The Clinical Impact of the EPH/Ephrin System in Cancer: Unwinding the Thread

Pergaris, Alexandros; Danas, Eugene; Goutas, Dimitrios; Sykaras, Alexandros G.; Soranidis, Angelos; Theocharis, Stamatios

doi:10.3390/ijms22168412

Cited by 36 publications

(42 citation statements)

References 95 publications

(193 reference statements)

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“…The complexity that characterizes the mechanisms behind the EPH/ephrin system’s tumor-promoting and tumor-suppressing properties has been reported by our group in an extensive review of the literature. We emphasized the clinical significance of the various EPHs/ephrins expression’s alterations in solid tumors, pointing out that up- or downregulation of a certain member of the aforementioned biomolecules could possibly enhance tumorigenesis in a certain organ while suppressing it in another [ 66 ].…”

Section: Discussionmentioning

confidence: 99%

EPHA2, EPHA4, and EPHA7 Expression in Triple-Negative Breast Cancer

et al. 2022

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Ongoing research continues to elucidate the complex role of ephrin receptors (EPHs) and their ligands (ephrins) in breast cancer pathogenesis, with their varying expression patterns implied to have an important impact on patients’ outcome. The current study aims to investigate the clinical significance of EPHA2, EPHA4, and EPHA7 expression in triple-negative breast cancer (TNBC) cases. EPHA2, EPHA4, and EPHA7 protein expression was assessed immunohistochemically on formalin-fixed and paraffin-embedded (FFPE) TNBC tissue sections from 52 TNBC patients and correlated with key clinicopathologic parameters and patients’ survival data (overall survival (OS); disease-free survival (DFS)). EPHA2, EPHA4, and EPHA7 expression was further examined in TNBC cell lines. EPHA2 overexpression was observed in 26 (50%) of the TNBC cases, who exhibited a shorter OS and DFS than their low-expression counterparts, with EPHA2 representing an independent prognostic factor for OS and DFS (p = 0.0041 and p = 0.0232, respectively). EPHA4 overexpression was associated with lymph node metastasis in TNBC patients (p = 0.0546). Alterations in EPHA2, EPHA4, and EPHA7 expression levels were also noted in the examined TNBC cell lines. Our study stresses that EPHA2 expression constitutes a potential prognostic factor for TNBC patients. Given the limited treatment options and poorer outcome that accompany the TNBC subtype, EPHA2 could also pose as a target for novel, more personalized, and effective therapeutic approaches for those patients.

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Section: Discussionmentioning

confidence: 99%

EPHA2, EPHA4, and EPHA7 Expression in Triple-Negative Breast Cancer

et al. 2022

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“…Eph and ephrin expression has been associated with tumor pathogenesis and progression in various cancer types, rendering Ephs and ephrins promising therapeutic targets [ 10 , 17 , 18 ]. However, the role of Ephs in the tumor microenvironment of thymic neoplasms and its potential clinical applications remain largely unexplored up to now.…”

Section: Discussionmentioning

confidence: 99%

“…Over the preceding years, an increasing number of studies has associated cancer development and progression with dysregulated Eph–ephrin expression [ 10 ]. Several Eph classes are expressed in cancer cells controlling a broad range of tumor processes by functioning as master regulators of the tumor microenvironment and either triggering or suppressing oncogenic signaling cascades.…”

Section: Introductionmentioning

confidence: 99%

Ephrin Receptors (Ephs) Expression in Thymic Epithelial Tumors: Prognostic Implications and Future Therapeutic Approaches

et al. 2021

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Ephrin receptors (Ephs) are receptor tyrosine kinases (RTKs) implicated in tissue development and homeostasis, and they are aberrantly expressed in tumors. Here, immunohistochemical Eph type-A and -B expression in thymic epithelial tumors (TETs) was assessed and correlated with clinicopathological parameters. Tissue microarrays from 98 TETs were stained for EphA1, -A2, -A4 -A6, -B1, -B2, -B4 and -B6. The relationship between neoplastic and lymphoid cell immunoreactivity score (H-score), histopathological parameters (Pearson’s test) and survival of 35 patients (Mantel-Cox model) was explored. Epithelial-rich subtypes showed higher EphA6 cytoplasmic H-score (B2/B3, carcinoma) (p < 0.001) and stronger EphA4 H-score (B3, carcinoma) (p = 0.011). The immature T-cells, especially in subtypes AB/B1, had higher EphB6 H-score than carcinoma-associated mature lymphocytes (p < 0.001); carcinomas had higher lymphocytic EphB1 H-score (p = 0.026). Higher lymphocytic and lower epithelial EphB6 H-score correlated with Masaoka stage ≤II (p = 0.043, p = 0.010, respectively). All cases showed variable epithelial and lymphocytic EphA2 expression, but clinicopathological associations were not reached. Our study confirmed that Eph type-A and -B expression in TETs is associated with established prognostic parameters, i.e., tumor subtype and Masaoka stage, although correlation with patient survival was not reached. Such findings suggest involvement of these RTKs in thymic neoplasia, as well as their potential utility as treatment targets.

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“…The expression of Ephrin receptors has been studied in different tumours with data indicating that they might have an important role as prognostic factors [ 228 , 229 ]. They constitute the largest known subfamily of receptor tyrosine kinases (RTKs), which play critical roles during the embryonic development, such as axon guidance, cell migration, segmentation and formation of tissue boundaries [ 230 , 231 , 232 , 233 ].…”

Section: Immunohistochemistry-based Novel Prognostic Biomarkers In Uveal Melanomamentioning

confidence: 99%

“…They constitute the largest known subfamily of receptor tyrosine kinases (RTKs), which play critical roles during the embryonic development, such as axon guidance, cell migration, segmentation and formation of tissue boundaries [ 230 , 231 , 232 , 233 ]. In addition, during adulthood, they have roles in angiogenesis, stem cell differentiation, immune system regulation and in cancer development, among others [ 228 , 229 ]. Our knowledge on the expression of Ephrin receptors in UM expanded recently with a study where the expression of EphA1, EphA5 and EphA7 was evaluated in 94 UM enucleation samples without previous treatment [ 192 ].…”

Section: Immunohistochemistry-based Novel Prognostic Biomarkers In Uveal Melanomamentioning

confidence: 99%

Prognostic Biomarkers in Uveal Melanoma: The Status Quo, Recent Advances and Future Directions

Lamas

Martel

Nahon-Estève

et al. 2021

Cancers

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Uveal melanoma (UM) is the most common malignant intraocular tumour in the adult population. It is a rare cancer with an incidence of nearly five cases per million inhabitants per year, which develops from the uncontrolled proliferation of melanocytes in the choroid (≈90%), ciliary body (≈6%) or iris (≈4%). Patients initially present either with symptoms like blurred vision or photopsia, or without symptoms, with the tumour being detected in routine eye exams. Over the course of the disease, metastases, which are initially dormant, develop in nearly 50% of patients, preferentially in the liver. Despite decades of intensive research, the only approach proven to mildly control disease spread are early treatments directed to ablate liver metastases, such as surgical excision or chemoembolization. However, most patients have a limited life expectancy once metastases are detected, since there are limited therapeutic approaches for the metastatic disease, including immunotherapy, which unlike in cutaneous melanoma, has been mostly ineffective for UM patients. Therefore, in order to offer the best care possible to these patients, there is an urgent need to find robust models that can accurately predict the prognosis of UM, as well as therapeutic strategies that effectively block and/or limit the spread of the metastatic disease. Here, we initially summarized the current knowledge about UM by compiling the most relevant epidemiological, clinical, pathological and molecular data. Then, we revisited the most important prognostic factors currently used for the evaluation and follow-up of primary UM cases. Afterwards, we addressed emerging prognostic biomarkers in UM, by comprehensively reviewing gene signatures, immunohistochemistry-based markers and proteomic markers resulting from research studies conducted over the past three years. Finally, we discussed the current hurdles in the field and anticipated the future challenges and novel avenues of research in UM.

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The Clinical Impact of the EPH/Ephrin System in Cancer: Unwinding the Thread

Cited by 36 publications

References 95 publications

EPHA2, EPHA4, and EPHA7 Expression in Triple-Negative Breast Cancer

EPHA2, EPHA4, and EPHA7 Expression in Triple-Negative Breast Cancer

Ephrin Receptors (Ephs) Expression in Thymic Epithelial Tumors: Prognostic Implications and Future Therapeutic Approaches

Prognostic Biomarkers in Uveal Melanoma: The Status Quo, Recent Advances and Future Directions

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