Expression of mTORC1/2-related proteins in primary and brain metastatic lung adenocarcinoma

Krencz, Ildikó; Sebestyén, Anna; Fábián, Katalin; Márk, Ágnes; Moldvay, Judit; Khoór, András; Kopper, László; Pápay, Judit

doi:10.1016/j.humpath.2016.12.012

Cited by 28 publications

(27 citation statements)

References 31 publications

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“…Immunostaining was performed by routine diagnostic antibodies (such as anti-IDH1 R132H), SSADH (Abcam #129017 1:500) antibody and Novolink Polymer Detection System (Novocastra, Wetzlar, Germany), visualised by DAB and counterstained with haematoxylin. H-scores (scale of 0–300) were determined by two independent pathologists with semi quantitative analysis of immunoreactivity using 3DHistech Pannoramic Viewer program according to Krencz et al [ 35 ]. The H-score was calculated from staining intensity (0, 1+, 2+, or 3+) and positively stained tumour cells (percentage).…”

Section: Methodsmentioning

confidence: 99%

GABA, glutamine, glutamate oxidation and succinic semialdehyde dehydrogenase expression in human gliomas

Hujber

Horváth

Petővári

et al. 2018

J Exp Clin Cancer Res

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BackgroundBioenergetic characterisation of malignant tissues revealed that different tumour cells can catabolise multiple substrates as salvage pathways, in response to metabolic stress. Altered metabolism in gliomas has received a lot of attention, especially in relation to IDH mutations, and the associated oncometabolite D-2-hydroxyglutarate (2-HG) that impact on metabolism, epigenetics and redox status. Astrocytomas and oligodendrogliomas, collectively called diffuse gliomas, are derived from astrocytes and oligodendrocytes that are in metabolic symbiosis with neurons; astrocytes can catabolise neuron-derived glutamate and gamma-aminobutyric acid (GABA) for supporting and regulating neuronal functions.MethodsMetabolic characteristics of human glioma cell models – including mitochondrial function, glycolytic pathway and energy substrate oxidation – in relation to IDH mutation status and after 2-HG incubation were studied to understand the Janus-faced role of IDH1 mutations in the progression of gliomas/astrocytomas. The metabolic and bioenergetic features were identified in glioma cells using wild-type and genetically engineered IDH1-mutant glioblastoma cell lines by metabolic analyses with Seahorse, protein expression studies and liquid chromatography-mass spectrometry.ResultsU251 glioma cells were characterised by high levels of glutamine, glutamate and GABA oxidation. Succinic semialdehyde dehydrogenase (SSADH) expression was correlated to GABA oxidation. GABA addition to glioma cells increased proliferation rates. Expression of mutated IDH1 and treatment with 2-HG reduced glutamine and GABA oxidation, diminished the pro-proliferative effect of GABA in SSADH expressing cells. SSADH protein overexpression was found in almost all studied human cases with no significant association between SSADH expression and clinicopathological parameters (e.g. IDH mutation).ConclusionsOur findings demonstrate that SSADH expression may participate in the oxidation and/or consumption of GABA in gliomas, furthermore, GABA oxidation capacity may contribute to proliferation and worse prognosis of gliomas. Moreover, IDH mutation and 2-HG production inhibit GABA oxidation in glioma cells. Based on these data, GABA oxidation and SSADH activity could be additional therapeutic targets in gliomas/glioblastomas.Electronic supplementary materialThe online version of this article (10.1186/s13046-018-0946-5) contains supplementary material, which is available to authorized users.

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Section: Methodsmentioning

confidence: 99%

GABA, glutamine, glutamate oxidation and succinic semialdehyde dehydrogenase expression in human gliomas

Hujber

Horváth

Petővári

et al. 2018

J Exp Clin Cancer Res

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“…Immunostained TMA sections Considering the intra-tumoral heterogeneity, the H-score was used to analyse the expression of mTOR and metabolismrelated proteins. Based on our previously described method, H-score was calculated for each core of the TMA multiplying the fraction of tumour cell immunopositivity (%) and staining intensity scale (0, 1+, 2+ or 3+) [28]. The mean of the Hscores for each sample was calculated from the evaluated cores of the same biopsy specimens using two independent evaluations.…”

Section: Tissue Microarray From Human High-grade Glioma Biopsies and mentioning

confidence: 99%

Inhibition of Metabolic Shift can Decrease Therapy Resistance in Human High-Grade Glioma Cells

Petővári

Dankó

Krencz

et al. 2019

Pathol. Oncol. Res.

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The high-grade brain malignancy, glioblastoma multiforme (GBM), is one of the most aggressive tumours in central nervous system. The developing resistance against recent therapies and the recurrence rate of GBMs are extremely high. In spite several new ongoing trials, GBM therapies could not significantly increase the survival rate of the patients as significantly. The presence of inter-and intra-tumoral heterogeneity of GBMs arise the problem to find both the pre-existing potential resistant clones and the cellular processes which promote the adaptation mechanisms such as multidrug resistance, stem cell-ness or metabolic alterations, etc. In our work, the in situ metabolic heterogeneity of high-grade human glioblastoma cases were analysed by immunohistochemistry using tissue-microarray. The potential importance of the detected metabolic heterogeneity was tested in three glioma cell lines (grade III-IV) using protein expression analyses (Western blot and WES Simple) and therapeutic drug (temozolomide), metabolic inhibitor treatments (including glutaminase inhibitor) to compare the effects of rapamycin (RAPA) and glutaminase inhibitor combinations in vitro (Alamar Blue and SRB tests). The importance of individual differences and metabolic alterations were observed in mono-therapeutic failures, especially the enhanced Rictor expressions after different monotreatments in correlation to lower sensitivity (temozolomide, doxycycline, etomoxir, BPTES). RAPA combinations with other metabolic inhibitors were the best strategies except for RAPA+glutaminase inhibitor. These observations underline the importance of multi-targeting metabolic pathways. Finally, our data suggest that the detected metabolic heterogeneity (the high mTORC2 complex activity, enhanced expression of Rictor, p-Akt, p-S6, CPT1A, and LDHA enzymes in glioma cases) and the microenvironmental or treatment induced metabolic shift can be potential targets in combination therapy. Therefore, it should be considered to map tissue heterogeneity and alterations with several cellular metabolism markers in biopsy materials after applying recently available or new treatments.

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“…108,175 In line with the role of the PI3K pathway in the development of brain metastases, expression of mTORC1/2-related proteins was found to be increased in brain metastatic lesions compared with primary tumors in lung adenocarcinoma. 176 Moreover, alterations in the PI3K/Akt pathway, i.e. activating mutations in PIK3CA or inactivating mutations in PTEN, are partly responsible for the therapy resistance of BRAF-mutant melanoma brain metastases.…”

Section: Characteristics Of Brain-homed Tumor Cellsmentioning

confidence: 99%

Foe or friend? Janus-faces of the neurovascular unit in the formation of brain metastases

Wilhelm

Fazakas

Molnár

et al. 2017

J Cereb Blood Flow Metab

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Despite the potential obstacle represented by the blood-brain barrier for extravasating malignant cells, metastases are more frequent than primary tumors in the central nervous system. Not only tightly interconnected endothelial cells can hinder metastasis formation, other cells of the brain microenvironment (like astrocytes and microglia) can also be very hostile, destroying the large majority of metastatic cells. However, malignant cells that are able to overcome these harmful mechanisms may benefit from the shielding and even support provided by cerebral endothelial cells, astrocytes and microglia, rendering the brain a sanctuary site against anti-tumor strategies. Thus, cells of the neurovascular unit have a Janus-faced attitude towards brain metastatic cells, being both destructive and protective. In this review, we present the main mechanisms of brain metastasis formation, including those involved in extravasation through the brain vasculature and survival in the cerebral environment.

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Expression of mTORC1/2-related proteins in primary and brain metastatic lung adenocarcinoma

Cited by 28 publications

References 31 publications

GABA, glutamine, glutamate oxidation and succinic semialdehyde dehydrogenase expression in human gliomas

GABA, glutamine, glutamate oxidation and succinic semialdehyde dehydrogenase expression in human gliomas

Inhibition of Metabolic Shift can Decrease Therapy Resistance in Human High-Grade Glioma Cells

Foe or friend? Janus-faces of the neurovascular unit in the formation of brain metastases

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