Glycolytic glioma cells with active glycogen synthase are sensitive to PTEN and inhibitors of PI3K and gluconeogenesis

Beckner, Marie E.; Gobbel, Glenn T.; Abounader, Roger; Burovic, Fatima; Agostino, Naomi R.; Laterra, John; Pollack, Ian F.

doi:10.1038/labinvest.3700355

Cited by 103 publications

(97 citation statements)

References 69 publications

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“…These two signaling networks earlier were linked to invasive cells within GBMs (13,40,41). Interestingly, the PI3K/Akt pathway is also critically involved in several steps of both anaerobic and aerobic glycolysis regulation, as, for example, in localization of glucose transporters at the cell surface and maintenance of hexokinase function in the absence of extrinsic regulatory factors (40,42,43). Thus, activation of Akt as a result of bev-induced hypoxia may increase intracellular glucose and stimulate anaerobic glycolysis and lactate production, thereby promoting invasiveness.…”

Section: Discussionmentioning

confidence: 99%

Anti-VEGF treatment reduces blood supply and increases tumor cell invasion in glioblastoma

Keunen

Johansson

Oudin

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

552

467

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Bevacizumab, an antibody against vascular endothelial growth factor (VEGF), is a promising, yet controversial, drug in human glioblastoma treatment (GBM). Its effects on tumor burden, recurrence, and vascular physiology are unclear. We therefore determined the tumor response to bevacizumab at the phenotypic, physiological, and molecular level in a clinically relevant intracranial GBM xenograft model derived from patient tumor spheroids. Using anatomical and physiological magnetic resonance imaging (MRI), we show that bevacizumab causes a strong decrease in contrast enhancement while having only a marginal effect on tumor growth. Interestingly, dynamic contrast-enhanced MRI revealed a significant reduction of the vascular supply, as evidenced by a decrease in intratumoral blood flow and volume and, at the morphological level, by a strong reduction of large-and medium-sized blood vessels. Electron microscopy revealed fewer mitochondria in the treated tumor cells. Importantly, this was accompanied by a 68% increase in infiltrating tumor cells in the brain parenchyma. At the molecular level we observed an increase in lactate and alanine metabolites, together with an induction of hypoxia-inducible factor 1α and an activation of the phosphatidyl-inositol-3-kinase pathway. These data strongly suggest that vascular remodeling induced by anti-VEGF treatment leads to a more hypoxic tumor microenvironment. This favors a metabolic change in the tumor cells toward glycolysis, which leads to enhanced tumor cell invasion into the normal brain. The present work underlines the need to combine anti-angiogenic treatment in GBMs with drugs targeting specific signaling or metabolic pathways linked to the glycolytic phenotype.angiogenesis | glioma | metabolism | perfusion G lioblastomas (GBMs) are highly vascularized brain tumors and are therefore attractive targets for anti-angiogenic therapies (1). In particular, vascular endothelial growth factor (VEGF) has been identified as a critical regulator of angiogenesis, and currently a number of clinical trials targeting the VEGFsignaling pathways are under development (2, 3). Bevacizumab (bev), a humanized anti-VEGF antibody, has shown promising results in exploratory phase II trials of recurrent GBM. Alone or in combination with irinotecan, it is well tolerated and shows a high radiological response rate and possibly an increase in median progression-free survival compared with historical controls (4-7), although no impact on overall survival has been reported (8). However, these results are based on small patient cohorts and, because anti-angiogenic agents directly affect vessel permeability, the imaging response assessment based on contrast enhancement (CE) is highly ambiguous (9). Indeed, a direct antitumor effect of bev has remained elusive and the infiltrative part of the tumor may even increase (10,11). In addition to a lack of robust clinical data, the cellular and molecular consequences of anti-VEGF treatment have not been outlined (12). Detailed information on how bev affects ...

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Section: Discussionmentioning

confidence: 99%

Anti-VEGF treatment reduces blood supply and increases tumor cell invasion in glioblastoma

Keunen

Johansson

Oudin

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

552

467

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“…10 It has also been reported that metformin, a well-known biguanide, inhibits cancer cell migration and proliferation, 11 an effect that is enhanced by combination treatment with other anticancer agents. 12 It has been reported that GBM cells preferentially utilize glycolysis for cellular energy production, 13 and glycolysis has been targeted in a GBM stem cell model. 14 On the other hand, some authors have reported that GBM-TS primarily rely on oxidative phosphorylation, 15 and have further shown that GBM-TS survive challenge by a single agent that blocks oxidative phosphorylation by using additional metabolic pathways.…”

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confidence: 99%

Inhibition of glioblastoma tumorspheres by combined treatment with 2-deoxyglucose and metformin

Kim

Lee

et al. 2016

NEUONC

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Background. Deprivation of tumor bioenergetics by inhibition of multiple energy pathways has been suggested as an effective therapeutic approach for various human tumors. However, this idea has not been evaluated in glioblastoma (GBM). We hypothesized that dual inhibition of glycolysis and oxidative phosphorylation could effectively suppress GBM tumorspheres (TS). Methods. Effects of 2-deoxyglucose (2DG) and metformin, alone and in combination, on GBM-TS were evaluated. Viability, cellular energy metabolism status, stemness, invasive properties, and GBM-TS transcriptomes were examined. In vivo efficacy was tested in a mouse orthotopic xenograft model. Results. GBM-TS viability was decreased by the combination of 2DG and metformin. ATP assay and PET showed that cellular energy metabolism was also decreased by this combination. Sphere formation, expression of stemnessrelated proteins, and invasive capacity of GBM-TS were also significantly suppressed by combined treatment with 2DG and metformin. A transcriptome analysis showed that the expression levels of stemness-and epithelial mesenchymal transition-related genes were also significantly downregulated by combination of 2DG and metformin. Combination treatment also prolonged survival of tumor-bearing mice and decreased invasiveness of GBM-TS. Conclusion. The combination of 2DG and metformin effectively decreased the stemness and invasive properties of GBM-TS and showed a potential survival benefit in a mouse orthotopic xenograft model. Our findings suggest that targeting TS-forming cells by this dual inhibition of cellular bioenergetics warrants expedited clinical evaluation for the treatment of GBM.

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“…Tumors, however, consistently rely on glycolysis even in the presence of abundant oxygen (Beckner et al, 2005;Griguer et al, 2005;Kelloff et al, 2005;Rajendran et al, 2003). Since the anaerobic metabolism of glucose to lactic acid is substantially less efficient than oxidation to CO 2 and H 2 O, tumor cells must increase glucose flux in order to maintain sufficient ATP production.…”

Section: The Warburg Effectmentioning

confidence: 99%

Evolutionary dynamics of the Warburg effect: Glycolysis as a collective action problem among cancer cells

Archetti

2014

Journal of Theoretical Biology

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The upregulation of glycolysis in tumors is common even when oxygen is not limiting. The adaptive value of this "Warburg effect" is unclear. Glycolysis is costly for a cell but the ensuing acidity is beneficial for the tumor. A collective action problem among cancer cells arises. Game theory shows that the acidity induced by glycolysis can explain the Warburg effect. a r t i c l e i n f o a b s t r a c tThe upregulation of glycolysis in cancer cells (the "Warburg effect") is common and has implications for prognosis and treatment. As it is energetically inefficient under adequate oxygen supply, its adaptive value for a tumor remains unclear. It has been suggested that the acidity produced by glycolysis is beneficial for cancer cells because it promotes proliferation against normal cells. Current models of this acid-mediated tumor invasion hypothesis, however, do not account for increased glycolysis under nonlimiting oxygen concentrations and therefore do not fully explain the Warburg effect. Here I show that the Warburg effect can be explained as a form of cooperation among cancer cells, in which the products of glycolysis act as a public good, even when oxygen supply is high enough to make glycolysis energetically inefficient. A multiplayer game with non-linear, non-monotonic payoff functions that models the benefits of the acidity induced by glycolysis reveals that clonal selection can stabilize glycolysis even when energetically costly, that is, under non-limiting oxygen concentration. Characterizing the evolutionary dynamics of glycolysis reveals cases in which anti-cancer therapies that rely on the modification of acidity can be effective.

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Glycolytic glioma cells with active glycogen synthase are sensitive to PTEN and inhibitors of PI3K and gluconeogenesis

Cited by 103 publications

References 69 publications

Anti-VEGF treatment reduces blood supply and increases tumor cell invasion in glioblastoma

Anti-VEGF treatment reduces blood supply and increases tumor cell invasion in glioblastoma

Inhibition of glioblastoma tumorspheres by combined treatment with 2-deoxyglucose and metformin

Evolutionary dynamics of the Warburg effect: Glycolysis as a collective action problem among cancer cells

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