The angiogenic switch leads to a metabolic shift in human glioblastoma

Talasila, Krishna M.; Røsland, Gro Vatne; Hagland, Hanne R.; Eskilsson, Eskil; Flønes, Irene H.; Fritah, Sabrina; Azuaje, Francisco; Atai, Nadia A.; Harter, Patrick N.; Mittelbronn, Michel; Andersen, Michael Asger; Joseph, Justin V.; Hossain, Jubayer A; Vallar, Laurent; Noorden, C. J. F. Van; Niclou, Simone P.; Thorsen, Frits; Tronstad, Karl Johan; Tzoulis, Charalampos; Bjerkvig, Rolf; Miletić, Hrvoje

doi:10.1093/neuonc/now175

Cited by 54 publications

(52 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In contrast, glioma cells infiltrating the normal brain have access to normal nutrient concentrations and oxygen tension and, therefore, may not require extensive metabolic reprograming to support tumor development, in agreement with the proposition that upregulation of glycolysis maybe associated with the angiogenic switch. 27 This would be compatible (i) with the relatively low levels of Lac observed in our invasive model that were comparable to non-tumor bearing mice (Figs. 1b and 2a), (ii) a minor role of Lac in the PCA during tumor evolution and at late time points (Figs.…”

Section: Infiltrating Glioma Cells Preserve Mitochondrial Glucose Oxisupporting

confidence: 82%

In vivo characterization of brain metabolism by ¹H MRS, ¹³C MRS and ¹⁸FDG PET reveals significant glucose oxidation of invasively growing glioma cells

Lai

Vassallo²,

Lanz

et al. 2018

Intl Journal of Cancer

View full text Add to dashboard Cite

Glioblastoma are notorious for their highly invasive growth, diffusely infiltrating adjacent brain structures that precludes complete resection, and is a major obstacle for cure. To characterize this "invisible" tumor part, we designed a high resolution multimodal imaging approach assessing in vivo the metabolism of invasively growing glioma xenografts in the mouse brain. Animals were subjected longitudinally to magnetic resonance imaging (MRI) and H spectroscopy (MRS) at ultra high field (14.1 Tesla) that allowed the measurement of 16 metabolic biomarkers to characterize the metabolic profiles. As expected, the neuronal functionality was progressively compromised as indicated by decreasing N-acetyl aspartate, glutamate and gamma-aminobutyric acid and reduced neuronal TCA cycle (-58%) and neurotransmission (-50%). The dynamic metabolic changes observed, captured differences in invasive growth that was modulated by re-expression of the tumor suppressor gene WNT inhibitory factor 1 (WIF1) in the orthotopic xenografts that attenuates invasion. At late stage mice were subjected to C MRS with infusion of [1,6- C]glucose and FDG positron emission tomography (PET) to quantify cell-specific metabolic fluxes involved in glucose metabolism. Most interestingly, this provided the first in vivo evidence for significant glucose oxidation in glioma cells. This suggests that the infiltrative front of glioma does not undergo the glycolytic switch per se, but that environmental triggers may induce metabolic reprograming of tumor cells.

show abstract

Section: Infiltrating Glioma Cells Preserve Mitochondrial Glucose Oxisupporting

confidence: 82%

In vivo characterization of brain metabolism by ¹H MRS, ¹³C MRS and ¹⁸FDG PET reveals significant glucose oxidation of invasively growing glioma cells

Lai

Vassallo²,

Lanz

et al. 2018

Intl Journal of Cancer

View full text Add to dashboard Cite

show abstract

“…In an in vitro model of melanoma, lactate exposure is associated with an increased EMT phenotype (Peppicelli et al, 2016). In a xenograft model of glioblastoma, lactate induces VEGF expression that promotes angiogenesis (Talasila et al, 2016). In pancreatic and ovarian cancer cell cultures, lactate promotes IL-8 production, leading to EMT and metastasis (Shi et al, 1999; Shi et al, 2000; Xu and Fidler, 2000), and the tumor cells can use the lactate as an alternate fuel source, promoting cell proliferation (Guillaumond et al, 2013).…”

Section: Metabolic Challenges In the Tme: Impact On T Lymphocytes Andmentioning

confidence: 99%

Obstacles Posed by the Tumor Microenvironment to T cell Activity: A Case for Synergistic Therapies

2017

View full text Add to dashboard Cite

T cell dysfunction in solid tumors results from multiple mechanisms. Altered signaling pathways in tumor cells help produce a suppressive tumor microenvironment enriched for inhibitory cells, posing a major obstacle for cancer immunity. Metabolic constraints to cell function and survival shape tumor progression and immune cell function. In the face of persistent antigen, chronic T cell receptor signaling drives T lymphocytes to a functionally exhausted state. Here we discuss how the tumor and its microenvironment influences T cell trafficking and function with a focus on melanoma, pancreatic and ovarian cancer, and discuss how scientific advances may help overcome these hurdles.

show abstract

“…Serial 3 μm thick sections were stained with primary antibodies (all from Abcam) against complex I (NDUFB8, ab110242, dilution 1:300), complex II (anti-SDHA, ab14715, dilution 1:4000), complex III (anti-UQCRC2, ab14745, dilution 1:10,000), complex IV (COX-I, ab14705, dilution 1:10,000), complex V (ATP-synthase, ab14748, dilution 1:10,000), and the mitochondrial membrane marker porin (VDAC1, ab14734, dilution 1:10,000). We chose the NDUFB8 subunit because it is central to complex I assembly and function [10,39,46] and has been widely used as a marker of the integrity of the complex [16,40,41]. Sections were deparaffinised in Histoclear and rehydrated in graded ethanol.…”

Section: Immunohistochemistrymentioning

confidence: 99%

Neuronal complex I deficiency occurs throughout the Parkinson’s disease brain, but is not associated with neurodegeneration or mitochondrial DNA damage

et al. 2017

Self Cite

View full text Add to dashboard Cite

Mitochondrial complex I deficiency occurs in the substantia nigra of individuals with Parkinson's disease. It is generally believed that this phenomenon is caused by accumulating mitochondrial DNA damage in neurons and that it contributes to the process of neurodegeneration. We hypothesized that if these theories are correct, complex I deficiency should extend beyond the substantia nigra to other affected brain regions in Parkinson's disease and correlate tightly with neuronal mitochondrial DNA damage. To test our hypothesis, we employed a combination of semiquantitative immunohistochemical analyses, Western blot and activity measurements, to assess complex I quantity and function in multiple brain regions from an extensively characterized population-based cohort of idiopathic Parkinson's disease (n = 18) and gender and age matched healthy controls (n = 11). Mitochondrial DNA was assessed in single neurons from the same areas by real-time PCR. Immunohistochemistry showed that neuronal complex I deficiency occurs throughout the Parkinson's disease brain, including areas spared by the neurodegenerative process such as the cerebellum. Activity measurements in brain homogenate confirmed a moderate decrease of complex I function, whereas Western blot was less sensitive, detecting only a mild reduction, which did not reach statistical significance at the group level. With the exception of the substantia nigra, neuronal complex I loss showed no correlation with the load of somatic mitochondrial DNA damage. Interestingly, α-synuclein aggregation was less common in complex I deficient neurons in the substantia nigra. We show that neuronal complex I deficiency is a widespread phenomenon in the Parkinson's disease brain which, contrary to mainstream theory, does not follow the anatomical distribution of neurodegeneration and is not associated with the neuronal load of mitochondrial DNA mutation. Our findings suggest that complex I deficiency in Parkinson's disease can occur independently of mitochondrial DNA damage and may not have a pathogenic role in the neurodegenerative process.

show abstract

The angiogenic switch leads to a metabolic shift in human glioblastoma

Cited by 54 publications

References 50 publications

In vivo characterization of brain metabolism by ¹H MRS, ¹³C MRS and ¹⁸FDG PET reveals significant glucose oxidation of invasively growing glioma cells

In vivo characterization of brain metabolism by ¹H MRS, ¹³C MRS and ¹⁸FDG PET reveals significant glucose oxidation of invasively growing glioma cells

Obstacles Posed by the Tumor Microenvironment to T cell Activity: A Case for Synergistic Therapies

Neuronal complex I deficiency occurs throughout the Parkinson’s disease brain, but is not associated with neurodegeneration or mitochondrial DNA damage

Contact Info

Product

Resources

About

The angiogenic switch leads to a metabolic shift in human glioblastoma

Cited by 54 publications

References 50 publications

In vivo characterization of brain metabolism by 1H MRS, 13C MRS and 18FDG PET reveals significant glucose oxidation of invasively growing glioma cells

In vivo characterization of brain metabolism by 1H MRS, 13C MRS and 18FDG PET reveals significant glucose oxidation of invasively growing glioma cells

Obstacles Posed by the Tumor Microenvironment to T cell Activity: A Case for Synergistic Therapies

Neuronal complex I deficiency occurs throughout the Parkinson’s disease brain, but is not associated with neurodegeneration or mitochondrial DNA damage

Contact Info

Product

Resources

About

In vivo characterization of brain metabolism by ¹H MRS, ¹³C MRS and ¹⁸FDG PET reveals significant glucose oxidation of invasively growing glioma cells

In vivo characterization of brain metabolism by ¹H MRS, ¹³C MRS and ¹⁸FDG PET reveals significant glucose oxidation of invasively growing glioma cells