety of pathways triggered by several proteins such as Cbl associated protein (CAP/ponsin), Abelson interacting protein 1 (Abi-1), dynamin, paxillin, FAK, PAK1, hnRNPK, and axin [155]. Ephrin-B containing cells, on the other hand, mediate reverse signaling by recruiting intracellular adapter proteins to the phosphotyrosine residues in the cytoplasmic domain and the carboxyterminal PDZ-binding motif [156].

Figure 3: Eph/Ephrin Forward/Reverse Signaling and Cis-Inhibition. (a) Ephrin ligand and Eph receptors expressed on opposite cells are in trans-configuration. Both Eph receptor and ephrins activate bidirectional signaling—forward signaling with Eph receptors and reverse signaling with ephrin ligands. The activation is depicted by the presence of phosphorylated residues in the receptor. (b) Coexpression of EphA family receptor and ephrin-A family ligand on the same cell results in a cis-configuration. Such arrangement impairs Eph receptor activation and prevents trans-interaction. The inactive receptor is indicated by the lack of phosphorylated residues.

5. Eph/Ephrin Signaling in Cancer

The overexpression of several Eph receptors/ephrin ligands and downregulation of a different set of Eph/ephrin molecules in a variety of tumors suggest that these proteins have growth promoting and growth suppressing activities. Despite the challenges of resolving the complexity of Eph/ephrin signaling pathways within cancer cells, Eph receptors and ephrin ligands remain attractive targets for cancer therapy. We focus here on the mechanisms underlying the upregulation/downregulation of Eph receptors and ephrin ligands in lung, breast, brain, prostate, and colorectal cancer.

6. Lung Cancer

Lung cancer is the leading cause of cancer mortality in the world, with more deaths than colorectal, breast, and prostate cancer combined, and smoking is the most important risk factor in the development of pulmonary carcinomas [157]. Non-small cell lung cancer (NSCLC), a highly invasive and aggressive carcinoma, accounts for approximately 80% of all lung cancers [158]. The 5-year survival rate remains less than 15% despite the development of new surgical procedures and chemotherapeutic protocols [157, 158].

EphA2 is one of the most frequently examined Eph receptors in pulmonary carcinomas. Similarly, its ligand ephrin-A1 [159] has also been investigated in lung cancer [160, 161]. Overexpression of EphA2 in NSCLC and its correlation with smoking and metastasis [23] have been replicated in cultured bronchial airway epithelial cells (BAEpC). These studies also suggested an association of EphA2 with E-cadherin, Erk1/Erk2, p53, and JNK-MAPK pathway [24]. Overexpression of EphA2 in NSCLC patients also correlates with brain metastasis [25], and EphA2 invasive signals have been attributed in some cases to G391R mutation and consequent phosphorylation of two serine residues within mTOR [26]. The therapeutic potential of EphA2 is evident from its elevated expression in lung cancer cells that are resistant to EGFR tyrosine kinase inhibitor (TKI) and decreased viability of these resistant cells by pharmacological inhibition of EphA2 [27]. Other studies that demonstrate upregulation of ephrin-A3 in NSCLC [29] and inhibitory effects of ephrin-A3 and ephrin-B2 on transactivation of EphA2/EphA3 and EphA3/EphB4, respectively, are indicative of context-dependent aberrations of Eph/ephrin molecules in cancer cells [29, 30]. The induction of EphA3 overexpression in chemoresistant lung carcinoma cells in vitro has been shown to decrease chemotherapy resistance and enhance apoptosis by affecting phosphorylation of specific proteins constituting the PI3K/BMX/STAT3 signaling pathway [162]. Moderate-to-high levels of EphA4, EphA5, or EphA7 have been associated with longer survival in NSCLC patients. The combined expression of EphA1, EphA4, EphA5, and EphA7 has been used to distinguish various stages of lung cancer [22].

Among the B class of Eph/ephrins, EphB3, EphB4, ephrin-B1, and ephrin-B3 have been investigated in lung carcinoma. EphB3 overexpression is linked to clinical features of tumors and accelerated growth characteristics [31]. While in vivo loss of EphB3 led to activation of capase-8 and apoptosis, ligand dependent activation of EphB3 suppresses NSCLC metastasis. Mechanistically, EphB3 appears to decrease Akt activity via formation of PP2A/RACK1/Akt signaling complex [32]. Although EphB4 overexpression affects proliferation, colony formation, and motility in vitro, paradoxically there is a positive correlation between EphB4 expression and patient survival [33]. Cross-talk between ephrins and Eph receptors and activated status of Eph receptors have also been demonstrated by phosphoproteomic profiling of NSCLC cells. These investigations revealed that EphA2 stabilization occurs by phosphorylation of Akt in ephrin-B3 deficient NSCLC cells, and increased EphA2 correlates with worse metastatic prognosis [23, 28]. EphB6 has been shown to be prognostic indicator for NSLC [163], and deleterious mutations in this protein have also been characterized in primary tumor specimens obtained from NSLC patients [164]. Table 1 summarizes alterations in representative receptors and ligands reported by various laboratories with a tentative mechanism associated with these changes.

Table 1: Altered expression of Eph receptors and ephrin ligands in lung cancer.

7. Breast Cancer

Eph receptors and ephrin ligands are important for mammary epithelial morphogenesis. These proteins are expressed in tumor cells as well as the tumor microenvironment, and their abundance is altered in breast carcinoma cells. We have described the following alterations in the levels of Eph receptors in breast cancer cells and briefly discussed the mechanisms underlying the expression of specific members of the Eph receptor family and their diagnostic/prognostic relevance.

EphA2 and EphB4 are the two most extensively studied receptors in breast carcinomas [23]. EphA2 is overexpressed in a majority of breast tumors, can transform normal breast cells, and is known to have both pro- and antioncogenic properties [34, 36, 165, 166]. Furthermore, expression of kinase-deficient variants of EphA2 in breast cancer cells led to decreased tumor volume and increased tumor cell apoptosis [167]. In vivo studies have demonstrated that chronic trastuzumab treatment results in the phosphorylation of EphA2 through Src kinase, causing the activation of PI3K/Akt and MAPK pathways, which lead to trastuzumab resistance [12]. Some effects of EphA2 on tumor phenotypes are mediated by its physical and functional interaction with ErbB2/EGFR and activation of signaling pathways that involve Ras/MAPK and RhoA [35]. At cellular level, the phosphoprotein Anks1 promotes tumorigenesis by facilitating export of EphA2/ErbB2 complexes into COPII vesicles [13]. An inverse relationship between EphA2 and estrogen dependence has been observed in breast cancer cells both in vivo and in vitro, and decreased tamoxifen sensitivity was noticed in estrogen receptor (ER) positive breast cancer cells with EphA2 overexpression [168]. Exposure of ER+ breast cell lines to paclitaxel or doxorubicin also leads to increased expression of EphA2 [169]. Microarray analyses have shown a negative correlation of EphA2, EphA4, and EphA7 expression with overall survival [36]. Physical interaction of EphA7 with EphA10 [37], a kinase null receptor [46], may provide mechanistic aspects of the involvement of various Eph receptors in tumorigenesis in a context-dependent manner. Such interactions become important to explain the correlation of EphA10 expression with lymph node metastasis in breast cancer patients [38].

Among EphB receptors, EphB4 has been shown to be upregulated as well as downregulated in breast cancer cells [41, 170, 171], and knockdown of EphB4 inhibits tumor cell viability. These observations suggest EphB4 to be performing both pro- and antioncogenic roles. EphB4 expression is induced by EGFR, and inhibitors of JAK-STAT and PI3K-Akt pathways abolish EGFR induced upregulation of EphB4 receptor [41]. While antioncogenic EphB4/ephrin-B2 effects are mediated by activation of Abl-Crk pathway and downregulation of matrix metalloprotease MMP-2 [42], its tumor promoting effects manifest via ligand-independent phosphorylation [51, 52]. Additional support for EphB4 and ephrin-B2 involvement in breast cancer is provided by PP2A (protein phosphatase) knockdown effects on ERK pathway in ephrin-B2 stimulated cells [43] and morphological changes in mammary gland as well as aberrant expression of E-cadherin in mutant ephrin-B2 transgenic mice [44]. The underlying mechanism of ephrin-B2 and inappropriate E-cadherin expression may be partly explained by interactions of EphB receptors with metalloproteinase ADAM10, and subsequent E-cadherin shedding [45].

EphB6, a kinase null receptor [172] with a high affinity for ephrin-B1 and ephrin-B2 [50], has been investigated extensively for its role in breast tumorigenesis. Binding of ephrin-B1 or ephrin-B2 to EphB6 leads to its heterodimerization with EphB1, which is followed by the phosphorylation of kinase null EphB6 [46, 47]. Upon phosphorylation, EphB6 interacts with c-Cbl to promote breast tumor cell motility [48]. EphB6 expression exists in normal mammary gland and noninvasive breast tumor cell lines, but it is downregulated or absent in invasive metastatic breast cancer cell lines [173]. Levels of EphB6 are regulated by methylation of its promoter sequence in a cell-specific manner [49]. The application of methylation-dependent regulation of EphB6 expression is further evident in an investigation utilizing MSP (methylation-specific polymerase chain reaction) for potential detection of breast tumor cells in circulation [174]. Molecular and phenotypical changes in breast cancer cells appear to involve EphB6 cross-talk with cadherin 17, and altered expression of EphB6 influences WNT pathway [15]. It is noteworthy that while EphB6 has been considered a tumor suppressor in cell line models of breast tumorigenesis [15, 39, 48, 49, 173175], its association with reduced survival in breast cancer patients has also been reported [36].

The signals transduced by the kinase-deficient EphB6 are dependent on its ability to form heterodimers with EphA2 and EphB2 [39]. Given the overexpression of EphA2 in breast cancer cells, tumor suppressor action of EphB6 may be explained by its heteromerization with EphA2 [39]. A recent study indicates the association of EphB2 expression with breast cancer survival [40]. These observations are clear indications of context-dependent biological relevance of various Eph receptors and ephrin ligands. Table 2 summarizes altered abundance of Eph receptors and ephrin ligands with the characteristics of breast carcinoma cells.

Table 2: Altered expression of Eph receptors and ephrin ligands in breast cancer.

8. Brain Cancer

Eph receptors have been extensively studied in glioblastoma multiforme (GBM), a subgroup of gliomas, and the pediatric brain tumor known as medulloblastoma [176178]. While gliomas arise from astrocytes and oligodendrocytes [176, 177], medulloblastoma originate from granule neuronal precursor cells in the cerebellum or neural stem cells of the rhombic lip [178]. The migratory and invasive cell phenotype of medulloblastoma cells allow them to rapidly disseminate along leptomeningeal surfaces [179]. The involvement of Eph receptors in these two important brain neoplasms is described below.

8.1. Glioblastoma

EphA2 is highly expressed in GBM but not in normal brain as demonstrated by 100-fold higher levels of EphA mRNA in human GBM specimens compared to normal brain tissue [53, 180]. Particularly, EphA2 supports tumor-propagating cells with stem-like characteristics to remain in an undifferentiated state in human GBM. This has been demonstrated by the loss of self-renewal and induction of differentiation in vitro when EphA2 is silenced in human GBM cells via siRNA knockdown as well as ephrinA1-Fc ligand-induced EphA2 downregulation [53]. A positive correlation between EphA2 expression and pathological grade as well as proliferation has been observed in astrocytic tumors [181]. In addition, an inverse relationship exists between increased EphA2 expression and apoptosis [181]. Furthermore, a positive correlation with adverse clinical outcomes has been established with higher levels of EphA2 expression [182]. The molecular action of EphA2 in glioblastoma involves decreased Erk phosphorylation, Akt interaction, Sox downregulation, and altered invasiveness of stem cells [5357]. These observations suggest that EphA2-mediated regulation of stemness and that of invasiveness are partly responsible for glioma phenotypes [57]. Soluble ephrin-A1, a ligand for EphA2, can lead to internalization of EphA2 and alterations in GBM cell morphology, migration, and adhesion [58, 59]. The tumorigenicity induced by EphA3, which is frequently overexpressed in the most aggressive subtype of GBM [61] but absent in normal brain tissue [62], is reduced by its ligand ephrin-A5 [63, 183]. Such effects of ephrin-A5 are attributed to an increase in the ubiquitination and subsequent degradation of the EGFR after its binding to c-Cbl [63]. Ephrin-A5 conjugated to a cytotoxin has been effective in killing GBM cells that overexpress EphA2, EphA3, and EphB2 receptors [62]. EphA3 transduces signal via MAPK pathway to maintain undifferentiated GBM cells and facilitates differentiation of neuronal progenitor cells [60, 61]. Though not well-characterized for their roles in GBM, altered expression of EphA4, EphA5, and EphA8 has been reported in GBM cells [6468, 183]. Preliminary observations in GBM cells reveal some of these receptors as modulators of proliferation or predictors of disease status and poor prognosis [64, 66, 67, 183].

The involvement of EphB receptors in GBM cell migration and invasion and tumor angiogenesis is evident from the observations that indicate both altered abundance and phosphorylation of EphB2 and overexpression of ephrin-B3 in invasive cell lines through activation of R-Ras and Rac1 [69, 70, 75, 76]. EphB2 appears to function as a promigratory and antiproliferative molecule [71]. EphB2 is posttranscriptionally regulated by miR-204, which is downregulated in both glioma cells and neural stem cells. Given the ability of miR-204 to target SOX4, it is suggested that altered abundances of SOX4 and EphB2 together are involved in modulating stemness and migration of glioma cells [72].

Ephrin-B2 together with its receptor EphB4 promotes angiogenesis via Notch and VGFR2 [184186] and enhances migration and invasiveness of U251 GBM cells both in vitro and ex vivo [74]. Higher expression of ephrin-B2 and EphB4 in gliomas also correlates with worse clinical prognosis [73].

The changes in Eph receptors and ephrin ligands in gliomas reported in the literature are listed in Table 3. As evident from the table, altered abundance of these molecules is brought about by different mechanisms that in turn modulate a variety of signaling molecules and pathways.

Table 3: Altered expression of Eph receptors and ephrin ligands in gliomas.
8.2. Medulloblastoma

Eph receptors have been implicated in vasculogenic mimicry, invasion, migration, and signaling pathways operative in medulloblastoma. EphA2 expression, in particular, is associated with phosphoinositide 3-kinase (PI3K) and vasculogenic mimicry via metalloproteinase MMP-2 [77]. Elevated expression of EphA2, EphB2, and EphB4 in medulloblastoma cell line is linked to ephrin-B1 mediated invasion [79]. The alterations in abundance and activation status of EphB2/ephrin-B1 correspond to changes in p38, Ras/Raf/Erk, PI3K, and Akt-mTOR signaling pathways [79, 187]. It is therefore not surprising that EphB2 knockdown in medulloblastoma cells combined with radiation exposure led to significant reduction of cell viability and invasion [80]. While ephrin-B1 is uniquely dysregulated in medulloblastoma, differential effects of ephrin-B1 and ephrin-B2 knockdown on phosphorylation of EphB1/B2 and Src suggest alterations in reverse signaling in medulloblastoma cells [85]. The reduction in growth and increase in radiosensitivity of medulloblastoma cells by EphB1 knockdown further substantiate the involvement of this receptor in maintaining the tumor cell phenotype [78]. A noteworthy study also demonstrates a relationship between ephrin-A5 and medulloblastoma by using a mouse model. The genetic loss of ephin-A5, a ligand for EphA4 and EphA7, led to tumor growth inhibition in a genetically engineered mouse model that harbors Smoothened gene under the control of the NeuroD2 promoter [81]. These transgenic mice have a tissue specific constitutively active form of Smoothened, which regulates ephrin-A5 expression in the dorsal midbrain and hindbrain during embryonic development of mice and chick [81, 82]. The external granule cell layer, which acts as medulloblastoma precursor, shows overexpression of ephrin-A5 [81, 83]. Molecular analysis of tumors isolated from engineered mice revealed the influence of ephrin-A5 on Akt, PI3K, and PTEN [81, 84, 188].

Table 4 summarizes variations in the levels of Eph receptors and ephrin ligands in medulloblastoma. These changes disturb relevant pathways that modulate cell proliferation, vascular reorganization, cell cycle, and tumor development.

Table 4: Altered expression of Eph receptors and ephrin ligands in medulloblastoma.

9. Prostate Cancer

Prostate cancer is the third leading cause of cancer mortality in American men. A major clinical challenge in prostate cancer is distinguishing between aggressive and nonaggressive tumors [189]. Serum PSA levels have been utilized as a biomarker for over 20 years for screening and clinical management of prostate cancer [190]. However, inherent limitations of PSA screening, including a lack of specificity, have led to overdiagnosis and overtreatment of prostate cancer. Eph receptors and ephrin ligands show promise as biomarkers in many cancers and are attractive potential molecular biomarkers as well as targeted therapeutic agents for prostate cancer.

In a study consisting of cell lines representing normal prostate epithelium, primary prostate tumor, and aggressive forms of prostate tumor, several members of the Eph family were upregulated, some were downregulated, and others were either absent or unaltered. While EphA1 abundance was decreased in prostate cancer cell lines, EphA2, EphA5, EphA6, EphA7, EphA8, and EphA10 levels were elevated in some of the prostate cancer cell lines as compared to the normal prostate cell line [86]. Similar to breast cancer, EphA2 is the most extensively studied EphA receptor in prostate cancer. Early studies identified EphA2 protein overexpression in prostate cancer cell lines with greater metastatic potential, while normal and benign prostate tumor cells showed weak or no staining with EphA2 antibody [191]. A tumor grade specific increase in EphA2 protein has also been observed [87]. Stimulation of benign prostate epithelial cell line pRNS-1-1 with a soluble form of ephrin-A1 leads to decreased proliferation [192], and activation of EphA2 in PC3 cells decreases cell migration [193]. Furthermore, stimulation of EphA2 by ephrin-A1 in PTEN null PC3 cell line demonstrated inhibition of the Akt-mTORC1 pathway [34, 187, 194]. Transfection of PC3 cells with kinase-deficient mutant forms of EphA2 showed reduced metastasis when compared to PC3 cells with overexpression of native EphA2 [195]. While EphA2 dependence on ephrin ligand manifests varied phenotypic effects [192194], overexpression of EphA2 is related to induction of metastasis [196]. It appears from these observations that EphA2 effects manifest in a context-dependent manner.

Upregulation of EphA3 in androgen independent prostate cancer cells compared to androgen dependent prostate cancer cells has been observed by microarray analysis [89], and a tentative relationship between mutant AMP-activated protein kinase (AMPK) and upregulation of EphA3 mRNA has been proposed [90]. An increase in EphA4 mRNA and protein levels has been reported when prostatic intraepithelial neoplasia progresses to prostate carcinoma, and knockdown of EphA4 has shown altered viability and colony forming ability of cancer cells [91]. In a separate study, EphA4 stimulation by ephrin-A5 resulted in inhibition of PC3 cell migration by impairment of cell-cell contact [88]. The linkage of EphA4 with prostate cancer associated receptor ERBB3/HER3 [92] is apparent from the observed decrease of EphA4 transcript following the knockdown of ERBB3 in DU145 cells [92].

The EphA receptors that are decreased or lost in prostate cancer include EphA5 in patients with a Gleason score of 8 [197], EphA6 in LNCaP-19 cell line [198], and EphA7 in prostate tumor specimens [199]. Transcriptional silencing of EphA7 in a subset of prostate cancer cells is regulated by methylation of the EphA7 promoter [199]. The presence of EphA7 in primary tumors and its loss in lymph and bone metastases suggests that promoter methylation is perhaps not an early event in prostate cancer [200]. A recent genome sequence analysis has identified a single nucleotide polymorphism (rs731174) in an intron of the EphA10 gene that may interact with other SNPs to modify prostate cancer risk [201].

The prostate cell line panel has indicated a decrease in EphB2 with elevations in both EphB3 and EphB6 in some prostate carcinoma cells compared to normal prostate epithelial cells [86]. Specimens from metastatic prostate carcinoma showed missense and nonsense mutations in the kinase domain of EphB2, and transfection of normal EphB2 in DU145 cell line led to the suppression of growth and colony formation [93]. A higher frequency of a germline nonsense mutation termed K1019X (3055A>T) has been observed in African American men as compared to Caucasian men [202, 203]. Microarray and RT-PCR analysis of prostate cancer tissue have also identified differential expression of EphB3 [204]. Several studies indicate upregulation of EphB4 in the development and progression of prostate cancer [52, 205, 206].

The literature on ephrin alterations in prostate cancer is scarce. The cell line panel indicates increased abundance of ephrin-A1 and eprin-A2 in LNCaP and DU145 cells as compared to normal cells. Ephrin-B3 was detected at higher levels in all prostate carcinoma cell lines [86]. Microdissections of prostate carcinoma samples showed lower levels of ephrin-A1 mRNA in samples with Gleason score > 7 and higher mRNA levels of ephrin-A1 from samples with Gleason score < 7 [94]. In light of the decreased migration of prostate cancer cells upon stimulation of EphA2 with ephrin-A1, downregulation of ephrin-A1 in aggressive prostate cancers is not surprising. Increased levels of ephrin-A5 in LNCaP cell culture media after androgen exposure suggests androgen-induced release of ephrin-A5 from prostate cancer cells [95]. Additionally, an independent retrospective study on metastatic castration-resistant prostate cancer has reported a correlation of lower serum levels of ephrin-A5 with shorter survival time [96].

The significant alterations of Eph/ephrin profiles observed in prostate tumors and prostate cancer cell lines are listed in Table 5. It warrants mention that the molecular changes in prostate cancer cells are also responsive to their dependence on androgen.

Table 5: Altered expression of Eph receptors and ephrin ligands in prostate cancer.

10. Colorectal Cancer

Colorectal cancer (CRC) is the third most commonly diagnosed cancer in both men and women and is the fourth leading cause of cancer-related death worldwide [207]. About 5% of CRC are monogenic, which include Lynch syndrome, familial adenomatous polyposis (FAP), MYH-associated polyposis, and rare hamartomatous polyposis syndromes [208]. Several Eph receptors and ephrin ligands exist as a gradient along the colon crypt axis of normal tissue [209]. While EphB1, EphB2, EphB3, EphB4, EphB6, EphA1, EphA4, and EphA7 are abundant in the basal crypt, the top of the crypt displays EphA2, EphA5, ephrin-A1, and ephrin-B2 [209].

The relationship of elevated expression of EphB2 and EphB3 with abnormal migration of epithelial cells in the crypt villus junction in colon tumors of mice is suggestive of Eph receptor involvement in colorectal cancer [210]. Immunohistochemical analyses have revealed decreased abundance of EphA6, EphA7, and EphB1 in colorectal tumors [211]. The expression of EphB2, an important molecule responsible for correct positioning of epithelial cells in the crypt [209], is reduced in CRC [212, 213], and its higher expression is associated with prolonged survival of CRC patients [210, 213215]. The altered expressions of EphB2 and EphB4 in colorectal cancer have been explained by changes in adenomatous polyposis coli (APC) suppressor gene activity, CBP complex, and Wnt pathway [104, 105, 216]. Transcriptional silencing or downregulation of specific Eph receptors in CRC is associated with promoter methylation [97, 103, 211]. The activation of EphB3 in HT-29 human colon cancer cells inhibits epithelial-to-mesenchymal transition via cell adhesion molecules [106, 107]. The elevated levels of EphB4 in CRC [104, 108] are being utilized for image guided colorectal surgery [109]. Although reduced abundance of EphB6 in CRC correlates with poor cell differentiation, advance disease, and poor prognosis [110], the mechanisms of EphB6 involvement in CRC are not well understood [111].

While the expression of EphA1 and EphA2 increases in early stages of CRC, the abundance of these receptors decreases in advanced stages of the cancer [9799, 101]. The linkage of decreased EphA1 levels with higher invasiveness is supported by alterations in adhesion and motility of HRT18 CRC cells that had been rendered EphA1 null by gene knockout [100]. The alterations of Eph/ephrin profiles of colorectal tumors and cell lines described in this section are summarized in Table 6.

Table 6: Altered expression of Eph receptors and ephrin ligands in colorectal carcinoma.

11. Conclusion

Based on the literature presented in this review, a composite network emerges that connects numerous pathways (Figure 4). This scheme was composed by adapting individual pathways described by other investigators [811]. The supporting data for other pathways and cross-talk among individual players is described in several publications, a few of which are cited here [1216]. Thus, the involvement of Eph receptors and ephrin ligands in such a complex network illustrates aberrant regulation of these important molecules in tumorigenesis. It also suggests the mechanisms underlying cancer cell phenotypes associated with aberrant expression of Eph receptors.

Figure 4: Summary of Potential Eph/Ephrin Tumor Promoting Pathways. A composite scheme of major tumorigenesis promoting Eph/ephrin signaling pathways is shown together. Ligand-independent forward signaling tumor promoting pathways shown for EphA and EphB receptors. Forward signaling pathways marked with an asterisk are known to be inhibited in ligand-dependent manner and participate in tumor suppression. Reverse signaling pathways are also shown for ephrin A and ephrin B. Yellow circles indicate phosphorylation of specific tyrosine/serine/threonine residues that are required for pathway activation. The broken bidirectional arrow represents cross-talk between Eph/ephrin and other types of receptors or pathways. Scissors symbol represents expression and/or function of proteases such as ADAM or MMP that are involved in the regulation of EphA and ephrin-B pathways, respectively. EMT indicates epithelial-to-mesenchymal transition. The figure is adapted from representative publications of Pasquale [8], Lisle et al. [9], Boyd et al. [10], and Xi et al. [11]. In addition, some of the pathways are substantiated from observations presented in several reports in the literature related to trastuzumab [12], COPII vesicles [13], NMDA receptor [14], E-cadherin [14], WNT pathway [15], and claudins [14, 16] for their relevance to tumor promoting pathways.

The description presented in this review clearly demonstrates that elevated expression and/or loss of expression of specific Eph receptors are associated with either tumor growth or tumor suppression in a context-dependent manner. We suggest these consequences to arise by interaction of phosphorylated receptors with distinct intracellular proteins involved in pathways that either promote or inhibit cell proliferation and actin organization. The investigations on protein-protein interactions indicate that kinase-deficient Eph receptors, EphB6 and EphB10, can heteromerize with kinase sufficient receptors. Specifically, EphB6 heteromerizes with EphA2 and EphB2, and EphA10 interacts with EphA7 [37, 39]. Such interactions in different contexts are likely to mediate different cancer phenotypes.

Mechanistically, cis-interaction of Eph receptors with ephrin ligands can inhibit transactivation-mediated tumor suppression activity [30, 150, 217]. Alternative mechanisms of tumorigenesis include activating oncogenic mutations or inactivating mutations in tumor suppressor functions of Eph receptors, regulation of epithelial-mesenchymal transition (EMT), control of motility and invasiveness, and alterations in Akt and MAP kinase pathways [26, 34, 57, 218221]. All these modalities of transformation include Eph receptor functionality or lack thereof. EMT, a critical aspect of cell migration, accompanies ligand-independent signaling, while ligand-dependent forward signaling restores cell-to-cell communication [219, 220]. A significant involvement of Eph receptors in tumorigenesis is based on their roles in regulating stemness of a subpopulation of cancer cells that are largely responsible for resistance to therapy [53, 61, 222]. In light of these observations, investigations on Eph receptor-mediated self-renewal of cancer stem cells are gaining momentum. The ability of Eph receptors to stimulate T cells has highlighted their importance in developing cancer immunotherapy [223228].

The therapeutic applications of Eph receptors include monoclonal antibody targeting, soluble Eph fusion protein targeting, small molecule Eph kinase inhibitors, dendritic-cell based vaccines, and siRNAs [10, 229233]. However, these therapeutic modalities suffer from deficiencies such as varying effectiveness of antibodies, deleterious side effects, redundancy of functions, receptor-independent activation of signaling pathways, variable effects of Eph receptors in T-cell lineage development, and epigenetic regulation of Eph expression [61, 97, 229241].

A potential therapy for cancer cells can be tailored around a synthetic Notch (synNotch), which would allow engineered cells to respond to multiple stimuli with distinct transcriptional programs [242]. Such engineered synNotch construct consisting of Eph/ephrin would be expected to emulate contact induced cis-inhibition in tumor cells. In light of the involvement of cancer stem cells (CSC) in metastasis [222] and the importance of Eph receptors in CSC maintenance [243], Eph/ephrins are important targets for therapeutic exploration. Illustrative examples of Eph receptors in stemness include the effects of EphA3 knockdown on GBM cell sphere formation [61] and the regulation of oncogenic Ras by EphA2 in transformed cells as well as expulsion of these cells from stem cell monolayer [244, 245].

The literature reviewed here clearly presents a common theme of tumorigenesis for various human cancers that involves a set of Eph receptors and ephrin ligands. Although some of these molecules appear to be facilitating similar processes in all cancers, the differences in the outcomes in certain situations may be attributed to the context and redundant expression of specific sets of Eph receptors and ephrin ligands. Further study in how mechanistically cancer cells initiate Eph cis-signaling, the role of Eph RTK in maintaining cancer-like stem cells within the microenvironment, and the extent of Eph functional redundancy may be beneficial in overcoming the challenges of developing targeted Eph therapy to combat the tumorigenic pathway.

Conflicts of Interest

The authors declare that there are no conflicts of interest regarding the publication of this paper.

References

  1. A. Y. Chow, “Cell cycle control by oncogenes and tumor suppressors: driving the transformation of normal cells into cancerous cells,” Nature Education, vol. 3, no. 9, 7 pages, 2010. View at Google Scholar
  2. A. B. Harvey Lodish, S. Lawrence Zipursky, P. Matsudaira, D. Baltimore, and J. Darnell, “Proto-oncogenes and tumor-suppressor genes,” in Molecular Cell Biology, W. H. Freeman, New York, 4th edition, 2000. View at Google Scholar
  3. G. M. Cooper, Tumor Suppressor Genes. The Cell: A Molecular Approach, Sinauer Associates, Sunderland (MA), 2nd edition, 2000.
  4. Y. Kiraz, A. Adan, M. Kartal Yandim, and Y. Baran, “Major apoptotic mechanisms and genes involved in apoptosis,” Tumor Biology, vol. 37, no. 7, pp. 8471–8486, 2016. View at Publisher · View at Google Scholar
  5. J. Folkman, “Tumor angiogenesis: therapeutic implications.,” The New England Journal of Medicine, vol. 285, no. 21, pp. 1182–1186, 1971. View at Publisher · View at Google Scholar · View at Scopus
  6. R. H. Adams and A. Eichmann, “Axon guidance molecules in vascular patterning.,” Cold Spring Harbor Perspectives in Biology, vol. 2, no. 5, p. a001875, 2010. View at Publisher · View at Google Scholar · View at Scopus
  7. A. Barquilla and E. B. Pasquale, “Eph receptors and ephrins: Therapeutic opportunities,” Annual Review of Pharmacology and Toxicology, vol. 55, no. 1, pp. 465–487, 2015. View at Publisher · View at Google Scholar · View at Scopus
  8. E. B. Pasquale, “Eph receptors and ephrins in cancer: bidirectional signalling and beyond,” Nature Reviews Cancer, vol. 10, no. 3, pp. 165–180, 2010. View at Publisher · View at Google Scholar · View at Scopus
  9. J. E. Lisle, I. Mertens-Walker, R. Rutkowski, A. C. Herington, and S.-A. Stephenson, “Eph receptors and their ligands: Promising molecular biomarkers and therapeutic targets in prostate cancer,” Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, vol. 1835, no. 2, pp. 243–257, 2013. View at Publisher · View at Google Scholar · View at Scopus
  10. A. W. Boyd, P. F. Bartlett, and M. Lackmann, “Therapeutic targeting of EPH receptors and their ligands,” Nature Reviews Drug Discovery, vol. 13, no. 1, pp. 39–62, 2014. View at Publisher · View at Google Scholar · View at Scopus
  11. H.-Q. Xi, X.-S. Wu, B. Wei, and L. Chen, “Eph receptors and ephrins as targets for cancer therapy,” Journal of Cellular and Molecular Medicine, vol. 16, no. 12, pp. 2894–2909, 2012. View at Publisher · View at Google Scholar · View at Scopus
  12. G. Zhuang, D. M. Brantley-Sieders, D. Vaught et al., “Elevation of receptor tyrosine kinase EphA2 mediates resistance to trastuzumab therapy,” Cancer Research, vol. 70, no. 1, pp. 299–308, 2010. View at Publisher · View at Google Scholar · View at Scopus
  13. H. Lee, H. Noh, J. Mun, C. Gu, S. Sever, and S. Park, “Anks1a regulates COPII-mediated anterograde transport of receptor tyrosine kinases critical for tumorigenesis,” Nature Communications, vol. 7, Article ID 12799, 2016. View at Publisher · View at Google Scholar · View at Scopus
  14. D. Arvanitis and A. Davy, “Eph/ephrin signaling: networks,” Genes & Development, vol. 22, no. 4, pp. 416–429, 2008. View at Publisher · View at Google Scholar · View at Scopus
  15. L. Bhushan, N. Tavitian, D. Dey, Z. Tumur, C. Parsa, and R. P. Kandpal, “Modulation of liver-intestine cadherin (cadherin 17) expression, ERK phosphorylation and WNT signaling in EPHB6 receptor-expressing MDA-MB-231 cells,” Cancer Genomics & Proteomics, vol. 11, no. 5, pp. 239–249, 2014. View at Google Scholar · View at Scopus
  16. N. K. Noren and E. B. Pasquale, “Eph receptor-ephrin bidirectional signals that target Ras and Rho proteins,” Cellular Signalling, vol. 16, no. 6, pp. 655–666, 2004. View at Publisher · View at Google Scholar · View at Scopus
  17. E. B. Pasquale, “Eph-ephrin promiscuity is now crystal clear,” Nature Neuroscience, vol. 7, no. 5, pp. 417-418, 2004. View at Publisher · View at Google Scholar · View at Scopus
  18. E. M. Lisabeth, G. Falivelli, and E. B. Pasquale, “Eph receptor signaling and ephrins,” Cold Spring Harbor Perspectives in Biology, vol. 5, no. 9, pp. a009159–a009159, 2013. View at Publisher · View at Google Scholar · View at Scopus
  19. M. E. Pitulescu and R. H. Adams, “Eph/ephrin molecules - A hub for signaling and endocytosis,” Genes & Development, vol. 24, no. 22, pp. 2480–2492, 2010. View at Publisher · View at Google Scholar · View at Scopus
  20. J. M. Mendrola, F. Shi, J. H. Park, and M. A. Lemmon, “Receptor tyrosine kinases with intracellular pseudokinase domains,” Biochemical Society Transactions, vol. 41, no. 4, pp. 1029–1036, 2013. View at Publisher · View at Google Scholar · View at Scopus
  21. E. B. Pasquale, “Developmental Cell Biology: Eph receptor signalling casts a wide net on cell behavior,” Nature Reviews Molecular Cell Biology, vol. 6, no. 6, pp. 462–475, 2005. View at Publisher · View at Google Scholar · View at Scopus
  22. C. Giaginis, N. Tsoukalas, E. Bournakis et al., “Ephrin (Eph) receptor A1, A4, A5 and A7 expression in human non-small cell lung carcinoma: Associations with clinicopathological parameters, tumor proliferative capacity and patients' survival,” BMC Clinical Pathology, vol. 14, no. 1, article no. 8, 2014. View at Publisher · View at Google Scholar · View at Scopus
  23. D. M. Brantley-Sieders, “Clinical relevance of Ephs and ephrins in cancer: Lessons from breast, colorectal, and lung cancer profiling,” Seminars in Cell & Developmental Biology, vol. 23, no. 1, pp. 102–108, 2012. View at Publisher · View at Google Scholar · View at Scopus
  24. N. Nasreen, N. Khodayari, P. S. Sriram, J. Patel, and K. A. Mohammed, “Tobacco smoke induces epithelial barrier dysfunction via receptor EphA2 signaling,” American Journal of Physiology-Cell Physiology, vol. 306, no. 12, pp. C1154–C1166, 2014. View at Publisher · View at Google Scholar · View at Scopus
  25. M. S. Kinch, M.-B. Moore, and D. H. Harpole Jr., “Predictive value of the EphA2 receptor tyrosine kinase in lung cancer recurrence and survival,” Clinical Cancer Research, vol. 9, no. 2, pp. 613–618, 2003. View at Google Scholar · View at Scopus
  26. L. Faoro, P. A. Singleton, G. M. Cervantes et al., “EphA2 mutation in lung squamous cell carcinoma promotes increased cell survival, cell invasion, focal adhesions, and mammalian target of rapamycin activation,” The Journal of Biological Chemistry, vol. 285, no. 24, pp. 18575–18585, 2010. View at Publisher · View at Google Scholar · View at Scopus
  27. K. R. Amato, S. Wang, L. Tan et al., “EPHA2 blockade overcomes acquired resistance to EGFR kinase inhibitors in lung cancer,” Cancer Research, vol. 76, no. 2, pp. 305–318, 2016. View at Publisher · View at Google Scholar · View at Scopus
  28. S. Ståhl, R. Branca, G. Efazat et al., “Phosphoproteomic profiling of NSCLC cells reveals that ephrin B3 regulates pro-survival signaling through Akt1-mediated phosphorylation of the EphA2 receptor,” Journal of Proteome Research, vol. 10, no. 5, pp. 2566–2578, 2011. View at Publisher · View at Google Scholar · View at Scopus
  29. C. Hafner, “Differential Gene Expression of Eph Receptors and Ephrins in Benign Human Tissues and Cancers,” Clinical Chemistry, vol. 50, no. 3, pp. 490–499, 2004. View at Google Scholar
  30. G. Falivelli, E. M. Lisabeth, E. R. De La Torre et al., “Attenuation of Eph receptor kinase activation in cancer cells by coexpressed ephrin ligands,” PLoS ONE, vol. 8, no. 11, Article ID e81445, 2013. View at Publisher · View at Google Scholar · View at Scopus
  31. X.-D. Ji, G. Li, Y.-X. Feng et al., “EphB3 is overexpressed in non-small-cell lung cancer and promotes tumor metastasis by enhancing cell survival and migration,” Cancer Research, vol. 71, no. 3, pp. 1156–1166, 2011. View at Publisher · View at Google Scholar · View at Scopus
  32. G. Li, X.-D. Ji, H. Gao et al., “EphB3 suppresses non-small-cell lung cancer metastasis via a PP2A/RACK1/Akt signalling complex,” Nature Communications, vol. 3, article no. 667, 2012. View at Publisher · View at Google Scholar · View at Scopus
  33. B. D. Ferguson, R. Liu, C. E. Rolle et al., “The EphB4 receptor tyrosine kinase promotes lung cancer growth: a potential novel therapeutic target,” PLoS ONE, vol. 8, no. 7, Article ID e67668, 2013. View at Publisher · View at Google Scholar · View at Scopus
  34. H. Miao, D.-Q. Li, A. Mukherjee et al., “EphA2 Mediates Ligand-Dependent Inhibition and Ligand-Independent Promotion of Cell Migration and Invasion via a Reciprocal Regulatory Loop with Akt,” Cancer Cell, vol. 16, no. 1, pp. 9–20, 2009. View at Publisher · View at Google Scholar · View at Scopus
  35. D. M. Brantley-Sieders, G. Zhuang, D. Hicks et al., “The receptor tyrosine kinase EphA2 promotes mammary adenocarcinoma tumorigenesis and metastatic progression in mice by amplifying ErbB2 signaling,” The Journal of Clinical Investigation, vol. 118, no. 1, pp. 64–78, 2008. View at Publisher · View at Google Scholar · View at Scopus
  36. D. M. Brantley-Sieders, A. Jiang, K. Sarma et al., “Eph/ephrin profiling in human breast cancer reveals significant associations between expression level and clinical outcome,” PLoS ONE, vol. 6, no. 9, Article ID e24426, 2011. View at Publisher · View at Google Scholar · View at Scopus
  37. C. Johnson, B. Segovia, and R. P. Kandpal, “EPHA7 and EPHA10 physically interact and differentially co-localize in normal breast and breast carcinoma cell lines, and the co-localization pattern is altered in EPHB6-expressing MDA-MB-231 cells,” Cancer Genomics & Proteomics, vol. 13, no. 5, pp. 359–368, 2016. View at Google Scholar · View at Scopus
  38. K. Nagano, S.-I. Kanasaki, T. Yamashita et al., “Expression of Eph receptor A10 is correlated with lymph node metastasis and stage progression in breast cancer patients,” Cancer Medicine, vol. 2, no. 6, pp. 972–977, 2013. View at Publisher · View at Google Scholar · View at Scopus
  39. B. P. Fox and R. P. Kandpal, “A paradigm shift in EPH receptor interaction: Biological relevance of EPHB6 interaction with EPHA2 and EPHB2 in breast carcinoma cell lines,” Cancer Genomics & Proteomics, vol. 8, no. 4, pp. 185–193, 2011. View at Google Scholar · View at Scopus
  40. A.-M. Husa, Ž. Magic, M. Larsson, T. Fornander, and G. Pérez-Tenorio, “EPH/ephrin profile and EPHB2 expression predicts patient survival in breast cancer,” Oncotarget , vol. 7, no. 16, pp. 21362–21380, 2016. View at Publisher · View at Google Scholar · View at Scopus
  41. S. R. Kumar, J. Singh, G. Xia et al., “Receptor tyrosine kinase EphB4 is a survival factor in breast cancer,” The American Journal of Pathology, vol. 169, no. 1, pp. 279–293, 2006. View at Publisher · View at Google Scholar · View at Scopus
  42. N. K. Noren, G. Foos, C. A. Hauser, and E. B. Pasquale, “The EphB4 receptor suppresses breast cancer cell tumorigenicity through an Abl-Crk pathway,” Nature Cell Biology, vol. 8, no. 8, pp. 815–825, 2006. View at Publisher · View at Google Scholar · View at Scopus
  43. Z. Xiao, R. Carrasco, K. Kinneer et al., “EphB4 promotes or suppresses Ras/MEK/ERK pathway in a context-dependent manner,” Cancer Biology & Therapy, vol. 13, no. 8, pp. 630–637, 2012. View at Google Scholar
  44. M. Haldimann, D. Custer, N. Munarini et al., “Deregulated ephrin-B2 expression in the mammary gland interferes with the development of both the glandular epithelium and vasculature and promotes metastasis formation,” International Journal of Oncology, vol. 35, no. 3, pp. 525–536, 2009. View at Publisher · View at Google Scholar · View at Scopus
  45. G. Solanas, C. Cortina, M. Sevillano, and E. Batlle, “Cleavage of E-cadherin by ADAM10 mediates epithelial cell sorting downstream of EphB signalling,” Nature Cell Biology, vol. 13, no. 9, pp. 1100–1109, 2011. View at Publisher · View at Google Scholar · View at Scopus
  46. L. Truitt and A. Freywald, “Dancing with the dead: Eph receptors and their kinase-null partners,” The International Journal of Biochemistry & Cell Biology, vol. 89, no. 2, pp. 115–129, 2011. View at Publisher · View at Google Scholar · View at Scopus
  47. A. Freywald, N. Sharfe, and C. M. Roifman, “The kinase-null EphB6 receptor undergoes transphosphorylation in a complex with EphB1,” The Journal of Biological Chemistry, vol. 277, no. 6, pp. 3823–3828, 2002. View at Publisher · View at Google Scholar · View at Scopus
  48. L. Truitt, T. Freywald, J. DeCoteau, N. Sharfe, and A. Freywald, “The EphB6 receptor cooperates with c-Cbl to regulate the behavior of breast cancer cells,” Cancer Research, vol. 70, no. 3, pp. 1141–1153, 2010. View at Publisher · View at Google Scholar · View at Scopus
  49. B. P. Fox and R. P. Kandpal, “Transcriptional silencing of EphB6 receptor tyrosine kinase in invasive breast carcinoma cells and detection of methylated promoter by methylation specific PCR,” Biochemical and Biophysical Research Communications, vol. 340, no. 1, pp. 268–276, 2006. View at Publisher · View at Google Scholar · View at Scopus
  50. P. Kaenel, M. Mosimann, and A.-C. Andres, “The multifaceted roles of Eph-ephrin signaling in breast cancer,” Cell Adhesion & Migration, vol. 6, no. 2, pp. 138–147, 2012. View at Publisher · View at Google Scholar · View at Scopus
  51. N. K. Noren, N.-Y. Yang, M. Silldorf, R. Mutyala, and E. B. Pasquale, “Ephrin-independent regulation of cell substrate adhesion by the EphB4 receptor,” Biochemical Journal, vol. 422, no. 3, pp. 433–442, 2009. View at Publisher · View at Google Scholar · View at Scopus
  52. R. Rutkowski, I. Mertens-Walker, J. E. Lisle, A. C. Herington, and S.-A. Stephenson, “Evidence for a dual function of EphB4 as tumor promoter and suppressor regulated by the absence or presence of the ephrin-B2 ligand,” International Journal of Cancer, vol. 131, no. 5, pp. E614–E624, 2012. View at Publisher · View at Google Scholar · View at Scopus
  53. E. Binda, A. Visioli, F. Giani et al., “The EphA2 Receptor Drives Self-Renewal and Tumorigenicity in Stem-like Tumor-Propagating Cells from Human Glioblastomas,” Cancer Cell, vol. 22, no. 6, pp. 765–780, 2012. View at Publisher · View at Google Scholar · View at Scopus
  54. Z. Li, M. H. Theus, and L. Wei, “Role of ERK 1/2 signaling in neuronal differentiation of cultured embryonic stem cells,” Development, Growth & Differentiation, vol. 48, no. 8, pp. 513–523, 2006. View at Publisher · View at Google Scholar · View at Scopus
  55. M. Wegner, “SOX after SOX: SOXession regulates neurogenesis,” Genes & Development, vol. 25, no. 23, pp. 2423–2428, 2011. View at Publisher · View at Google Scholar · View at Scopus
  56. L. H. Pevny and S. K. Nicolis, “Sox2 roles in neural stem cells,” The International Journal of Biochemistry & Cell Biology, vol. 42, no. 3, pp. 421–424, 2010. View at Publisher · View at Google Scholar · View at Scopus
  57. H. Miao, N. W. Gale, H. Guo et al., “EphA2 promotes infiltrative invasion of glioma stem cells in vivo through cross-talk with Akt and regulates stem cell properties,” Oncogene, vol. 34, no. 5, pp. 558–567, 2015. View at Publisher · View at Google Scholar · View at Scopus
  58. J. Wykosky, E. Palma, D. M. Gibo, S. Ringler, C. P. Turner, and W. Debinski, “Soluble monomeric EphrinA1 is released from tumor cells and is a functional ligand for the EphA2 receptor,” Oncogene, vol. 27, no. 58, pp. 7260–7273, 2008. View at Publisher · View at Google Scholar · View at Scopus
  59. D.-P. Liu, Y. Wang, H. P. Koeffler, and D. Xie, “Ephrin-A1 is a negative regulator in glioma through down-reguation of EphA2 and FAK,” International Journal of Oncology, vol. 30, no. 4, pp. 865–871, 2007. View at Google Scholar · View at Scopus
  60. M. Aoki, T. Yamashita, and M. Tohyama, “EphA receptors direct the differentiation of mammalian neural precursor cells through a mitogen-activated protein kinase-dependent pathway,” The Journal of Biological Chemistry, vol. 279, no. 31, pp. 32643–32650, 2004. View at Publisher · View at Google Scholar · View at Scopus
  61. B. W. Day, B. W. Stringer, F. Al-Ejeh et al., “EphA3 Maintains Tumorigenicity and Is a Therapeutic Target in Glioblastoma Multiforme,” Cancer Cell, vol. 23, no. 2, pp. 238–248, 2013. View at Publisher · View at Google Scholar · View at Scopus
  62. S. Ferluga, C. M. L. Tomé, D. M. Herpai, R. D'Agostino, and W. Debinski, “Simultaneous targeting of Eph receptors in glioblastoma,” Oncotarget , vol. 7, no. 37, pp. 59860–59876, 2016. View at Publisher · View at Google Scholar · View at Scopus
  63. J.-J. Li, D.-P. Liu, G.-T. Liu, and D. Xie, “EphrinA5 acts as a tumor suppressor in glioma by negative regulation of epidermal growth factor receptor,” Oncogene, vol. 28, no. 15, pp. 1759–1768, 2009. View at Publisher · View at Google Scholar · View at Scopus
  64. J. Fukai, H. Yokote, R. Yamanaka, T. Arao, K. Nishio, and T. Itakura, “EphA4 promotes cell proliferation and migration through a novel EphA4-FGFR1 signaling pathway in the human glioma U251 cell line,” Molecular Cancer Therapeutics, vol. 7, no. 9, pp. 2768–2778, 2008. View at Publisher · View at Google Scholar · View at Scopus
  65. V. Bruce, G. Olivieri, O. Eickelberg, and G. C. Miescher, “Functional activation of EphA5 receptor does not promote cell proliferation in the aberrant EphA5 expressing human glioblastoma U-118 MG cell line,” Brain Research, vol. 821, no. 1, pp. 169–176, 1999. View at Publisher · View at Google Scholar · View at Scopus
  66. N. Almog, L. Ma, R. Raychowdhury et al., “Transcriptional switch of dormant tumors to fast-growing angiogenic phenotype,” Cancer Research, vol. 69, no. 3, pp. 836–844, 2009. View at Publisher · View at Google Scholar · View at Scopus
  67. L.-F. Wang, E. Fokas, J. Juricko et al., “Increased expression of EphA7 correlates with adverse outcome in primary and recurrent glioblastoma multiforme patients,” BMC Cancer, vol. 8, article no. 79, 2008. View at Publisher · View at Google Scholar · View at Scopus
  68. C. Gu, S. Shim, J. Shin et al., “The EphA8 receptor induces sustained MAP kinase activation to promote neurite outgrowth in neuronal cells,” Oncogene, vol. 24, no. 26, pp. 4243–4256, 2005. View at Publisher · View at Google Scholar · View at Scopus
  69. M. Nakada, J. A. Niska, H. Miyamori et al., “The Phosphorylation of EphB2 Receptor Regulates Migration and Invasion of Human Glioma Cells,” Cancer Research, vol. 64, no. 9, pp. 3179–3185, 2004. View at Publisher · View at Google Scholar · View at Scopus
  70. M. Nakada, J. A. Niska, N. L. Tran, W. S. McDonough, and M. E. Berens, “EphB2/R-ras signaling regulates glioma cell adhesion, growth, and invasion,” The American Journal of Pathology, vol. 167, no. 2, pp. 565–576, 2005. View at Publisher · View at Google Scholar · View at Scopus
  71. S. D. Wang, P. Rath, B. Lal et al., “EphB2 receptor controls proliferation/migration dichotomy of glioblastoma by interacting with focal adhesion kinase,” Oncogene, vol. 31, no. 50, pp. 5132–5143, 2012. View at Publisher · View at Google Scholar · View at Scopus
  72. Z. Ying, Y. Li, J. Wu et al., “Loss of miR-204 expression enhances glioma migration and stem cell-like phenotype,” Cancer Research, vol. 73, no. 2, pp. 990–999, 2013. View at Publisher · View at Google Scholar · View at Scopus
  73. Y. Tu, S. He, J. Fu et al., “Expression of EphrinB2 and EphB4 in glioma tissues correlated to the progression of glioma and the prognosis of glioblastoma patients,” Clinical and Translational Oncology, vol. 14, no. 3, pp. 214–220, 2012. View at Publisher · View at Google Scholar · View at Scopus
  74. M. Nakada, E. M. Anderson, T. Demuth et al., “The phosphorylation of ephrin-B2 ligand promotes glioma cell migration and invasion,” International Journal of Cancer, vol. 126, no. 5, pp. 1155–1165, 2010. View at Publisher · View at Google Scholar · View at Scopus
  75. M. Nakada, K. L. Drake, S. Nakada, J. A. Niska, and M. E. Berens, “Ephrin-B3 ligand promotes glioma invasion through activation of Rac1,” Cancer Research, vol. 66, no. 17, pp. 8492–8500, 2006. View at Publisher · View at Google Scholar · View at Scopus
  76. Y.-Y. Chuang, N. L. Tran, N. Rusk, M. Nakada, M. E. Berens, and M. Symons, “Role of synaptojanin 2 in glioma cell migration and invasion,” Cancer Research, vol. 64, no. 22, pp. 8271–8275, 2004. View at Publisher · View at Google Scholar · View at Scopus
  77. S.-y. Wang, L. Yu, G.-q. Ling et al., “Vasculogenic mimicry and its clinical significance in medulloblastoma,” Cancer Biology & Therapy, vol. 13, no. 5, pp. 341–348, 2012. View at Google Scholar
  78. S. Bhatia, N. A. Baig, O. Timofeeva et al., “Knockdown of ephb1 receptor decreases medulloblastoma cell growth and migration and increases cellular radiosensitization,” Oncotarget , vol. 6, no. 11, pp. 8929–8946, 2015. View at Google Scholar · View at Scopus
  79. A. H. Sikkema, W. F. A. Den Dunnen, E. Hulleman et al., “EphB2 activity plays a pivotal role in pediatric medulloblastoma cell adhesion and invasion,” Neuro-Oncology, vol. 14, no. 9, pp. 1125–1135, 2012. View at Publisher · View at Google Scholar · View at Scopus
  80. S. Bhatia, K. Hirsch, S. Bukkapatnam et al., “Combined EphB2 receptor knockdown with radiation decreases cell viability and invasion in medulloblastoma,” Cancer Cell International, vol. 17, no. 1, article no. 41, 2017. View at Publisher · View at Google Scholar · View at Scopus
  81. S. Bhatia, K. Hirsch, N. A. Baig et al., “Effects of altered ephrin-A5 and EphA4/EphA7 expression on tumor growth in a medulloblastoma mouse model,” Journal of Hematology & Oncology, vol. 8, no. 1, article no. 105, 2015. View at Publisher · View at Google Scholar · View at Scopus
  82. M. Hynes, W. Ye, K. Wang et al., “The seven-transmembrane receptor Smoothened cell-autonomously induces multiple ventral cell types,” Nature Neuroscience, vol. 3, no. 1, pp. 41–46, 2000. View at Publisher · View at Google Scholar · View at Scopus
  83. S. D. Karam, R. C. Burrows, C. Logan, S. Koblar, E. B. Pasquale, and M. Bothwell, “Eph receptors and ephrins in the developing chick cerebellum: Relationship to sagittal patterning and granule cell migration,” The Journal of Neuroscience, vol. 20, no. 17, pp. 6488–6500, 2000. View at Google Scholar · View at Scopus
  84. W. Hartmann, B. Digon-Söntgerath, A. Koch et al., “Phosphatidylinositol 3-kinase/AKT signaling is activated in medulloblastoma cell proliferation and is associated with reduced expression of PTEN,” Clinical Cancer Research, vol. 12, no. 10, pp. 3019–3027, 2006. View at Publisher · View at Google Scholar · View at Scopus
  85. N. McKinney, L. Yuan, H. Zhang et al., “EphrinB1 expression is dysregulated and promotes oncogenic signaling in medulloblastoma,” Journal of Neuro-Oncology, vol. 121, no. 1, pp. 109–118, 2015. View at Publisher · View at Google Scholar · View at Scopus
  86. B. P. Fox, C. J. Tabone, and R. P. Kandpal, “Potential clinical relevance of Eph receptors and ephrin ligands expressed in prostate carcinoma cell lines,” Biochemical and Biophysical Research Communications, vol. 342, no. 4, pp. 1263–1272, 2006. View at Publisher · View at Google Scholar · View at Scopus
  87. G. Zeng, Z. Hu, M. S. Kinch et al., “High-Level Expression of EphA2 Receptor Tyrosine Kinase in Prostatic Intraepithelial Neoplasia,” The American Journal of Pathology, vol. 163, no. 6, pp. 2271–2276, 2003. View at Publisher · View at Google Scholar · View at Scopus
  88. J. W. Astin, J. Batson, S. Kadir et al., “Competition amongst Eph receptors regulates contact inhibition of locomotion and invasiveness in prostate cancer cells,” Nature Cell Biology, vol. 12, no. 12, pp. 1194–1204, 2010. View at Publisher · View at Google Scholar · View at Scopus
  89. A. P. Singh, S. Bafna, K. Chaudhary et al., “Genome-wide expression profiling reveals transcriptomic variation and perturbed gene networks in androgen-dependent and androgen-independent prostate cancer cells,” Cancer Letters, vol. 259, no. 1, pp. 28–38, 2008. View at Publisher · View at Google Scholar · View at Scopus
  90. J. Zhou, W. Huang, R. Tao et al., “Inactivation of AMPK alters gene expression and promotes growth of prostate cancer cells,” Oncogene, vol. 28, no. 18, pp. 1993–2002, 2009. View at Publisher · View at Google Scholar · View at Scopus
  91. S. Ashida, H. Nakagawa, T. Katagiri et al., “Molecular features of the transition from prostatic intraepithelial neoplasia (PIN) to prostate cancer: genome-wide gene-expression profiles of prostate cancers and PINs,” Cancer Research, vol. 64, no. 17, pp. 5963–5972, 2004. View at Publisher · View at Google Scholar · View at Scopus
  92. M. Soler, F. Mancini, Ó. Meca-Cortés et al., “HER3 is required for the maintenance of neuregulin-dependent and -independent attributes of malignant progression in prostate cancer cells,” International Journal of Cancer, vol. 125, no. 11, pp. 2565–2575, 2009. View at Publisher · View at Google Scholar · View at Scopus
  93. P. Huusko, D. Ponciano-Jackson, M. Wolf et al., “Nonsense-mediated decay microarray analysis identifies mutations of EPHB2 in human prostate cancer,” Nature Genetics, vol. 36, no. 9, pp. 979–983, 2004. View at Publisher · View at Google Scholar · View at Scopus
  94. S. E. T. Larkin, S. Holmes, I. A. Cree et al., “Identification of markers of prostate cancer progression using candidate gene expression,” British Journal of Cancer, vol. 106, no. 1, pp. 157–165, 2012. View at Publisher · View at Google Scholar · View at Scopus
  95. D. B. Martin, D. R. Gifford, M. E. Wright et al., “Quantitative Proteomic Analysis of Proteins Released by Neoplastic Prostate Epithelium,” Cancer Research, vol. 64, no. 1, pp. 347–355, 2004. View at Publisher · View at Google Scholar · View at Scopus
  96. M. Kälin, I. Cima, R. Schiess et al., “Novel prognostic markers in the serum of patients with castration-resistant prostate cancer derived from quantitative analysis of the pten conditional knockout mouse proteome,” European Urology, vol. 60, no. 6, pp. 1235–1243, 2011. View at Publisher · View at Google Scholar · View at Scopus
  97. N. I. Herath, M. D. Spanevello, J. D. Doecke, F. M. Smith, C. Pouponnot, and A. W. Boyd, “Complex expression patterns of Eph receptor tyrosine kinases and their ephrin ligands in colorectal carcinogenesis,” European Journal of Cancer, vol. 48, no. 5, pp. 753–762, 2012. View at Publisher · View at Google Scholar · View at Scopus
  98. N. I. Herath, J. Doecke, M. D. Spanevello, B. A. Leggett, and A. W. Boyd, “Epigenetic silencing of EphA1 expression in colorectal cancer is correlated with poor survival,” British Journal of Cancer, vol. 100, no. 7, pp. 1095–1102, 2009. View at Publisher · View at Google Scholar · View at Scopus
  99. Y. Dong, J. Wang, Z. Sheng et al., “Downregulation of EphA1 in colorectal carcinomas correlates with invasion and metastasis,” Modern Pathology, vol. 22, no. 1, pp. 151–160, 2009. View at Publisher · View at Google Scholar · View at Scopus
  100. B. O. Wu, W. G. Jiang, D. Zhou, and Y.-X. Cui, “Knockdown of epha1 by crispr/cas9 promotes adhesion and motility of hrt18 colorectal carcinoma cells,” Anticancer Reseach, vol. 36, no. 3, pp. 1211–1220, 2016. View at Google Scholar · View at Scopus
  101. P. D. Dunne, S. Dasgupta, J. K. Blayney et al., “EphA2 expression is a key driver of migration and invasion and a poor prognostic marker in colorectal cancer,” Clinical Cancer Research, vol. 22, no. 1, pp. 230–242, 2016. View at Publisher · View at Google Scholar · View at Scopus
  102. G. Zhang, J. Brady, W.-C. Liang, Y. Wu, M. Henkemeyer, and M. Yan, “EphB4 forward signalling regulates lymphatic valve development,” Nature Communications, vol. 6, article 6625, 2015. View at Publisher · View at Google Scholar · View at Scopus
  103. J. Wang, H. Kataoka, M. Suzuki et al., “Downregulation of EphA7 by hypermethylation in colorectal cancer,” Oncogene, vol. 24, no. 36, pp. 5637–5647, 2005. View at Publisher · View at Google Scholar · View at Scopus
  104. S. R. Kumar, J. S. Scehnet, E. J. Ley et al., “Preferential induction of EphB4 over EphB2 and its implication in colorectal cancer progression,” Cancer Research, vol. 69, no. 9, pp. 3736–3745, 2009. View at Publisher · View at Google Scholar · View at Scopus
  105. N. I. Herath and A. W. Boyd, “The role of Eph receptors and ephrin ligands in colorectal cancer,” International Journal of Cancer, vol. 126, no. 9, pp. 2003–2011, 2010. View at Publisher · View at Google Scholar · View at Scopus
  106. S.-T. Chiu, K.-J. Chang, C.-H. Ting, H.-C. Shen, H. Li, and F.-J. Hsieh, “Over-expression of EphB3 enhances cell-cell contacts and suppresses tumor growth in HT-29 human colon cancer cells,” Carcinogenesis, vol. 30, no. 9, pp. 1475–1486, 2009. View at Publisher · View at Google Scholar · View at Scopus
  107. C. Cortina, S. Palomo-Ponce, M. Iglesias et al., “EphB-ephrin-B interactions suppress colorectal cancer progression by compartmentalizing tumor cells,” Nature Genetics, vol. 39, no. 11, pp. 1376–1383, 2007. View at Publisher · View at Google Scholar · View at Scopus
  108. J. Lv, Q. Xia, J. Wang, Q. Shen, J. Zhang, and X. Zhou, “EphB4 promotes the proliferation, invasion, and angiogenesis of human colorectal cancer,” Experimental and Molecular Pathology, vol. 100, no. 3, pp. 402–408, 2016. View at Publisher · View at Google Scholar · View at Scopus
  109. M. A. Stammes, H. A. J. M. Prevoo, M. C. Ter Horst et al., “Evaluation of EphA2 and EphB4 as targets for image-guided colorectal cancer surgery,” International Journal of Molecular Sciences, vol. 18, no. 2, article no. 307, 2017. View at Publisher · View at Google Scholar · View at Scopus
  110. L. Peng, P. Tu, X. Wang, S. Shi, X. Zhou, and J. Wang, “Loss of EphB6 protein expression in human colorectal cancer correlates with poor prognosis,” Journal of Molecular Histology, vol. 45, no. 5, pp. 555–563, 2014. View at Publisher · View at Google Scholar · View at Scopus
  111. S. Mateo-Lozano, S. Bazzocco, P. Rodrigues et al., “Loss of the EPH receptor B6 contributes to colorectal cancer metastasis,” Scientific Reports, vol. 7, Article ID 43702, 2017. View at Publisher · View at Google Scholar · View at Scopus
  112. J. K. Chilton, “Molecular mechanisms of axon guidance,” Developmental Biology, vol. 292, no. 1, pp. 13–24, 2006. View at Publisher · View at Google Scholar · View at Scopus
  113. N. J. Xu and M. Henkemeyer, “Ephrin reverse signaling in axon guidance and synaptogenesis,” Seminars in Cell & Developmental Biology, vol. 23, no. 1, pp. 58–64, 2012. View at Publisher · View at Google Scholar · View at Scopus
  114. E. Herrera, L. Brown, J. Aruga et al., “Zic2 patterns binocular vision by specifying the uncrossed retinal projection,” Cell, vol. 114, no. 5, pp. 545–557, 2003. View at Publisher · View at Google Scholar · View at Scopus
  115. L. Erskine, S. Reijntjes, T. Pratt et al., “VEGF Signaling through Neuropilin 1 Guides Commissural Axon Crossing at the Optic Chiasm,” Neuron, vol. 70, no. 5, pp. 951–965, 2011. View at Publisher · View at Google Scholar · View at Scopus
  116. S. E. Williams, M. Grumet, D. R. Colman, M. Henkemeyer, C. A. Mason, and T. Sakurai, “A Role for Nr-CAM in the Patterning of Binocular Visual Pathways,” Neuron, vol. 50, no. 4, pp. 535–547, 2006. View at Publisher · View at Google Scholar · View at Scopus
  117. T. Kuwajima, Y. Yoshida, N. Takegahara et al., “Optic Chiasm Presentation of Semaphorin6D in the Context of Plexin-A1 and Nr-CAM Promotes Retinal Axon Midline Crossing,” Neuron, vol. 74, no. 4, pp. 676–690, 2012. View at Publisher · View at Google Scholar · View at Scopus
  118. S. E. Williams, F. Mann, L. Erskine et al., “Ephrin-B2 and EphB1 mediate retinal axon divergence at the optic chiasm,” Neuron, vol. 39, no. 6, pp. 919–935, 2003. View at Publisher · View at Google Scholar · View at Scopus
  119. A. Escalante, B. Murillo, C. Morenilla-Palao, A. Klar, and E. Herrera, “Zic2-dependent axon midline avoidance controls the formation of major ipsilateral tracts in the CNS,” Neuron, vol. 80, no. 6, pp. 1392–1406, 2013. View at Publisher · View at Google Scholar · View at Scopus
  120. J. C. Conover, F. Doetsch, J.-M. Garcia-Verdugo, N. W. Gale, G. D. Yancopoulos, and A. Alvarez-Buylla, “Disruption of Eph/ephrin signaling affects migration and proliferation in the adult subventricular zone,” Nature Neuroscience, vol. 3, no. 11, pp. 1091–1097, 2000. View at Publisher · View at Google Scholar · View at Scopus
  121. Y. Hara, T. Nomura, K. Yoshizaki, J. Frisén, and N. Osumi, “Impaired hippocampal neurogenesis and vascular formation in ephrin-A5-deficient mice,” Stem Cells, vol. 28, no. 5, pp. 974–983, 2010. View at Publisher · View at Google Scholar · View at Scopus
  122. J. Holmberg, A. Armulik, K.-A. Senti et al., “Ephrin-A2 reverse signaling negatively regulates neural progenitor proliferation and neurogenesis,” Genes & Development, vol. 19, no. 4, pp. 462–471, 2005. View at Publisher · View at Google Scholar · View at Scopus
  123. J. Ricard, J. Salinas, L. Garcia, and D. J. Liebl, “EphrinB3 regulates cell proliferation and survival in adult neurogenesis,” Molecular and Cellular Neuroscience, vol. 31, no. 4, pp. 713–722, 2006. View at Publisher · View at Google Scholar · View at Scopus
  124. K. del Valle, M. H. Theus, J. R. Bethea, D. J. Liebl, and J. Ricard, “Neural progenitors proliferation is inhibited by EphB3 in the developing subventricular zone,” International Journal of Developmental Neuroscience, vol. 29, no. 1, pp. 9–14, 2011. View at Publisher · View at Google Scholar · View at Scopus
  125. J.-W. Jiao, D. A. Feldheim, and D. F. Chen, “Ephrins as negative regulators of adult neurogenesis in diverse regions of the central nervous system,” Proceedings of the National Acadamy of Sciences of the United States of America, vol. 105, no. 25, pp. 8778–8783, 2008. View at Publisher · View at Google Scholar · View at Scopus
  126. H. U. Wang, Z.-F. Chen, and D. J. Anderson, “Molecular distinction and angiogenic interaction between embryonic arteries and veins revealed by ephrin-B2 and its receptor Eph-B4,” Cell, vol. 93, no. 5, pp. 741–753, 1998. View at Publisher · View at Google Scholar · View at Scopus
  127. R. H. Adams, G. A. Wilkinson, C. Weiss et al., “Roles of ephrinB ligands and EphB receptors in cardiovascular development: Demarcation of arterial/venous domains, vascular morphogenesis, and sprouting angiogenesis,” Genes & Development, vol. 13, no. 3, pp. 295–306, 1999. View at Publisher · View at Google Scholar · View at Scopus
  128. S. P. Herbert, J. Huisken, T. N. Kim et al., “Arterial-venous segregation by selective cell sprouting: an alternative mode of blood vessel formation,” Science, vol. 326, no. 5950, pp. 294–298, 2009. View at Publisher · View at Google Scholar · View at Scopus
  129. Y. Wang, M. Nakayama, M. E. Pitulescu et al., “Ephrin-B2 controls VEGF-induced angiogenesis and lymphangiogenesis,” Nature, vol. 465, no. 7297, pp. 483–486, 2010. View at Publisher · View at Google Scholar · View at Scopus
  130. M. Nakayama, A. Nakayama, M. van Lessen et al., “Spatial regulation of VEGF receptor endocytosis in angiogenesis,” Nature Cell Biology, vol. 15, no. 3, pp. 249–260, 2013. View at Publisher · View at Google Scholar · View at Scopus
  131. K.-W. Kim and J.-H. Song, “Emerging roles of lymphatic vasculature in immunity,” Immune Network, vol. 17, no. 1, pp. 68–76, 2017. View at Publisher · View at Google Scholar · View at Scopus
  132. E. Bazigou and T. Makinen, “Flow control in our vessels: Vascular valves make sure there is no way back,” Cellular and Molecular Life Sciences, vol. 70, no. 6, pp. 1055–1066, 2013. View at Publisher · View at Google Scholar · View at Scopus
  133. T. Mäkinen, R. H. Adams, J. Bailey et al., “PDZ interaction site in ephrinB2 is required for the remodeling of lymphatic vasculature,” Genes & Development, vol. 19, no. 3, pp. 397–410, 2005. View at Publisher · View at Google Scholar · View at Scopus
  134. S. S. Foo, C. J. Turner, S. Adams et al., “Ephrin-B2 controls cell motility and adhesion during blood-vessel-wall assembly,” Cell, vol. 124, no. 1, pp. 161–173, 2006. View at Publisher · View at Google Scholar · View at Scopus
  135. A. Nakayama, M. Nakayama, C. J. Turner, S. Hoing, J. J. Lepore, and R. H. Adams, “Ephrin-B2 controls PDGFR internalization and signaling,” Genes & Development, vol. 27, no. 23, pp. 2576–2589, 2013. View at Google Scholar
  136. M. Lackmann and A. W. Boyd, “Eph, a protein family coming of age: more confusion, insight, or complexity?” Science Signaling, vol. 1, no. 15, article re2, 2008. View at Publisher · View at Google Scholar · View at Scopus
  137. C. Baldwin, Z. W. Chen, A. Bedirian et al., “Upregulation of EphA2 during in vivo and in vitro renal ischemia-reperfusion injury: Role of Src kinases,” American Journal of Physiology-Renal Physiology, vol. 291, no. 5, pp. F960–F971, 2006. View at Publisher · View at Google Scholar · View at Scopus
  138. M. M. Vihanto, J. Plock, D. Erni, B. M. Frey, F. J. Frey, and U. Huynh-Do, “Hypoxia up-regulates expression of Eph receptors and ephrins in mouse skin,” The FASEB Journal, vol. 19, no. 12, pp. 1689–1691, 2005. View at Publisher · View at Google Scholar · View at Scopus
  139. X. Liu, E. Hawkes, T. Ishimaru, T. Tran, and D. W. Sretavan, “EphB3: An endogenous mediator of adult axonal plasticity and regrowth after CNS injury,” The Journal of Neuroscience, vol. 26, no. 12, pp. 3087–3101, 2006. View at Publisher · View at Google Scholar · View at Scopus
  140. M. G. Coulthard, M. Morgan, T. M. Woodruff et al., “Eph/ephrin signaling in injury and inflammation,” The American Journal of Pathology, vol. 181, no. 5, pp. 1493–1503, 2012. View at Publisher · View at Google Scholar · View at Scopus
  141. Y. Goldshmit, M. P. Galea, G. Wise, P. F. Bartlett, and A. M. Turnley, “Axonal regeneration and lack of astrocytic gliosis in EphA4-deficient mice,” The Journal of Neuroscience, vol. 24, no. 45, pp. 10064–10073, 2004. View at Publisher · View at Google Scholar · View at Scopus
  142. Y. Goldshmit and J. Bourne, “Upregulation of epha4 on astrocytes potentially mediates astrocytic gliosis after cortical lesion in the marmoset monkey,” Journal of Neurotrauma, vol. 27, no. 7, pp. 1321–1332, 2010. View at Publisher · View at Google Scholar · View at Scopus
  143. J.-P. Himanen and D. B. Nikolov, “Eph signaling: a structural view,” Trends in Neurosciences, vol. 26, no. 1, pp. 46–51, 2003. View at Publisher · View at Google Scholar · View at Scopus
  144. J. P. Himanen, L. Yermekbayeva, P. W. Janes et al., “Architecture of Eph receptor clusters,” Proceedings of the National Acadamy of Sciences of the United States of America, vol. 107, no. 24, pp. 10860–10865, 2010. View at Publisher · View at Google Scholar · View at Scopus
  145. A. Schaupp, O. Sabet, I. Dudanova, M. Ponserre, P. Bastiaens, and R. Klein, “The composition of EphB2 clusters determines the strength in the cellular repulsion response,” The Journal of Cell Biology, vol. 204, no. 3, pp. 409–422, 2014. View at Publisher · View at Google Scholar · View at Scopus
  146. M. Zimmer, A. Palmer, J. Köhler, and R. Klein, “EphB-ephrinB bi-directional endocytosis terminates adhesion allowing contact mediated repulsion,” Nature Cell Biology, vol. 5, no. 10, pp. 869–878, 2003. View at Publisher · View at Google Scholar · View at Scopus
  147. D. J. Marston, S. Dickinson, and C. D. Nobes, “Rac-dependent trans-endocytosis of ephrinBs regulates Eph-ephrin contact repulsion,” Nature Cell Biology, vol. 5, no. 10, pp. 879–888, 2003. View at Publisher · View at Google Scholar · View at Scopus
  148. J. Egea and R. Klein, “Bidirectional Eph-ephrin signaling during axon guidance,” Trends in Cell Biology, vol. 17, no. 5, pp. 230–238, 2007. View at Publisher · View at Google Scholar · View at Scopus
  149. C. J. Vearing and M. Lackmann, “Eph receptor signalling; dimerisation just isn't enough,” Growth Factors, vol. 23, no. 1, pp. 67–76, 2005. View at Publisher · View at Google Scholar · View at Scopus
  150. Y. Yin, Y. Yamashita, H. Noda, T. Okafuji, M. J. Go, and H. Tanaka, “EphA receptor tyrosine kinases interact with co-expressed ephrin-A ligands in cis,” Neuroscience Research, vol. 48, no. 3, pp. 285–296, 2004. View at Publisher · View at Google Scholar · View at Scopus
  151. R. F. Carvalho, M. Beutler, K. J. M. Marler et al., “Silencing of EphA3 through a cis interaction with ephrinA5,” Nature Neuroscience, vol. 9, no. 3, pp. 322–330, 2006. View at Publisher · View at Google Scholar · View at Scopus
  152. M. S. Kalo and E. B. Pasquale, “Multiple in vivo tyrosine phosphorylation sites in EphB receptors,” Biochemistry, vol. 38, no. 43, pp. 14396–14408, 1999. View at Publisher · View at Google Scholar · View at Scopus
  153. L. Van Aelst and C. D'Souza-Schorey, “Rho GTPases and signaling networks,” Genes & Development, vol. 11, no. 18, pp. 2295–2322, 1997. View at Publisher · View at Google Scholar · View at Scopus
  154. A. Palmer, M. Zimmer, K. S. Erdmann et al., “EphrinB phosphorylation and reverse signaling: Regulation by Src kinases and PTP-BL phosphatase,” Molecular Cell, vol. 9, no. 4, pp. 725–737, 2002. View at Publisher · View at Google Scholar · View at Scopus
  155. C. A. Cowan and M. Henkemeyer, “The SH2/SH3 adaptor Grb4 transduces B-ephrin reverse signals,” Nature, vol. 413, no. 6852, pp. 174–179, 2001. View at Publisher · View at Google Scholar · View at Scopus
  156. K. Kullander and R. Klein, “Mechanisms and functions of Eph and ephrin signalling,” Nature Reviews Molecular Cell Biology, vol. 3, no. 7, pp. 475–486, 2002. View at Publisher · View at Google Scholar · View at Scopus
  157. R. L. Siegel, K. D. Miller, and A. Jemal, “Cancer statistics, 2016,” CA: A Cancer Journal for Clinicians, vol. 66, no. 1, pp. 7–30, 2016. View at Publisher · View at Google Scholar
  158. G. D'Addario and E. Felip, “Non-small-cell lung cancer: ESMO Clinical Recommendations for diagnosis, treatment and follow-up,” Annals of Oncology, vol. 20, no. 4, pp. iv68–iv70, 2009. View at Publisher · View at Google Scholar · View at Scopus
  159. T. D. Bartley, R. W. Hunt, A. A. Welcher et al., “B61 is a ligand for the ECK receptor protein-tyrosine kinase,” Nature, vol. 368, no. 6471, pp. 558–560, 1994. View at Publisher · View at Google Scholar · View at Scopus
  160. A. K. Rud, M. Lund-Iversen, G. Berge et al., “Expression of S100A4, ephrin-A1 and osteopontin in non-small cell lung cancer,” BMC Cancer, vol. 12, article no. 333, 2012. View at Publisher · View at Google Scholar · View at Scopus
  161. M. Ishikawa, R. Miyahara, M. Sonobe et al., “Higher expression of EphA2 and ephrin-A1 is related to favorable clinicopathological features in pathological stage I non-small cell lung carcinoma,” Lung Cancer, vol. 76, no. 3, pp. 431–438, 2012. View at Publisher · View at Google Scholar · View at Scopus
  162. J. Peng, Q. Wang, H. Liu, M. Ye, X. Wu, and L. Guo, “EPHA3 regulates the multidrug resistance of small cell lung cancer via the PI3K/BMX/STAT3 signaling pathway,” Tumor Biology, vol. 37, no. 9, pp. 11959–11971, 2016. View at Publisher · View at Google Scholar · View at Scopus
  163. C. Müller-Tidow, S. Diederichs, E. Bulk et al., “Identification of metastasis-associated receptor tyrosine kinases in non-small cell lung cancer,” Cancer Research, vol. 65, no. 5, pp. 1778–1782, 2005. View at Publisher · View at Google Scholar · View at Scopus
  164. E. Bulk, J. Yu, A. Hascher et al., “Mutations of the EPHB6 Receptor Tyrosine Kinase Induce a Pro-Metastatic Phenotype in Non-Small Cell Lung Cancer,” PLoS ONE, vol. 7, no. 12, Article ID e44591, 2012. View at Publisher · View at Google Scholar · View at Scopus
  165. K. Carles-Kinch, K. E. Kilpatrick, J. C. Stewart, and M. S. Kinch, “Antibody targeting of the EphA2 tyrosine kinase inhibits malignant cell behavior,” Cancer Research, vol. 62, no. 10, pp. 2840–2847, 2002. View at Google Scholar · View at Scopus
  166. D. P. Zelinski, N. D. Zantek, J. C. Stewart, A. R. Irizarry, and M. S. Kinch, “EphA2 overexpression causes tumorigenesis of mammary epithelial cells,” Cancer Research, vol. 61, no. 5, pp. 2301–2306, 2001. View at Google Scholar · View at Scopus
  167. W. B. Fang, D. M. Brantley-Sieders, M. A. Parker, A. D. Reith, and J. Chen, “A kinase-dependent role for EphA2 receptor in promoting tumor growth and metastasis,” Oncogene, vol. 24, no. 53, pp. 7859–7868, 2005. View at Publisher · View at Google Scholar · View at Scopus
  168. M. Lu, K. D. Miller, Y. Gokmen-Polar, M.-H. Jeng, and M. S. Kinch, “EphA2 overexpression decreases estrogen dependence and tamoxifen sensitivity,” Cancer Research, vol. 63, no. 12, pp. 3425–3429, 2003. View at Google Scholar · View at Scopus
  169. J. Kurebayashi, M. Nukatsuka, H. Sonoo, J. Uchida, and M. Kiniwa, “Preclinical rationale for combined use of endocrine therapy and 5-fluorouracil but neither doxorubicin nor paclitaxel in the treatment of endocrine-responsive breast cancer,” Cancer Chemotherapy and Pharmacology, vol. 65, no. 2, pp. 219–225, 2010. View at Publisher · View at Google Scholar · View at Scopus
  170. G. Berclaz, B. Flütsch, H. J. Altermatt et al., “Loss of EphB4 receptor tyrosine kinase protein expression during carcinogenesis of the human breast.,” Oncology Reports, vol. 9, no. 5, pp. 985–989, 2002. View at Google Scholar · View at Scopus
  171. Q. Wu, Z. Suo, B. Risberg, M. G. Karlsson, K. Villman, and J. M. Nesland, “Expression of Ephb2 and Ephb4 in breast carcinoma,” Pathology & Oncology Research, vol. 10, no. 1, pp. 26–33, 2004. View at Publisher · View at Google Scholar · View at Scopus
  172. K. K. Murai and E. B. Pasquale, “'Eph'ective signaling: forward, reverse and crosstalk,” Journal of Cell Science, vol. 116, no. 14, pp. 2823–2832, 2003. View at Publisher · View at Google Scholar · View at Scopus
  173. B. P. Fox and R. P. Kandpal, “Invasiveness of breast carcinoma cells and transcript profile: Eph receptors and ephrin ligands as molecular markers of potential diagnostic and prognostic application,” Biochemical and Biophysical Research Communications, vol. 318, no. 4, pp. 882–892, 2004. View at Publisher · View at Google Scholar · View at Scopus
  174. B. P. Fox and R. P. Kandpal, “DNA-based assay for EPHB6 expression in breast carcinoma cells as a potential diagnostic test for detecting tumor cells in circulation,” Cancer Genomics & Proteomics, vol. 7, no. 1, pp. 9–16, 2010. View at Google Scholar · View at Scopus
  175. B. P. Fox and R. P. Kandpal, “EphB6 receptor significantly alters invasiveness and other phenotypic characteristics of human breast carcinoma cells,” Oncogene, vol. 28, no. 14, pp. 1706–1713, 2009. View at Publisher · View at Google Scholar · View at Scopus
  176. Q. T. Ostrom, L. Bauchet, F. G. Davis et al., “The epidemiology of glioma in adults: A state of the science review,” Neuro-Oncology, vol. 16, no. 7, pp. 896–913, 2014. View at Publisher · View at Google Scholar · View at Scopus
  177. D. N. Louis, H. Ohgaki, O. D. Wiestler et al., “The 2007 WHO classification of tumours of the central nervous system,” Acta Neuropathologica, vol. 114, no. 2, pp. 97–109, 2007. View at Publisher · View at Google Scholar · View at Scopus
  178. P. A. Northcott, D. T. W. Jones, M. Kool et al., “Medulloblastomics: the end of the beginning,” Nature Reviews Cancer, vol. 12, no. 12, pp. 818–834, 2012. View at Publisher · View at Google Scholar · View at Scopus
  179. P. Fiorilli, D. Partridge, I. Staniszewska et al., “Integrins mediate adhesion of medulloblastoma cells to tenascin and activate pathways associated with survival and proliferation,” Laboratory Investigation, vol. 88, no. 11, pp. 1143–1156, 2008. View at Publisher · View at Google Scholar · View at Scopus
  180. J. Wykosky, D. M. Gibo, C. Stanton, and W. Debinski, “EphA2 as a novel molecular marker and target in glioblastoma multiforme,” Molecular Cancer Research, vol. 3, no. 10, pp. 541–551, 2005. View at Publisher · View at Google Scholar · View at Scopus
  181. X. Li, Y. Wang, Y. Wang et al., “Expression of EphA2 in human astrocytic tumors: correlation with pathologic grade, proliferation and apoptosis,” Tumor Biology, vol. 28, no. 3, pp. 165–172, 2007. View at Publisher · View at Google Scholar · View at Scopus
  182. L-F. Wang, E. Fokas, M. Bieker et al., “Increased expression of EphA2 correlates with adverse outcome in primary and recurrent glioblastoma multiforme patients,” Oncol Rep, vol. 19, no. 1, pp. 151–156, 2008. View at Google Scholar
  183. B. W. Day, B. W. Stringer, and A. W. Boyd, “Eph receptors as therapeutic targets in glioblastoma,” British Journal of Cancer, vol. 111, no. 7, pp. 1255–1261, 2014. View at Publisher · View at Google Scholar · View at Scopus
  184. R. Erber, U. Eichelsbacher, V. Powajbo et al., “EphB4 controls blood vascular morphogenesis during postnatal angiogenesis,” EMBO Journal, vol. 25, no. 3, pp. 628–641, 2006. View at Publisher · View at Google Scholar · View at Scopus
  185. J.-L. Li, R. C. A. Sainson, C. E. Oon et al., “DLL4-Notch signaling mediates tumor resistance to anti-VEGF therapy in vivo,” Cancer Research, vol. 71, no. 18, pp. 6073–6083, 2011. View at Publisher · View at Google Scholar · View at Scopus
  186. S. Sawamiphak, S. Seidel, C. L. Essmann et al., “Ephrin-B2 regulates VEGFR2 function in developmental and tumour angiogenesis,” Nature, vol. 465, no. 7297, pp. 487–491, 2010. View at Publisher · View at Google Scholar · View at Scopus
  187. N.-Y. Yang, C. Fernandez, M. Richter et al., “Crosstalk of the EphA2 receptor with a serine/threonine phosphatase suppresses the Akt-mTORC1 pathway in cancer cells,” Cellular Signalling, vol. 23, no. 1, pp. 201–212, 2011. View at Publisher · View at Google Scholar · View at Scopus
  188. J.-P. Lin, B.-C. Pan, B. Li, Y. Li, X.-Y. Tian, and Z. Li, “DJ-1 is activated in medulloblastoma and is associated with cell proliferation and differentiation,” World Journal of Surgical Oncology, vol. 12, no. 1, article no. 373, 2014. View at Publisher · View at Google Scholar · View at Scopus
  189. J. Romero Otero, B. Garcia Gomez, F. Campos Juanatey, and K. A. Touijer, “Prostate cancer biomarkers: an update,” Urologic Oncology: Seminars and Original Investigations, vol. 32, no. 3, pp. 252–260, 2014. View at Publisher · View at Google Scholar · View at Scopus
  190. K. C. Cary and M. R. Cooperberg, “Biomarkers in prostate cancer surveillance and screening: Past, present, and future,” Therapeutic Advances in Urology, vol. 5, no. 6, pp. 318–329, 2013. View at Publisher · View at Google Scholar · View at Scopus
  191. J. Walker-Daniels, K. Coffman, M. Azimi et al., “Overexpression of the EphA2 tyrosine kinase in prostate cancer,” The Prostate, vol. 41, no. 4, pp. 275–280, 1999. View at Publisher · View at Google Scholar · View at Scopus
  192. H. Miao, B.-R. Wei, D. M. Peehl et al., “Activation of EphA receptor tyrosine kinase inhibits the Ras/MAPK pathway,” Nature Cell Biology, vol. 3, no. 5, pp. 527–530, 2001. View at Publisher · View at Google Scholar · View at Scopus
  193. H. Miao, E. Burnett, M. Kinch, E. Simon, and B. Wang, “Activation of EphA2 kinase suppresses integrin function and causes focal-adhesion-kinase dephosphorylation,” Nature Cell Biology, vol. 2, no. 2, pp. 62–69, 2000. View at Publisher · View at Google Scholar · View at Scopus
  194. L. Salmena, A. Carracedo, and P. P. Pandolfi, “Tenets of PTEN tumor suppression,” Cell, vol. 133, no. 3, pp. 403–414, 2008. View at Publisher · View at Google Scholar · View at Scopus
  195. M. L. Taddei, M. Parri, A. Angelucci et al., “Kinase-dependent and -independent roles of EphA2 in the regulation of prostate cancer invasion and metastasis,” The American Journal of Pathology, vol. 174, no. 4, pp. 1492–1503, 2009. View at Publisher · View at Google Scholar · View at Scopus
  196. M. L. Taddei, M. Parri, A. Angelucci et al., “EphA2 induces metastatic growth regulating amoeboid motility and clonogenic potential in prostate carcinoma cells,” Molecular Cancer Research, vol. 9, no. 2, pp. 149–160, 2011. View at Publisher · View at Google Scholar · View at Scopus
  197. A. E. Ross, L. Marchionni, M. Vuica-Ross et al., “Gene expression pathways of high grade localized prostate cancer,” The Prostate, vol. 71, no. 14, pp. 1568–1578, 2011. View at Publisher · View at Google Scholar · View at Scopus
  198. K. Jennbacken, H. Gustavsson, T. Tešan et al., “The prostatic environment suppresses growth of androgen-independent prostate cancer xenografts: An effect influenced by testosterone,” The Prostate, vol. 69, no. 11, pp. 1164–1175, 2009. View at Publisher · View at Google Scholar · View at Scopus
  199. M. Guan, C. Xu, F. Zhang, and C. Ye, “Aberrant methylation of EphA7 in human prostate cancer and its relation to clinicopathologic features,” International Journal of Cancer, vol. 124, no. 1, pp. 88–94, 2009. View at Publisher · View at Google Scholar · View at Scopus
  200. A. J. Oudes, J. C. Roach, L. S. Walashek et al., “Application of affymetrix array and massively parallel signature sequencing for identification of genes involved in prostate cancer progression,” BMC Cancer, vol. 5, article no. 86, 2005. View at Publisher · View at Google Scholar · View at Scopus
  201. S. Tao, Z. Wang, J. Feng et al., “A genome-wide search for loci interacting with known prostate cancer risk-associated genetic variants,” Carcinogenesis, vol. 33, no. 3, pp. 598–603, 2012. View at Publisher · View at Google Scholar · View at Scopus
  202. R. A. Kittles, A. B. Boffoe-Bonnie, T. Y. Moses et al., “A common nonsense mutation in EphB2 is associated with prostate cancer risk in African American men with a positive family history,” Journal of Medical Genetics, vol. 43, no. 6, pp. 507–511, 2006. View at Publisher · View at Google Scholar · View at Scopus
  203. A. Jemal, M. M. Center, C. DeSantis, and E. M. Ward, “Global patterns of cancer incidence and mortality rates and trends,” Cancer Epidemiology, Biomarkers & Prevention, vol. 19, no. 8, pp. 1893–1907, 2010. View at Publisher · View at Google Scholar · View at Scopus
  204. H. Chaib, E. K. Cockrell, M. A. Rubin, and J. A. Macoska, “Profiling and verification of gene expression patterns in normal and malignant human prostate tissues by cDNA microarray analysis,” Neoplasia, vol. 3, no. 1, pp. 43–52, 2001. View at Publisher · View at Google Scholar · View at Scopus
  205. Y.-C. Lee, J. R. Perren, E. L. Douglas et al., “Investigation of the expression of the EphB4 receptor tyrosine kinase in prostate carcinoma,” BMC Cancer, vol. 5, article no. 119, 2005. View at Publisher · View at Google Scholar · View at Scopus
  206. G. Xia, S. R. Kumar, R. Masood et al., “EphB4 expression and biological significance in prostate cancer,” Cancer Research, vol. 65, no. 11, pp. 4623–4632, 2005. View at Publisher · View at Google Scholar · View at Scopus
  207. M. Arnold, M. S. Sierra, M. Laversanne, I. Soerjomataram, A. Jemal, and F. Bray, “Global patterns and trends in colorectal cancer incidence and mortality,” Gut, 2016. View at Publisher · View at Google Scholar · View at Scopus
  208. F. Kastrinos and S. Syngal, “Inherited colorectal cancer syndromes,” Cancer Journal, vol. 17, no. 6, pp. 405–415, 2011. View at Publisher · View at Google Scholar · View at Scopus
  209. E. Batlle, J. T. Henderson, H. Beghtel et al., “β-catenin and TCF mediate cell positioning in the intestinal epithelium by controlling the expression of EphB/EphrinB,” Cell, vol. 111, no. 2, pp. 251–263, 2002. View at Publisher · View at Google Scholar · View at Scopus
  210. E. Batlle, J. Bacani, H. Begthel et al., “EphB receptor activity suppresses colorectal cancer progression,” Nature, vol. 435, no. 7045, pp. 1126–1130, 2005. View at Publisher · View at Google Scholar · View at Scopus
  211. C. Hafner, G. Schmitz, S. Meyer et al., “Differential gene expression of Eph receptors and ephrins in benign human tissue and cancers,” Clinical Chemistry, vol. 50, no. 3, pp. 490–490, 2004. View at Google Scholar
  212. D. L. Guo, J. Zhang, S. T. Yuen et al., “Reduced expression of EphB2 that parallels invasion and metastasis in colorectal tumours,” Carcinogenesis, vol. 27, no. 3, pp. 454–464, 2006. View at Publisher · View at Google Scholar · View at Scopus
  213. A. Lugli, H. Spichtin, R. Maurer et al., “EphB2 expression across 138 human tumor types in a tissue microarray: High levels of expression in gastrointestinal cancers,” Clinical Cancer Research, vol. 11, no. 18, pp. 6450–6458, 2005. View at Publisher · View at Google Scholar · View at Scopus
  214. A. M. Jubb, F. Zhong, S. Bheddah et al., “EphB2 is a prognostic factor in colorectal cancer,” Clinical Cancer Research, vol. 11, no. 14, pp. 5181–5187, 2005. View at Publisher · View at Google Scholar · View at Scopus
  215. S.-A. Stephenson, S. Slomka, E. L. Douglas, P. J. Hewett, and J. E. Hardingham, “Receptor protein tyrosine kinase EphB4 is up-regulated in colon cancer,” BMC Molecular Biology, vol. 2, article no. 15, 2001. View at Publisher · View at Google Scholar · View at Scopus
  216. G. Ciasca, M. Papi, E. Minelli, V. Palmieri, and M. De Spirito, “Changes in cellular mechanical properties during onset or progression of colorectal cancer,” World Journal of Gastroenterology, vol. 22, no. 32, pp. 7203–7214, 2016. View at Publisher · View at Google Scholar · View at Scopus
  217. T.-J. Kao and A. Kania, “Ephrin-Mediated cis-Attenuation of Eph Receptor Signaling Is Essential for Spinal Motor Axon Guidance,” Neuron, vol. 71, no. 1, pp. 76–91, 2011. View at Publisher · View at Google Scholar · View at Scopus
  218. E. M. Lisabeth, C. Fernandez, and E. B. Pasquale, “Cancer somatic mutations disrupt functions of the EphA3 receptor tyrosine kinase through multiple mechanisms,” Biochemistry, vol. 51, no. 7, pp. 1464–1475, 2012. View at Publisher · View at Google Scholar · View at Scopus
  219. M. A. Huber, N. Kraut, and H. Beug, “Molecular requirements for epithelial-mesenchymal transition during tumor progression,” Current Opinion in Cell Biology, vol. 17, no. 5, pp. 548–558, 2005. View at Publisher · View at Google Scholar · View at Scopus
  220. H. Maio and B. Wang, “EphA receptor signaling – complexity and emerging themes,” Seminarsin Cell & Developmental Biology, vol. 23, no. 1, pp. 16–25, 2012. View at Google Scholar
  221. S. K. Singh, I. D. Clarke, T. Hide, and P. B. Dirks, “Cancer stem cells in nervous system tumors,” Oncogene, vol. 23, no. 43, pp. 7267–7273, 2004. View at Publisher · View at Google Scholar · View at Scopus
  222. A. Kreso and J. Dick, “Evolution of the cancer stem cell model,” Cell Stem Cell, vol. 14, no. 3, pp. 275–291, 2014. View at Publisher · View at Google Scholar
  223. D. S. Chen and I. Mellman, “Oncology meets immunology: the cancer-immunity cycle,” Immunity, vol. 39, no. 1, pp. 1–10, 2013. View at Publisher · View at Google Scholar · View at Scopus
  224. G. Yu, H. Luo, Y. Wu, and J. Wu, “Ephrin B2 induces T cell costimulation,” The Journal of Immunology, vol. 171, no. 1, pp. 106–114, 2003. View at Publisher · View at Google Scholar · View at Scopus
  225. G. Yu, H. Luo, Y. Wu, and J. Wu, “Mouse EphrinB3 Augments T-cell Signaling and Responses to T-cell Receptor Ligation,” The Journal of Biological Chemistry, vol. 278, no. 47, pp. 47209–47216, 2003. View at Publisher · View at Google Scholar · View at Scopus
  226. G. Yu, H. Luo, Y. Wu, and J. Wu, “EphrinB1 is essential in T-cell-T-cell co-operation during T-cell activation,” The Journal of Biological Chemistry, vol. 279, no. 53, pp. 55531–55539, 2004. View at Publisher · View at Google Scholar · View at Scopus
  227. H. Luo, G. Yu, Y. Wu, and J. Wu, “EphB6 crosslinking results in costimulation of T cells,” The Journal of Clinical Investigation, vol. 110, no. 8, pp. 1141–1150, 2002. View at Publisher · View at Google Scholar · View at Scopus
  228. H. Luo, G. Yu, J. Tremblay, and J. Wu, “EphB6-null mutation results in compromised T cell function,” The Journal of Clinical Investigation, vol. 114, no. 12, pp. 1762–1773, 2004. View at Publisher · View at Google Scholar · View at Scopus
  229. C. E. Chee, S. Krishnamurthi, C. J. Nock et al., “Phase II study of dasatinib (BMS-354825) in patients with metastatic adenocarcinoma of the pancreas,” The Oncologist, vol. 18, no. 10, pp. 1091-1092, 2013. View at Publisher · View at Google Scholar · View at Scopus
  230. M. J. Kelley, G. Jha, D. Shoemaker et al., “Phase II Study of Dasatinib in Previously Treated Patients with Advanced Non-Small Cell Lung Cancer,” Cancer Investigation, vol. 35, no. 1, pp. 32–35, 2017. View at Publisher · View at Google Scholar · View at Scopus
  231. S. M. Schuetze, J. K. Wathen, D. R. Lucas et al., “SARC009: Phase 2 study of dasatinib in patients with previously treated, high-grade, advanced sarcoma,” Cancer, vol. 122, no. 6, pp. 868–874, 2016. View at Publisher · View at Google Scholar · View at Scopus
  232. Y. Ishida, K. Murai, K. Yamaguchi et al., “Pharmacokinetics and pharmacodynamics of dasatinib in the chronic phase of newly diagnosed chronic myeloid leukemia,” European Journal of Clinical Pharmacology, vol. 72, no. 2, pp. 185–193, 2016. View at Publisher · View at Google Scholar · View at Scopus
  233. C. M. Annunziata, E. C. Kohn, P. Lorusso et al., “Phase 1, open-label study of MEDI-547 in patients with relapsed or refractory solid tumors,” Investigational New Drugs, vol. 31, no. 1, pp. 77–84, 2013. View at Publisher · View at Google Scholar · View at Scopus
  234. S. Charmsaz and A. W. Boyd, “Eph receptors as oncotargets,” Oncotarget , vol. 8, no. 47, pp. 81727-81728, 2017. View at Publisher · View at Google Scholar · View at Scopus
  235. S. Charmsaz, A. M. Scott, and A. W. Boyd, “Targeted therapies in hematological malignancies using therapeutic monoclonal antibodies against Eph family receptors,” Experimental Hematology, vol. 54, Supplement C, pp. 31–39, 2017. View at Publisher · View at Google Scholar · View at Scopus
  236. J. J. Munoz, L. M. Alonso-C, R. Sacedon et al., “Expression and function of the EphA receptors and their ligand ephrin in the rat thymus,” Journal of Immunology, vol. 169, no. 1, p. 177, 2002. View at Google Scholar
  237. M. Shimoyama, H. Matsuoka, A. Nagata et al., “Developmental expression of EphB6 in the thymus: Lessons from EphB6 knockout mice,” Biochemical and Biophysical Research Communications, vol. 298, no. 1, pp. 87–94, 2002. View at Publisher · View at Google Scholar · View at Scopus
  238. G. Yu, J. Mao, Y. Wu, H. Luo, and J. Wu, “Ephrin-B1 is critical in T-cell development,” The Journal of Biological Chemistry, vol. 281, no. 15, pp. 10222–10229, 2006. View at Publisher · View at Google Scholar · View at Scopus
  239. M. G. Coulthard, J. D. Lickliter, N. Subanesan et al., “Characterization of the EphA1 receptor tyrosine kinase: Expression in epithelial tissues,” Growth Factors, vol. 18, no. 4, pp. 303–317, 2001. View at Publisher · View at Google Scholar · View at Scopus
  240. N. I. Herath, M. D. Spanevello, J. D. Doecke, F. M. Smith, C. Pouponnot, and D. W. Boywd, “Complex expression patterns of Eph receptor tyrosine kinase and their ephrin ligands in colorectal carcinogenesis,” European Journal of Cancer, vol. 48, no. 5, pp. 753–762, 2012. View at Google Scholar
  241. L. Mathot, S. Kundu, V. Ljungström et al., “Somatic ephrin receptor mutations are associated with metastasis in primary colorectal cancer,” Cancer Research, vol. 77, no. 7, pp. 1730–1740, 2017. View at Publisher · View at Google Scholar · View at Scopus
  242. L. Morsut, K. T. Roybal, X. Xiong et al., “Engineering Customized Cell Sensing and Response Behaviors Using Synthetic Notch Receptors,” Cell, vol. 164, no. 4, pp. 780–791, 2016. View at Publisher · View at Google Scholar · View at Scopus
  243. B. Beck and C. Blanpain, “Unravelling cancer stem cell potential,” Nature Reviews Cancer, vol. 13, no. 10, pp. 727–738, 2013. View at Publisher · View at Google Scholar · View at Scopus
  244. C. Hogan, S. Dupré-Crochet, M. Norman et al., “Characterization of the interface between normal and transformed epithelial cells,” Nature Cell Biology, vol. 11, no. 4, pp. 460–467, 2009. View at Publisher · View at Google Scholar · View at Scopus
  245. S. Porazinski, J. de Navascués, Y. Yako et al., “EphA2 Drives the Segregation of Ras-Transformed Epithelial Cells from Normal Neighbors,” Current Biology, vol. 26, no. 23, pp. 3220–3229, 2016. View at Publisher · View at Google Scholar · View at Scopus