Phosphorylated 4E-binding protein 1 (p-4E-BP1): A novel prognostic marker in human astrocytomas

First Department of Pathology, Laiko Hospital, Medical School, National and Kapodistrian University of Athens, 11527, Athens, Greece.
Histopathology (Impact Factor: 3.45). 06/2012; 61(2):293-305. DOI: 10.1111/j.1365-2559.2012.04236.x
Source: PubMed


To investigate the significance of the mammalian target of rapamycin (mTOR) pathway in astrocytic tumours, published information in this context being limited, especially regarding phosphorylated 4E-binding protein (p-4E-BP) 1.
Paraffin-embedded tissue from 111 patients with astroglial tumours (grades II-IV) was investigated for the association of phosphorylated mTOR (p-mTOR) signalling components with phosphorylated extracellular signal-related kinase 1/2 (p-ERK1/2) and phosphorylated AKT (p-AKT) expression, clinicopathological features, angiogenesis, isocitrate dehydrogenase 1 (IDH1)-R132H, and survival. Expression was also quantified by western blot analysis in 12 cases and in three primary glioma cell cultures following rapamycin treatment. p-mTOR expression correlated with p-4E-BP1 expression and marginally with p-p70S6K expression. p-4E-BP1 expression increased with tumour grade. Rapamycin induced a decline in phosphorylation levels of all three proteins. Nuclear p-AKT and cytoplasmic p-ERK1/2 immunoexpression correlated with p-4E-BP1 expression, whereas cytoplasmic p-AKT expression correlated with p-p70S6K expression. All three proteins were associated with increased angiogenesis but not with IDH1-R132H expression status. p-mTOR adversely affected overall and disease-free survival in univariate analysis. In multivariate survival analysis, the presence of p-4E-BP1 predicted shortened overall survival in the entire cohort and glioblastomas.
mTOR signalling components are differentially involved in the acquisition of a more aggressive and angiogenic phenotype in astrocytic tumours. Moreover, p-4E-BP1 emerges as a novel prognostic marker, which might aid in the selection of patients who are more likely to benefit from therapy with mTOR inhibitors.

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    • "The crucial role of 4E-BP1 as a key effector of the AKT and ERK signaling pathways in tumors has been elegantly studied by She et al [29]. Moreover, high expression levels of 4E-BP1 have been found to have prognostic value in several tumor types [33-37]. Therefore, further exploration of targeting 4E-BP1 should be explored in the future for multiple tumor types, including, and especially, pancreatic cancer. "
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    ABSTRACT: Astrocytomas, the most common type of gliomas, and especially grade IV glioblastomas are "endowed" with strong proliferation and invasion potentials, high recurrence rate, and poor patients' prognosis. Aberrant signaling of AKT-mTOR (mammalian target of rapamycin) has been implicated in carcinogenesis. This paper is focused on the impact of deregulated AKT-mTOR signaling components in the clinical outcome and prognosis of human astrocytomas. Current therapeutic targeting of astrocytomas with AKT-mTOR inhibitors in preclinical and clinical stage is also discussed, including future perspectives regarding the management of these devastating tumors.
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