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

Korkolopoulou P, Levidou G, El‐Habr E A, Piperi C, Adamopoulos C, Samaras V, Boviatsis E, Thymara I, Trigka E‐A, Sakellariou S, Kavantzas N, Patsouris E & Saetta A A 
(2012) Histopathology 61, 293–305 Phosphorylated 4E‐binding protein 1 (p‐4E‐BP1): a novel prognostic marker in human astrocytomas...

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Published in:Histopathology 2012-08, Vol.61 (2), p.293-305
Main Authors: Korkolopoulou, Penelope, Levidou, Georgia, El-Habr, Elias A, Piperi, Christina, Adamopoulos, Christos, Samaras, Vassilis, Boviatsis, Efstathios, Thymara, Irene, Trigka, Eleni-Andriana, Sakellariou, Stratigoula, Kavantzas, Nikolaos, Patsouris, Efstratios, Saetta, Angelica A
Format: Article
Language:English
Subjects:
Adaptor Proteins, Signal Transducing - metabolism
Adolescent
Adult
Aged
Aged, 80 and over
angiogenesis
Astrocytoma - blood supply
Astrocytoma - metabolism
Astrocytoma - pathology
astrocytomas
Biological and medical sciences
Biomarkers, Tumor - metabolism
Blotting, Western
Female
Glioblastoma - metabolism
Humans
IDH1-R132H
Immunohistochemistry
Investigative techniques, diagnostic techniques (general aspects)
Kaplan-Meier Estimate
Life Sciences
Male
MAP Kinase Signaling System
Medical sciences
Middle Aged
Neovascularization, Pathologic
Neurology
Neurons and Cognition
p-4E-BP1
p-mTOR
p-p70S6K
Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques
Phosphoproteins - metabolism
Phosphorylation
Prognosis
Proto-Oncogene Proteins c-akt - metabolism
Ribosomal Protein S6 Kinases, 70-kDa - metabolism
Signal Transduction
TOR Serine-Threonine Kinases - metabolism
Tumor Cells, Cultured
Tumors of the nervous system. Phacomatoses
Vascular Endothelial Growth Factor A - metabolism
Young Adult
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Summary:Korkolopoulou P, Levidou G, El‐Habr E A, Piperi C, Adamopoulos C, Samaras V, Boviatsis E, Thymara I, Trigka E‐A, Sakellariou S, Kavantzas N, Patsouris E & Saetta A A 
(2012) Histopathology 61, 293–305 Phosphorylated 4E‐binding protein 1 (p‐4E‐BP1): a novel prognostic marker in human astrocytomas Aims:  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. Methods and results:  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. Conclusions:  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.
ISSN:0309-0167
1365-2559
DOI:10.1111/j.1365-2559.2012.04236.x