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The Suitability of Glioblastoma Cell Lines as Models for Primary Glioblastoma Cell Metabolism.

ABSTRACT: In contrast to most non-malignant tissue, cells comprising the brain tumour glioblastoma (GBM) preferentially utilise glycolysis for metabolism via "the Warburg effect". Research into therapeutics targeting the disease's highly glycolytic state offer a promising avenue to improve patient survival. These studies often employ GBM cell lines for in vitro studies which translate poorly to the in vivo patient context. The metabolic traits of five of the most used GBM cell lines were assessed and compared to primary GBM and matched, healthy brain tissue. In patient-derived GBM cell lines, the basal mitochondrial rate (p = 0.043) and ATP-linked respiration (p < 0.001) were lower than primary adjacent normal cells from the same patient, while reserve capacity (p = 0.037) and Krebs cycle capacity (p = 0.002) were higher. Three cell lines, U251MG, U373MG and D54, replicate the mitochondrial metabolism of primary GBM cells. Surprisingly, glycolytic capacity is not different between healthy and GBM tissue. The T98G cell line recapitulated glycolysis-related metabolic parameters of the primary GBM cells and is recommended for research relating to glycolysis. These findings can guide preclinical research into the development of novel therapeutics targeting metabolic pathways in GBM.

SUBMITTER: Arthurs AL

PROVIDER: S-EPMC7764800 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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The Suitability of Glioblastoma Cell Lines as Models for Primary Glioblastoma Cell Metabolism.

Arthurs Anya L AL Keating Damien J DJ Stringer Brett W BW Conn Simon J SJ

Cancers 20201211 12

In contrast to most non-malignant tissue, cells comprising the brain tumour glioblastoma (GBM) preferentially utilise glycolysis for metabolism via "the Warburg effect". Research into therapeutics targeting the disease's highly glycolytic state offer a promising avenue to improve patient survival. These studies often employ GBM cell lines for in vitro studies which translate poorly to the in vivo patient context. The metabolic traits of five of the most used GBM cell lines were assessed and comp ...[more]

PMID: 33322454

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Project description:BackgroundMammary cell cultures are convenient tools for in vitro studies of mammary gland biology. However, the heterogeneity of mammary cell types, e.g., glandular milk secretory epithelial or myoepithelial cells, often complicates the interpretation of cell-based data. The present study was undertaken to determine the relevance of bovine primary mammary epithelial cells isolated from American Holstein (bMECUS) or Swiss Holstein-Friesian (bMECCH) cows, and of primary bovine mammary alveolar epithelial cells stably transfected with simian virus-40 (SV-40) large T-antigen (MAC-T) for in vitro analyses. This was evaluated by testing their expression pattern of cytokeratin (CK) 7, 18, 19, vimentin, and ?-smooth muscle actin (?-SMA).ResultsThe expression of the listed markers was assessed using real-time quantitative PCR, flow cytometry and immunofluorescence microscopy. Characteristic markers of the mesenchymal (vimentin), myoepithelial (?-SMA) and glandular secretory cells (CKs) showed differential expression among the studied cell cultures, partly depending on the analytical method used. The relative mRNA expression of vimentin, CK7 and CK19, respectively, was lower (P < 0.05) in immortalized than in primary mammary cell cultures. The stain index (based on flow cytometry) of CK7 and CK19 protein was lower (P < 0.05) in MAC-T than in bMECs, while the expression of ?-SMA and CK18 showed an inverse pattern. Immunofluorescence microscopy analysis mostly confirmed the mRNA data, while partly disagreed with flow cytometry data (e.g., vimentin level in MAC-T). The differential expression of CK7 and CK19 allowed discriminating between immortal and primary mammary cultures.ConclusionsThe expression of the selected widely used cell type markers in primary and immortalized MEC cells did not allow a clear preference between these two cell models for in vitro analyses studying aspects of milk composition. All tested cell models exhibited to a variable degree epithelial and mesenchymal features. Thus, based on their characterization with widely used cell markers, none of these cultures represent an unequivocal alveolar mammary epithelial cell model. For choosing the appropriate in vitro model additional properties such as the expression profile of specific proteins of interest (e.g., transporter proteins) should equally be taken into account.

Project description:BackgroundIt is well-known that glioblastoma contains self-renewing, stem-like subpopulation with the ability to sustain tumor growth. These cells - called cancer stem-like cells - share certain phenotypic characteristics with untransformed stem cells and are resistant to many conventional cancer therapies, which might explain the limitations in curing human malignancies. Thus, the identification of genes controlling the differentiation of these stem-like cells is becoming a successful therapeutic strategy, owing to the promise of novel targets for treating malignancies.MethodsRecently, we developed SWIM, a software able to unveil a small pool of genes - called switch genes - critically associated with drastic changes in cell phenotype. Here, we applied SWIM to the expression profiling of glioblastoma stem-like cells and conventional glioma cell lines, in order to identify switch genes related to stem-like phenotype.ResultsSWIM identifies 171 switch genes that are all down-regulated in glioblastoma stem-like cells. This list encompasses genes like CAV1, COL5A1, COL6A3, FLNB, HMMR, ITGA3, ITGA5, MET, SDC1, THBS1, and VEGFC, involved in "ECM-receptor interaction" and "focal adhesion" pathways. The inhibition of switch genes highly correlates with the activation of genes related to neural development and differentiation, such as the 4-core OLIG2, POU3F2, SALL2, SOX2, whose induction has been shown to be sufficient to reprogram differentiated glioblastoma into stem-like cells. Among switch genes, the transcription factor FOSL1 appears as the brightest star since: it is down-regulated in stem-like cells; it highly negatively correlates with the 4-core genes that are all up-regulated in stem-like cells; the promoter regions of the 4-core genes harbor a consensus binding motif for FOSL1.ConclusionsWe suggest that the inhibition of switch genes in stem-like cells could induce the deregulation of cell communication pathways, contributing to neoplastic progression and tumor invasiveness. Conversely, their activation could restore the physiological equilibrium between cell adhesion and migration, hampering the progression of cancer. Moreover, we posit FOSL1 as promising candidate to orchestrate the differentiation of cancer stem-like cells by repressing the 4-core genes' expression, which severely halts cancer growth and might affect the therapeutic outcome. We suggest FOSL1 as novel putative therapeutic and prognostic biomarker, worthy of further investigation.

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The Suitability of Glioblastoma Cell Lines as Models for Primary Glioblastoma Cell Metabolism.

Publications

The Suitability of Glioblastoma Cell Lines as Models for Primary Glioblastoma Cell Metabolism.

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