Artikel
Metabolic reprogramming in glioblastoma – intratumoral distribution of lactate and the monocarboxylate transporters 1 and 4 and their relationships to other tumour progression-associated processes
Metabolische Reprogrammierung im Glioblastom – intratumorale Verteilung von Laktat sowie den Monocarboxylattransportern 1 und 4 und ihre Zusammenhänge mit anderen tumorprogressionsrelevanten Prozessen
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Autoren
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Carolin Kubelt
- University Hospital of Schleswig-Holstein, Campus Kiel, Department of Neurosurgery, Kiel, Deutschland
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Sönke Peters
- University Hospital of Schleswig-Holstein, Campus Kiel, Neuroradiology, Kiel, Deutschland
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Hajrullah Ahmeti
- University Hospital of Schleswig-Holstein, Campus Kiel, Department of Neurosurgery, Kiel, Deutschland
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Monika Huhndorf
- University Hospital of Schleswig-Holstein, Campus Kiel, Neuroradiology, Kiel, Deutschland
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Lukas Huber
- University, Kiel, Deutschland
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Gesa Cohrs
- University Hospital of Schleswig-Holstein, Campus Kiel, Department of Neurosurgery, Kiel, Deutschland
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Jan-Bernd Hövener
- University Hospital of Schleswig-Holstein, Campus Kiel, Neuroradiology, Kiel, Deutschland; University, Kiel, Deutschland
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Olav Jansen
- University Hospital of Schleswig-Holstein, Campus Kiel, Neuroradiology, Kiel, Deutschland
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Michael Synowitz
- University Hospital of Schleswig-Holstein, Campus Kiel, Department of Neurosurgery, Kiel, Deutschland
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Janka Held-Feindt
- University Hospital of Schleswig-Holstein, Campus Kiel, Department of Neurosurgery, Kiel, Deutschland
| Veröffentlicht: | 4. Juni 2021 |
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Gliederung
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Objective: Glioblastoma multiforme (GBM) is the most common and most malignant brain tumor. Rapid growth, despite a lack of energy substrates, is one reason for its poor prognosis. To develop this aggressive property, tumor cells can undergo metabolic reprogramming (mr), leading to an oxygen-independent glycolysis. Thus, mr depicts a promising therapeutic target also in GBM. Proton-coupled monocarboxylate transporters (MCT) have been described in connection with the distribution or membrane passage of lactate produced by oxygen-independent glycolysis. MCT1 and MCT4, in particular, are overexpressed in GBM cells. Till date, only a few studies focus on their role and connection to other tumor progression related processes in GBM. Furthermore, only little is known concerning a possible connection between MCT expression and changes in multi voxel magnetic resonance spectroscopic imaging (MRSI), a method for assessing local metabolites noninvasively. Thus, the objective of this study was to gain more insights into the molecular mechanisms involved in mr in order to use this knowledge for an advancement of diagnostic, monitoring and therapy of GBM in the future.
Methods: We examined the distribution of lactate by MRSI and ELISA in GBM patients. In addition, we investigated the expression and cellular localization of MCT1, MCT4, and of several markers connected to tumor progression by quantitative PCR and immunofluorescence double-staining in human GBM ex vivo tissues.
Results: The highest lactate concentration was found at the center of the vital parts of the tumor. Whereas MCT1 (p: 0.025) showed a higher gene expression at the center of the tumor compared to the edge, glial acidic fibrillary protein (p:0.010), the epithelial to mesenchymal transition (EMT) marker ß-catenin (p: 0.039) and the stem-like cell markers krüppel-like factor4 (p: 0.035) and octamer-binding transcription factor4 (p: 0.026) showed an increased expression. Three main GBM groups could be distinguished according to their regional gene expression differences of the investigated genes. MCT1 and MCT4 were found on cells undergoing EMT and on tumor stem-like cells. GBM cells revealing an expression of cellular dormancy markers, showed positive staining for MCT4.
Conclusion: Our findings indicate the existence of individual differences in the regional distribution of MCT1 and MCT4 and suggest that both transporters have distinct connections to GBM progression processes, which could contribute to the drug resistance of MCT-inhibitors.
