Overexpression of Ephrin A2 receptors in cancer stromal cells is a prognostic factor for the relapse of gastric cancer

Kikuchi, Shojiro; Kaibe, Nobuaki; Fukui, Hirokazu; Niwa, Hitoshi; Maeyama, Yoshihiro; Takemura, Masashi; Matsumoto, Masaki; Nakamori, Shoji; Miwa, Hiroto; Hirota, Seiichi; Sasako, Mitsuru

doi:10.1007/s10120-014-0390-y

Cited by 18 publications

(31 citation statements)

References 31 publications

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“…This was in line with recent findings based on studies focused on the oncogenic role of EphA2 in CRC and other tumors (31,34,37). …”

Section: Discussionsupporting

confidence: 92%

“…Differently than normal tissue, adenocarcinoma displayed a highly heterogeneous and not gradient-disposed staining for both EphB2 and EphA2 proteins and it was enriched in EphA2 high cell fractions also showed in the cytofluorimetric analysis. The overexpression of EphA2 has been recently reported in different kinds of solid tumors, included the colon (31,34–37). Conversely, a reduction of EphB2 high cell subpopulation was observed in adenocarcinoma.…”

Section: Discussionmentioning

confidence: 98%

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Dysregulation of EGFR Pathway in EphA2 Cell Subpopulation Significantly Associates with Poor Prognosis in Colorectal Cancer

Robertis

Loiacono

Fusilli

et al. 2017

Clinical Cancer Research

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Purpose EphA2 receptor is involved in multiple cross-talks with other cellular networks including EGFR, FAK and VEGF pathways, with which it collaborates to stimulate cell migration, invasion and metastasis. Colorectal cancer (CRC) EphA2 overexpression has also been correlated to stem-like properties of cells and tumor malignancy. We investigated the molecular crosstalk and microRNAs modulation of the EphA2 and EGFR pathways. We also explored the role of EphA2/EGFR pathway mediators as prognostic factors or predictors of cetuximab benefit in CRC patients. Experimental Design Gene expression analysis was performed in EphA2high cells isolated from CRC of AOM/DSS murine model by FACS-assisted procedures. Six independent cohorts of patients were stratified by EphA2 expression to determine the potential prognostic role of a EphA2/EGFR signature and its effect on cetuximab treatment response. Results We identified a gene expression pattern (EphA2, Efna1, EGFR, Ptpn12, Atf2) reflecting the activation of EphA2 and EGFR pathways and a coherent dysregulation of mir-26b and mir-200a. Such pattern showed prognostic significance in stage I-III CRC patients, in both univariate and multivariate analysis. In patients with stage IV and WT KRAS, EphA2/Efna1/EGFR gene expression status was significantly associated with poor response to cetuximab treatment. Furthermore, EphA2 and EGFR overexpression showed a combined effect relative to cetuximab resistance, independently from KRAS mutation status. Conclusions These results suggest that EphA2/Efna1/EGFR genes, linked to a possible control by mir-200a and mir-26b, could be proposed as novel CRC prognostic biomarkers. Moreover, EphA2 could be linked to a mechanism of resistance to cetuximab alternative to KRAS mutations.

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“…This was in line with recent findings based on studies focused on the oncogenic role of EphA2 in CRC and other tumors (31,34,37). …”

Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 98%

Dysregulation of EGFR Pathway in EphA2 Cell Subpopulation Significantly Associates with Poor Prognosis in Colorectal Cancer

Robertis

Loiacono

Fusilli

et al. 2017

Clinical Cancer Research

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“…It has been reported that tyrosine kinase Src can induce phosphorylation and activation of YAP. 31 We and others have previously reported that EphA2 overexpression is associated with poor prognosis for GC patients and promotes the EMT and invasion of GC cells through the Wnt/β-catenin pathway. 28 Altogether, it seems to be that except few cases, serine/threonine kinases phosphorylate YAP, leading to cytoplasmic retention, degradation and inactivation of YAP, while tyrosine kinase phosphorylate YAP, resulting in stabilization, nuclear translocation and activation of YAP.…”

Section: Discussionmentioning

confidence: 81%

“…30 Overexpression of Ephrin A2 receptors in cancer stromal cells is a prognostic factor for the relapse of gastric cancer. 31 We and others have previously reported that EphA2 overexpression is associated with poor prognosis for GC patients and promotes the EMT and invasion of GC cells through the Wnt/β-catenin pathway. 8,11,12 In present study, we further confirm the role of EphA2 in GC growth and development, and find that the regulation of YAP by EphA2 is one of the major mechanisms underlying EphA2-driven GC development, progression and therapy resistance.…”

Section: Discussionmentioning

confidence: 81%

EphA2‐to‐YAP pathway drives gastric cancer growth and therapy resistance

Huang

Yuan

Chen

et al. 2019

Intl Journal of Cancer

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Yes‐associated protein (YAP) is a transcriptional coactivator that promotes cell proliferation, stem cell maintenance and tissue homeostasis. The YAP activity is primarily regulated through an inhibitory phosphorylation by the serine/threonine kinases of Hippo pathway. Here, we show that receptor tyrosine kinase (RTK) erythropoietin‐producing hepatocellular receptor A2 (EphA2) interacts with and phosphorylates YAP protein, leading to stabilization, nuclear translocation and activation of YAP in gastric cancer (GC) cells. EphA2 induces chemotherapy‐resistance by increasing YAP stability and nuclear YAP protein. Knockdown of YAP blocks EphA2‐induced tumor growth in GC xenograft mouse models. Importantly, the coactivation of EphA2 and YAP is manifested in clinical human GC, and is related to GC recurrence. Thus, our results establish a novel EphA2‐to‐YAP pathway that drives GC growth, progression and therapy‐resistance, targeting this pathway would be an efficient way for the treatment of GC, particularly chemotherapy‐resistant GC.

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“…While the role of these genes in RMS remains to be specifically defined, majority of them have been implicated in cancer. EPHA2 receptor overexpression in gastric cancer stromal cells is a prognostic factor for relapse (23). It also promotes tumor cell proliferation and motility in non-small cell lung cancer (24); and increases infiltrative capacity of glioma stem cells in glioblastoma multiforme models (25).…”

Section: Discussionmentioning

confidence: 99%

Clinical Application of Prognostic Gene Expression Signature in Fusion Gene–Negative Rhabdomyosarcoma: A Report from the Children's Oncology Group

Hingorani

Missiaglia

Shipley

et al. 2015

Clinical Cancer Research

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Purpose Pediatric rhabdomyosarcoma has two common histological subtypes: embryonal (ERMS) and alveolar (ARMS). PAX/FOXO1 fusion gene status is a more reliable prognostic marker than alveolar histology while fusion gene-negative (FN) ARMS patients are clinically similar to ERMS patients. A five-gene expression signature (MG5) previously identified two diverse risk groups within the fusion-gene negative RMS (FN-RMS) patients but this has not been independently validated. The goal of the current study was to test whether expression of the MG5 metagene, measured using a technical platform that can be applied to routine pathology material, would correlate with outcome in a new cohort of patients with FN-RMS. Experimental Design Cases were taken from the Children's Oncology Group (COG) D9803 study of children with intermediate-risk RMS and gene expression profiling for the MG5 genes was performed using the nCounter assay. The MG5 score was correlated with clinical and pathological characteristics as well as overall and event-free survival. Results MG5 standardized score showed no significant association with any of the available clinical-pathological variables. The MG5 signature score showed a significant correlation with overall (N=57; HR 7.3 95%CI[1.9-27.0], p=0.003) and failure-free survival (N=57; HR 6.1 95%CI[1.9-19.7], p=0.002). Conclusions This represents the first, validated molecular prognostic signature for children with FN-RMS who otherwise have intermediate-risk disease. The capacity to measure the expression of a small number of genes in routine pathology material and apply a simple mathematical formula to calculate the MG5 metagene score provides a clear path toward better risk-stratification in future, prospective clinical trial.

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Overexpression of Ephrin A2 receptors in cancer stromal cells is a prognostic factor for the relapse of gastric cancer

Cited by 18 publications

References 31 publications

Dysregulation of EGFR Pathway in EphA2 Cell Subpopulation Significantly Associates with Poor Prognosis in Colorectal Cancer

Dysregulation of EGFR Pathway in EphA2 Cell Subpopulation Significantly Associates with Poor Prognosis in Colorectal Cancer

EphA2‐to‐YAP pathway drives gastric cancer growth and therapy resistance

Clinical Application of Prognostic Gene Expression Signature in Fusion Gene–Negative Rhabdomyosarcoma: A Report from the Children's Oncology Group

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