Elevated Expression of EPHA2 Is Associated With Poor Prognosis After Radical Prostatectomy in Prostate Cancer

Kurose, Hirofumi; Ueda, Kosuke; Kondo, Reiichiro; Ogasawara, Satoshi; Kusano, Hironori; Sanada, Sakiko; Naito, Yoshiki; Nakiri, Makoto; Nishihara, Kiyoaki; Kakuma, Tatsuyuki; Akiba, Jun; Igawa, Tsukasa; Yano, Hirohisa

doi:10.21873/anticanres.13834

Cited by 22 publications

(15 citation statements)

References 36 publications

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“…This suggests that changes in expression of EphA2 itself could be of potential benefit as a prognostic marker using diagnostic tissue specimens, supporting previous findings that elevated EphA2 expression was associated with increased risk of treatment failure, e.g. following radical prostatectomy [ 48 ]. This observed phenomenon is also a potentially important observation for pathologists in their analysis and interpretation of prostate tissue samples, where, on the balance of evidence presented herein, greater emphasis needs to be given to closer analysis and grading of the leading edge/margin of the tumour itself.…”

Section: Discussionsupporting

confidence: 85%

“…High expression of both EphA2 and pEphA2 S897 were shown to be a prognostic marker for poorer overall survival in both univariate and multivariate analysis. High EphA2 expression has been shown to be an independent prognostic marker for biochemical recurrence in the post-surgical setting [ 48 ]. Lin et al [ 49 ] reported a correlation of PCa stage with EphA2 expression but our study is the first to report the prognostic potential of EphA2 hi /PTEN low , showing substantially reduced overall survival when this phenotype is observed in diagnostic tissue specimens.…”

Section: Discussionmentioning

confidence: 99%

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Non-canonical EphA2 activation underpins PTEN-mediated metastatic migration and poor clinical outcome in prostate cancer

et al. 2022

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Background The key process of mesenchymal to amoeboid transition (MAT), which enables prostate cancer (PCa) transendothelial migration and subsequent development of metastases in red bone marrow stroma, is driven by phosphorylation of EphA2S897 by pAkt, which is induced by the omega-6 polyunsaturated fatty acid arachidonic acid. Here we investigate the influence of EphA2 signalling in PCa progression and long-term survival. Methods The mechanisms underpinning metastatic biopotential of altered EphA2 signalling in relation to PTEN status were assessed in vitro using canonical (EphA2D739N) and non-canonical (EphA2S897G) PC3-M mutants, interrogation of publicly available PTEN-stratified databases and clinical validation using a PCa TMA (n = 177) with long-term follow-up data. Spatial heterogeneity of EphA2 was assessed using a radical prostatectomy cohort (n = 67). Results Non-canonical EphA2 signalling via pEphA2S897 is required for PCa transendothelial invasion of bone marrow endothelium. High expression of EphA2 or pEphA2S897 in a PTENlow background is associated with poor overall survival. Expression of EphA2, pEphA2S897 and the associated MAT marker pMLC2 are spatially regulated with the highest levels found within lesion areas within 500 µm of the prostate margin. Conclusion EphA2 MAT-related signalling confers transendothelial invasion. This is associated with a substantially worse prognosis in PTEN-deficient PCa.

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Section: Discussionsupporting

confidence: 85%

Section: Discussionmentioning

confidence: 99%

Non-canonical EphA2 activation underpins PTEN-mediated metastatic migration and poor clinical outcome in prostate cancer

et al. 2022

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“…EphA2 expression in the adult occurs in normal tissues only when they have highly proliferating epithelial cells [ 1 ], where its importance and function are not well understood. However, an accumulating body of evidence suggests human EphA2 is abundantly expressed in diverse cancers such as prostate [ 24 ], lung [ 25 ], esophageal [ 26 ], colorectal [ 27 ], cervical [ 28 ], ovarian [ 29 ], and breast [ 30 ] and skin cancers [ 31 ]. EphA2 is upregulated at the gene and protein levels in human tumor tissue specimens and established cancer cell lines [ 9 , 16 ].…”

Section: Epha2 In Cancermentioning

confidence: 99%

Targeting EphA2 in cancer

et al. 2020

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Eph receptors and the corresponding Eph receptor-interacting (ephrin) ligands jointly constitute a critical cell signaling network that has multiple functions. The tyrosine kinase EphA2, which belongs to the family of Eph receptors, is highly produced in tumor tissues, while found at relatively low levels in most normal adult tissues, indicating its potential application in cancer treatment. After 30 years of investigation, a large amount of data regarding EphA2 functions have been compiled. Meanwhile, several compounds targeting EphA2 have been evaluated and tested in clinical studies, albeit with limited clinical success. The present review briefly describes the contribution of EphA2-ephrin A1 signaling axis to carcinogenesis. In addition, the roles of EphA2 in resistance to molecular-targeted agents were examined. In particular, we focused on EphA2's potential as a target for cancer treatment to provide insights into the application of EphA2 targeting in anticancer strategies. Overall, EphA2 represents a potential target for treating malignant tumors.

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“…In mice transplanted with small cell lung cancer cells, the VM network-forming cells are identified as xenogeneic tumor cells that highly express VE-cadherin, which is essential for tumor aggressiveness and VM, and is involved in the adhesion between endothelial cells; VEcadherin expression is significantly increased under hypoxia [186,187]. EphA2 is a transmembrane tyrosine kinase receptor in human epithelial cells and its high expression in prostate cancer cells is found to be significantly related to the poor prognosis of patients [188,189]. VE-cadherin can induce EphA2 to relocate to the cell membrane in VM, and can cause EphA2 phosphorylation [190].…”

Section: Hypoxia Promotes Vasculogenic Mimicry Network Formation By Pmentioning

confidence: 99%

Mechanisms of vasculogenic mimicry in hypoxic tumor microenvironments

et al. 2021

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Background Vasculogenic mimicry (VM) is a recently discovered angiogenetic process found in many malignant tumors, and is different from the traditional angiogenetic process involving vascular endothelium. It involves the formation of microvascular channels composed of tumor cells; therefore, VM is considered a new model for the formation of new blood vessels in aggressive tumors, and can provide blood supply for tumor growth. Many studies have pointed out that in recent years, some clinical treatments against angiogenesis have not been satisfactory possibly due to the activation of VM. Although the mechanisms underlying VM have not been fully elucidated, increasing research on the soil “microenvironment” for tumor growth suggests that the initial hypoxic environment in solid tumors is inseparable from VM. Main body In this review, we describe that the stemness and differentiation potential of cancer stem cells are enhanced under hypoxic microenvironments, through hypoxia-induced epithelial-endothelial transition (EET) and extracellular matrix (ECM) remodeling to form the specific mechanism of vasculogenic mimicry; we also summarized some of the current drugs targeting VM through these processes, suggesting a new reference for the clinical treatment of tumor angiogenesis. Conclusion Overall, the use of VM inhibitors in combination with conventional anti-angiogenesis treatments is a promising strategy for improving the effectiveness of targeted angiogenesis treatments; further, considering the importance of hypoxia in tumor invasion and metastasis, drugs targeting the hypoxia signaling pathway seem to achieve good results.

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Elevated Expression of EPHA2 Is Associated With Poor Prognosis After Radical Prostatectomy in Prostate Cancer

Cited by 22 publications

References 36 publications

Non-canonical EphA2 activation underpins PTEN-mediated metastatic migration and poor clinical outcome in prostate cancer

Non-canonical EphA2 activation underpins PTEN-mediated metastatic migration and poor clinical outcome in prostate cancer

Targeting EphA2 in cancer

Mechanisms of vasculogenic mimicry in hypoxic tumor microenvironments

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