The Acidic Brain—Glycolytic Switch in the Microenvironment of Malignant Glioma
Malignant glioma represents a fatal disease with a poor prognosis and development of resistance mechanisms against conventional therapeutic approaches. The distinct tumor zones of this heterogeneous neoplasm develop their own microenvironment, in which subpopulations of cancer cells communicate. Ada...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-05-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/11/5518 |
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| author | Anna Maria Reuss Dominik Groos Michael Buchfelder Nicolai Savaskan |
| author_facet | Anna Maria Reuss Dominik Groos Michael Buchfelder Nicolai Savaskan |
| author_sort | Anna Maria Reuss |
| collection | DOAJ |
| description | Malignant glioma represents a fatal disease with a poor prognosis and development of resistance mechanisms against conventional therapeutic approaches. The distinct tumor zones of this heterogeneous neoplasm develop their own microenvironment, in which subpopulations of cancer cells communicate. Adaptation to hypoxia in the center of the expanding tumor mass leads to the glycolytic and angiogenic switch, accompanied by upregulation of different glycolytic enzymes, transporters, and other metabolites. These processes render the tumor microenvironment more acidic, remodel the extracellular matrix, and create energy gradients for the metabolic communication between different cancer cells in distinct tumor zones. Escape mechanisms from hypoxia-induced cell death and energy deprivation are the result. The functional consequences are more aggressive and malignant behavior with enhanced proliferation and survival, migration and invasiveness, and the induction of angiogenesis. In this review, we go from the biochemical principles of aerobic and anaerobic glycolysis over the glycolytic switch, regulated by the key transcription factor hypoxia-inducible factor (HIF)-1α, to other important metabolic players like the monocarboxylate transporters (MCTs)1 and 4. We discuss the metabolic symbiosis model via lactate shuttling in the acidic tumor microenvironment and highlight the functional consequences of the glycolytic switch on glioma malignancy. Furthermore, we illustrate regulation by micro ribonucleic acids (miRNAs) and the connection between <i>isocitrate dehydrogenase (IDH)</i> mutation status and glycolytic metabolism. Finally, we give an outlook about the diagnostic and therapeutic implications of the glycolytic switch and the relation to tumor immunity in malignant glioma. |
| first_indexed | 2024-03-10T11:07:04Z |
| format | Article |
| id | doaj.art-15c9fc8cb6574cbfa6f5d496016d6392 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T11:07:04Z |
| publishDate | 2021-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-15c9fc8cb6574cbfa6f5d496016d63922023-11-21T21:04:36ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-05-012211551810.3390/ijms22115518The Acidic Brain—Glycolytic Switch in the Microenvironment of Malignant GliomaAnna Maria Reuss0Dominik Groos1Michael Buchfelder2Nicolai Savaskan3Laboratory for Translational Cell Biology and Neurooncology, Department of Neurosurgery, University Hospital Erlangen-Nürnberg, Friedrich-Alexander University Erlangen-Nürnberg (FAU), 91054 Erlangen, GermanyInstitute of Physiology and Pathophysiology, Friedrich-Alexander University Erlangen-Nürnberg (FAU), 91054 Erlangen, GermanyLaboratory for Translational Cell Biology and Neurooncology, Department of Neurosurgery, University Hospital Erlangen-Nürnberg, Friedrich-Alexander University Erlangen-Nürnberg (FAU), 91054 Erlangen, GermanyLaboratory for Translational Cell Biology and Neurooncology, Department of Neurosurgery, University Hospital Erlangen-Nürnberg, Friedrich-Alexander University Erlangen-Nürnberg (FAU), 91054 Erlangen, GermanyMalignant glioma represents a fatal disease with a poor prognosis and development of resistance mechanisms against conventional therapeutic approaches. The distinct tumor zones of this heterogeneous neoplasm develop their own microenvironment, in which subpopulations of cancer cells communicate. Adaptation to hypoxia in the center of the expanding tumor mass leads to the glycolytic and angiogenic switch, accompanied by upregulation of different glycolytic enzymes, transporters, and other metabolites. These processes render the tumor microenvironment more acidic, remodel the extracellular matrix, and create energy gradients for the metabolic communication between different cancer cells in distinct tumor zones. Escape mechanisms from hypoxia-induced cell death and energy deprivation are the result. The functional consequences are more aggressive and malignant behavior with enhanced proliferation and survival, migration and invasiveness, and the induction of angiogenesis. In this review, we go from the biochemical principles of aerobic and anaerobic glycolysis over the glycolytic switch, regulated by the key transcription factor hypoxia-inducible factor (HIF)-1α, to other important metabolic players like the monocarboxylate transporters (MCTs)1 and 4. We discuss the metabolic symbiosis model via lactate shuttling in the acidic tumor microenvironment and highlight the functional consequences of the glycolytic switch on glioma malignancy. Furthermore, we illustrate regulation by micro ribonucleic acids (miRNAs) and the connection between <i>isocitrate dehydrogenase (IDH)</i> mutation status and glycolytic metabolism. Finally, we give an outlook about the diagnostic and therapeutic implications of the glycolytic switch and the relation to tumor immunity in malignant glioma.https://www.mdpi.com/1422-0067/22/11/5518tumor microenvironmentglycolyticacidicgliomalactateMCT1 |
| spellingShingle | Anna Maria Reuss Dominik Groos Michael Buchfelder Nicolai Savaskan The Acidic Brain—Glycolytic Switch in the Microenvironment of Malignant Glioma International Journal of Molecular Sciences tumor microenvironment glycolytic acidic glioma lactate MCT1 |
| title | The Acidic Brain—Glycolytic Switch in the Microenvironment of Malignant Glioma |
| title_full | The Acidic Brain—Glycolytic Switch in the Microenvironment of Malignant Glioma |
| title_fullStr | The Acidic Brain—Glycolytic Switch in the Microenvironment of Malignant Glioma |
| title_full_unstemmed | The Acidic Brain—Glycolytic Switch in the Microenvironment of Malignant Glioma |
| title_short | The Acidic Brain—Glycolytic Switch in the Microenvironment of Malignant Glioma |
| title_sort | acidic brain glycolytic switch in the microenvironment of malignant glioma |
| topic | tumor microenvironment glycolytic acidic glioma lactate MCT1 |
| url | https://www.mdpi.com/1422-0067/22/11/5518 |
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