Therapeutic Paradigms That Target Glioblastoma Multiform (GBM) Tumor Metabolism and Available Substrates for Glycolysis in the Tumor Microenvironments (TME)

Donya Iranpoor

Introduction. Glioblastoma Multiforme (GBM), is a Type IV astrocytoma and has the highest incidence of all malignant brain tumors. The estimated median survival time for patients diagnosed with GBM is 12 to 15 months. Current treatment options consist of neurosurgery, radiation, and temozolomide chemotherapy.1 Within the cellular heterogeneity of GBM, the tumor uses cancer-associated metabolic remodeling in malignant cells and tumor-surrounding, non-transformed stromal cells to drive metabolic shifts that drive tumor growth. 2,3 GBM tumor cells and mesenchymal stem cells undergo the ‘Warburg effect’, whereby the cells shift from a reliance on cytosolic glycolysis, the tricarboxylic acid cycle, and oxidative phosphorylation to rely heavily on glycolysis for enhanced glucose metabolism to support the high anabolic activity of the tumor.1 Methods. Varying concentrations of exosomes extracted from glioma cells were inoculated with mesenchymal stem cells at varying concentrations. When exposed to these exosomes, the mesenchymal stem cells increase the rate of glucose, lactate, and ATP consumption and production.4 These metabolic products can then act as a substrate for the glioma to increase anabolic metabolism and promote tumor growth and metastasis.5 Results. The greater the concentration of glioma-derived exosomes inoculated with the mesenchymal stem cells, lead to a dose dependent increase in protein and mRNA levels of Glut-1, a glucose transporter, and hexokinase-2 and phosphokinase-2 glycolytic, both of which are glycolytic enzymes.4 High-dose progesterone treatments target the glycolytic pathway and have been shown to decrease tumor size and increase survival rates in mouse models by targeting Glut-1 and GAPDH, a glycolysis enzyme.1 Ketogenic diets, when used in conjunction with current therapies, have been shown to decrease tumor size in both human and mouse models, possibly by limiting dietary carbohydrates leading to a decrease in glucose in the tumor microenvironment.6 Conclusion. Studies on GBM have shown that communication via exosomes between glioma cancer and the mesenchymal stem cells in the tumor microenvironment can enhance the Warburg effect on stromal cells. Therapies that target the glycolytic pathway by either decrease the availability of glucose in the environment or by inhibiting enzymes key to the glycolytic pathway disrupt the metabolic shift seen in GBM. Future therapies can, therefore, blunt the progression of tumor development and metastasis by preventing communication via exosomes between the glioma cells and the tumor microenvironment or by blocking glycolytic enzymes.

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