Activation of multiple growth factor signalling pathways is frequent in meningiomas

Hilton, David A.; Shivane, Aditya G.; Kirk, Leanne; Bassiri, Kayleigh; Enki, Doyo; Hanemann, C. Oliver

doi:10.1111/neup.12266

Cited by 33 publications

(35 citation statements)

References 58 publications

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Section: Discussionsupporting

confidence: 68%

“…There are sparse data on this issue in meningioma tissue (Carroll et al, 1997; Hilton et al, 2016), and according to our findings the activated receptor is expressed at high levels in most tumors. In their study, Hilton et al found significantly higher expression of phosphorylated EGFR in tumor tissues compared with non-neoplastic tissues, and high expression of downstream signaling molecules (Hilton et al, 2016). The literature is conflicting concerning EGFR and malignancy, as some have found that high expression is positively related to tumor grade (Caltabiano et al, 2013; Diedrich et al, 1995; Halper et al, 1999) whereas others have found the opposite or no differences (Baxter et al, 2014; Guillaudeau et al, 2012; Jones et al, 1990; Kuratsu et al, 1994; Narla et al, 2014; Wernicke et al, 2010).…”

Section: Discussionsupporting

confidence: 68%

“…Both membranous and cytoplasmic EGFR immunoreactivity have been described in meningiomas (Guillaudeau et al, 2012; Halper et al, 1999; Horsfall et al, 1989; Johnson et al, 1994; Jones et al, 1990; Smith et al, 2007; Torp et al, 1992), however, the prognostic relevance is scarcely described (Guillaudeau et al, 2012). The receptor also seems to be activated (phosphorylated) (Carroll et al, 1997; Hilton et al, 2016). Moreover, the literature is conflicting regarding expression levels of EGFR across malignancy grades, as some report increasing expression with higher grades (Caltabiano et al, 2013; Diedrich et al, 1995; Halper et al, 1999) and others the opposite or no connection at all (Baxter et al, 2014; Guillaudeau et al, 2012; Jones et al, 1990; Kuratsu et al, 1994; Narla et al, 2014; Wernicke et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

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Expression and clinical value of EGFR in human meningiomas

Arnli

Backer-Grøndahl

Ytterhus

et al. 2017

PeerJ

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BackgroundMeningiomas are common intracranial tumors in humans that frequently recur despite having a predominantly benign nature. Even though these tumors have been shown to commonly express EGFR/c-erbB1 (epidermal growth factor receptor), results from previous studies are uncertain regarding the expression of either intracellular or extracellular domains, cellular localization, activation state, relations to malignancy grade, and prognosis.AimsThis study was designed to investigate the expression of the intracellular and extracellular domains of EGFR and of the activated receptor as well as its ligands EGF and TGFα in a large series of meningiomas with long follow-up data, and investigate if there exists an association between antibody expression and clinical and histological data.MethodsA series of 186 meningiomas consecutively operated within a 10-year period was included. Tissue microarrays were constructed and immunohistochemically analyzed with antibodies targeting intracellular and extracellular domains of EGFR, phosphorylated receptor, and EGF and TGFα. Expression levels were recorded as a staining index (SI).ResultsPositive immunoreactivity was observed for all antibodies in most cases. There was in general high SIs for the intracellular domain of EGFR, phosphorylated EGFR, EGF, and TGFα but lower for the extracellular domain. Normal meninges were negative for all antibodies. Higher SIs for the phosphorylated EGFR were observed in grade II tumors compared with grade I (p = 0.018). Survival or recurrence was significantly decreased in the time to recurrence analysis (TTR) with high SI-scores of the extracellular domain in a univariable survival analysis (HR 1.152, CI (1.036–1.280, p = 0.009)). This was not significant in a multivariable analysis. Expression of the other antigens did not affect survival.ConclusionEGFR is overexpressed and in an activated state in human meningiomas. High levels of ligands also support this growth factor receptor system to be involved in meningioma tumorigenesis. EGFR may be a potential candidate for targeted therapy.

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Section: Discussionsupporting

confidence: 68%

Section: Discussionsupporting

confidence: 68%

Section: Introductionmentioning

confidence: 99%

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Expression and clinical value of EGFR in human meningiomas

Arnli

Backer-Grøndahl

Ytterhus

et al. 2017

PeerJ

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“…We also identi ed the EGFR pathway as driving miR-9-1 overexpression in malignant meningioma, via FOS, which is predicted to bind to the promoter/enhancer region of miR-9-1 (43). This is in keeping with previous studies, which have shown that EGF/ERBB2 receptors and FOS are upregulated, and are involved in the molecular process that drives meningioma pathogenesis and/or progression to highergrade tumors (32,(44)(45)(46)(47)(48). FOS knock out experiments supported this observation, resulting in decreased miR-9-1 and increased E-cadherin in malignant KT21-MG1 cells (49,50).…”

Section: Discussionsupporting

confidence: 92%

miR-9-1 Is a New Circulating Biomarker for Higher-grade Meningioma Regulated via the EGFR-FOS Network

Daniele¹,

Negroni²,

Ferluga³

et al. 2020

Preprint

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Background: Meningiomas are the most common primary CNS tumors. According to the World Health Organization Classification (WHO), they are classified as benign (grade I), atypical (grade II), and anaplastic/malignant (grade III). Chemotherapy has proven ineffective in treating these tumors, which are primarily managed by surgery, radiotherapy, or a combination of them. Morbidity and mortality correlate with meningioma grade. Currently, risk assessment for treatment is based on the radiological assessment of tumor size, tumor growth rate, and/or clinical progression of symptoms. Methods: We performed a cancer miRNA array in an in vitro model of meningioma in order to identify circulating biomarkers in meningioma patients. We validated the miRNA biomarker candidate in cells and tissues and analyzed its regulation. We then investigated expression in tissues and blood. Results: We identified miR-9-1 as significantly overexpressed in atypical and anaplastic cells compared to benign. We further demonstrated that miR-9-1 overexpression is due to increased levels of FOS via upregulation of the EGFR receptor, and showed that miR-9-1 and FOS are upregulated in a cohort of higher-grade meningioma biopsies. Next, we isolated circulating exosomes from meningioma patients’ serum samples, and found higher levels of miR-9-1 in higher-grade compared to low-grade meningiomas patients. Conclusions: Overall, our study shows overexpression and the mechanism of miR-9-1 regulation and suggests miR-9-1 as a novel circulating biomarker candidate to identify tumor grade in meningioma.

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“…While alterations in the NF2 gene frequently occur, recent molecular genetic studies have identified mutations in AKT1 , SMO , KLF4 , TRAF7 , POLR2A in non-NF2 meningiomas (Brastianos et al, 2013; Clark et al, 2013; Clark et al, 2016). In addition, gene expression analyses have identified AKT as one of the key drivers for meningioma growth (Wang et al, 2012; Hilton et al, 2016). Activation of AKT promotes protein translation initiation, which is dependent upon expression and assembly of several eIF complexes (Jackson et al, 2010; Silvera et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

Overexpression of eIF4F components in meningiomas and suppression of meningioma cell growth by inhibiting translation initiation

Oblinger

Burns

Huang

et al. 2018

Experimental Neurology

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Meningiomas frequently display activation of the PI3K/AKT/mTOR pathway, leading to elevated levels of phospho-4E binding proteins, which enhances protein synthesis; however, it is not known whether inhibition of protein translation is an effective treatment option for meningiomas. We found that human meningiomas expressed high levels of the three components of the eukaryotic initiation factor 4F (eIF4F) translation initiation complex, eIF4A, eIF4E, and eIF4G. The expression of eIF4A and eIF4E was important in sustaining the growth of NF2-deficient benign meningioma Ben-Men-1 cells, as shRNA-mediated knockdown of these proteins strongly reduced cell proliferation. Among a series of 23 natural compounds evaluated, silvestrol, which inhibits eIF4A, was identified as being the most growth inhibitory in both primary meningioma and Ben-Men-1 cells. Silvestrol treatment of meningioma cells prominently induced G2/M arrest. Consistently, silvestrol significantly decreased the amounts of cyclins D1, E1, A, and B, PCNA and Aurora A. In addition, total and phosphorylated AKT, ERK and FAK, which have been shown to be important drivers for meningioma cell proliferation, were markedly lower in silvestrol-treated Ben-Men-1 cells. Our findings suggest that inhibiting protein translation could be a potential treatment for meningiomas.

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Activation of multiple growth factor signalling pathways is frequent in meningiomas

Cited by 33 publications

References 58 publications

Expression and clinical value of EGFR in human meningiomas

Expression and clinical value of EGFR in human meningiomas

miR-9-1 Is a New Circulating Biomarker for Higher-grade Meningioma Regulated via the EGFR-FOS Network

Overexpression of eIF4F components in meningiomas and suppression of meningioma cell growth by inhibiting translation initiation

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