Beyond glucose: alternative sources of energy in glioblastoma

Caniglia, John L.; Jalasutram, Anvesh; Asuthkar, Swapna; Sahagun, Joseph; Park, Simon; Ravindra, Aditya; Tsung, Andrew J.; Guda, Maheedhara R.; Velpula, Kiran Kumar

doi:10.7150/thno.53506

Cited by 28 publications

(30 citation statements)

References 60 publications

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“…Glutamine dependency in different cancers promotes invasion and tumor aggressiveness 94 . Also, glutamine dependency can downregulate glycolysis reducing glucose uptake and lactate production, contributing to the Warburg effects observed in ischemic tumors 95 , 96 . In agreement, we identified that TNT formation also protects astrocytes from hypoxic conditions.…”

Section: Discussionmentioning

confidence: 99%

Tunneling nanotubes, TNT, communicate glioblastoma with surrounding non-tumor astrocytes to adapt them to hypoxic and metabolic tumor conditions

Valdebenito

Malik

Luu

et al. 2021

Sci Rep

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Cell-to-cell communication is essential for the development and proper function of multicellular systems. We and others demonstrated that tunneling nanotubes (TNT) proliferate in several pathological conditions such as HIV, cancer, and neurodegenerative diseases. However, the nature, function, and contribution of TNT to cancer pathogenesis are poorly understood. Our analyses demonstrate that TNT structures are induced between glioblastoma (GBM) cells and surrounding non-tumor astrocytes to transfer tumor-derived mitochondria. The mitochondrial transfer mediated by TNT resulted in the adaptation of non-tumor astrocytes to tumor-like metabolism and hypoxia conditions. In conclusion, TNT are an efficient cell-to-cell communication system used by cancer cells to adapt the microenvironment to the invasive nature of the tumor.

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Section: Discussionmentioning

confidence: 99%

Tunneling nanotubes, TNT, communicate glioblastoma with surrounding non-tumor astrocytes to adapt them to hypoxic and metabolic tumor conditions

Valdebenito

Malik

Luu

et al. 2021

Sci Rep

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“…In addition, many of the oncogenes and tumor suppressor proteins, commonly mutated in GBM, regulate cancer metabolism leading to an increased glucose uptake, the switch to the Warburg effect, de novo lipogenesis and other alternative metabolic pathways. For the reason above, targeting tumor metabolism represents an attractive therapeutic strategy for GBM (5,6) particularly using combined strategies (7). The oral antidiabetic Metformin (MET), that modulates 5' AMP-activated protein kinase (AMPK) and mitochondrial functions, showed promising in vitro and in vivo results in different types of cancer, including GBM (8)(9)(10).…”

Section: Introductionmentioning

confidence: 99%

Imaging Metformin Efficacy as Add-On Therapy in Cells and Mouse Models of Human EGFR Glioblastoma

et al. 2021

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Glioblastoma (GBM) is a highly aggressive tumor of the brain. Despite the efforts, response to current therapies is poor and 2-years survival rate ranging from 6-12%. Here, we evaluated the preclinical efficacy of Metformin (MET) as add-on therapy to Temozolomide (TMZ) and the ability of [18F]FLT (activity of thymidine kinase 1 related to cell proliferation) and [18F]VC701 (translocator protein, TSPO) Positron Emission Tomography (PET) radiotracers to predict tumor response to therapy. Indeed, TSPO is expressed on the outer mitochondrial membrane of activated microglia/macrophages, tumor cells, astrocytes and endothelial cells. TMZ-sensitive (Gli36ΔEGFR-1 and L0627) or -resistant (Gli36ΔEGFR-2) GBM cell lines representative of classical molecular subtype were tested in vitro and in vivo in orthotopic mouse models. Our results indicate that in vitro, MET increased the efficacy of TMZ on TMZ-sensitive and on TMZ-resistant cells by deregulating the balance between pro-survival (bcl2) and pro-apoptotic (bax/bad) Bcl-family members and promoting early apoptosis in both Gli36ΔEGFR-1 and Gli36ΔEGFR-2 cells. In vivo, MET add-on significantly extended the median survival of tumor-bearing mice compared to TMZ-treated ones and reduced the rate of recurrence in the TMZ-sensitive models. PET studies with the cell proliferation radiopharmaceutical [18F]FLT performed at early time during treatment were able to distinguish responder from non-responder to TMZ but not to predict the duration of the effect. On the contrary, [18F]VC701 uptake was reduced only in mice treated with MET plus TMZ and levels of uptake negatively correlated with animals’ survival. Overall, our data showed that MET addition improved TMZ efficacy in GBM preclinical models representative of classical molecular subtype increasing survival time and reducing tumor relapsing rate. Finally, results from PET imaging suggest that the reduction of cell proliferation represents a common mechanism of TMZ and combined treatment, whereas only the last was able to reduce TSPO. This reduction was associated with the duration of treatment response. TSPO-ligand may be used as a complementary molecular imaging marker to predict tumor microenvironment related treatment effects.

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“…Glioblastoma multiforme (GBM) is the most common type of primary brain cancer in adults, and a stage IV glioma as classified by the world health organization [ 156 ]. GBM has a poor survival rate with a median survival of only fifteen months even after resection, radiation, and chemotherapy [ 157 , 158 , 159 ]. GBM tumors are extremely invasive and extensively angiogenic and necrotic [ 160 , 161 ].…”

Section: The Immunosuppressive Role Of Relb In Gbmmentioning

confidence: 99%

RelB and Neuroinflammation

Mockenhaupt

Gonsiewski

Kordula

2021

Cells

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Neuroinflammation within the central nervous system involves multiple cell types that coordinate their responses by secreting and responding to a plethora of inflammatory mediators. These factors activate multiple signaling cascades to orchestrate initial inflammatory response and subsequent resolution. Activation of NF-κB pathways in several cell types is critical during neuroinflammation. In contrast to the well-studied role of p65 NF-κB during neuroinflammation, the mechanisms of RelB activation in specific cell types and its roles during neuroinflammatory response are less understood. In this review, we summarize the mechanisms of RelB activation in specific cell types of the CNS and the specialized effects this transcription factor exerts during neuroinflammation.

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Beyond glucose: alternative sources of energy in glioblastoma

Cited by 28 publications

References 60 publications

Tunneling nanotubes, TNT, communicate glioblastoma with surrounding non-tumor astrocytes to adapt them to hypoxic and metabolic tumor conditions

Tunneling nanotubes, TNT, communicate glioblastoma with surrounding non-tumor astrocytes to adapt them to hypoxic and metabolic tumor conditions

Imaging Metformin Efficacy as Add-On Therapy in Cells and Mouse Models of Human EGFR Glioblastoma

RelB and Neuroinflammation

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