21 research outputs found
Metabolic therapy and bioenergetic analysis: The missing piece of the puzzle.
Background
Aberrant metabolism is recognized as a hallmark of cancer, a pillar necessary for cellular proliferation. Regarding bioenergetics (ATP generation), most cancers display a preference not only toward aerobic glycolysis (“Warburg effect”) and glutaminolysis (mitochondrial substrate level-phosphorylation) but also toward other metabolites such as lactate, pyruvate, and fat-derived sources. These secondary metabolites can assist in proliferation but cannot fully cover ATP demands.
Scope of review
The concept of a static metabolic profile is challenged by instances of heterogeneity and flexibility to meet fuel/anaplerotic demands. Although metabolic therapies are a promising tool to improve therapeutic outcomes, either via pharmacological targets or press-pulse interventions, metabolic plasticity is rarely considered. Lack of bioenergetic analysis in vitro and patient-derived models is hindering translational potential. Here, we review the bioenergetics of cancer and propose a simple analysis of major metabolic pathways, encompassing both affordable and advanced techniques. A comprehensive compendium of Seahorse XF bioenergetic measurements is presented for the first time.
Major conclusions
Standardization of principal readouts might help researchers to collect a complete metabolic picture of cancer using the most appropriate methods depending on the sample of interest.post-print3250 K
Suppressor of fused associates with dissemination patterns in patients with glioma
Gliomas are the most common brain tumors, which present poor prognosis, due, in part, to tumor cell migration and infiltration into distant brain areas. However, the underlying mechanisms causing such effects are unknown. Hedgehog (HH)-Gli axis is one of the signaling pathways involved, with a high number of molecular mediators. In this study, we investigated the association between HH-Gli intermediates and clinical parameters. We found that high levels of SuFu are associated with high dissemination patterns in patients with glioma. Therefore, we analyzed SuFu expression data in three glioma cohorts of surgical samples (N =1,759) and modified its expression in Glioblastoma Cancer Stem Cells (GB CSC) in vitro models. Our data reveal that SuFu overexpression increases cancer stemness properties together with a migratory phenotype. This work identifies SuFu as a new molecular player in glioma cell migration and a promising target to develop blocking agents to decrease GB dissemination.This research was funded by grants from the "Proyectos de Investigación en Salud" (PI21/01353) and La Universidad Francisco de Vitoria-Banco Santander (UFV2021-23).S
A New Natural Antimycotic Agent is Effective Against Oropharyngeal Candidiasis: The VIPROCAN Study.
Background:
The incidence of community and nosocomial candidiasis has dramatically increased in the last two decades. There are multiple treatments for this
infection, but the toxicity of some and the induction of resistant strains require the development of new compounds.
Objectives:
With the aim of reducing the Candida population in the oropharyngeal cavity, we have formulated a toothpaste with VG-01 agent, composed of a
mixture of carnosic acid (CA) and propolis (PP).
Methods:
We investigated the ability of VG-01 toothpaste to minimize and stabilize fungal presence in 21 patients diagnosed with clinical oropharyngeal
candidiasis.
Results:
Our data indicate that VG-01 toothpaste showed an effect not only against the most frequent species of Candida, C. albicans, but also in the other
species analyzed. 82% of patients stated that they would continue using it outside the study.
Conclusion:
Our data demonstrate that VG-01, composed of CA and PP is a potential antimycotic agent effective against the most common species that cause
oropharyngeal candidiasis present in clinical practicepost-print988 K
Beyond the Warburg Effect: Oxidative and Glycolytic Phenotypes Coexist within the Metabolic Heterogeneity of Glioblastoma.
Glioblastoma (GBM) is the most aggressive primary brain tumor, with a median survival at diagnosis of 16–20 months. Metabolism represents a new attractive therapeutic target; however, due to high intratumoral heterogeneity, the application of metabolic drugs in GBM is challenging. We characterized the basal bioenergetic metabolism and antiproliferative potential of metformin (MF), dichloroacetate (DCA), sodium oxamate (SOD) and diazo-5-oxo-L-norleucine (DON) in three distinct glioma stem cells (GSCs) (GBM18, GBM27, GBM38), as well as U87MG. GBM27, a highly oxidative cell line, was the most resistant to all treatments, except DON. GBM18 and GBM38, Warburg-like GSCs, were sensitive to MF and DCA, respectively. Resistance to DON was not correlated with basal metabolic phenotypes. In combinatory experiments, radiomimetic bleomycin exhibited therapeutically relevant synergistic effects with MF, DCA and DON in GBM27 and DON in all other cell lines. MF and DCA shifted the metabolism of treated cells towards glycolysis or oxidation, respectively. DON consistently decreased total ATP production. Our study highlights the need for a better characterization of GBM from a metabolic perspective. Metabolic therapy should focus on both glycolytic and oxidative subpopulations of GSCs.post-print3439 K
The low affinity A2B adenosine receptor enhances migratory and invasive capacity in vitro and angiogenesis in vivo of glioblastoma stem-like cells.
Glioblastoma (GBM) is the most common and deadlymalignant brain tumor,with
a median survival of 15 to 17 months for a patient. GBM contains a cellular
subpopulation known as GBM stem-like cells (GSCs) that persist in hypoxic
niches and are capable of infiltrating into healthy brain tissue. For this reason,
GSCs are considered one of the main culprits for GBM recurrence. A hypoxic
microenvironment increases extracellular adenosine levels, activating the low
affinity A2B adenosine receptor (A2BAR). Adenosine, through A2BAR, is capable of
modulating invasiveness. However, its role in the invasion/migration of hypoxic-
GSCs is still unknown. This study aims to understand the importance of A2BAR in
modulating themigratory/invasive capacity of GSCs under hypoxia. Data analysis
from The Cancer Genome Atlas (TCGA) program correlates A2BAR expression
with high-grade glioma and hypoxic necrotic areas. U87MG and primary culturederived
GSCs under hypoxic conditions (0.5% O2) increased A2BAR mRNA and
protein levels. As expected, the migratory and invasive capacity of GSCs
increased under hypoxia, which was counteracted by blocking A2BAR, through
the downregulation of MMP9 activity and epithelial–mesenchymal transition
marker expression. Finally, in a xenograft mouse model, we demonstrate that
treatment with MRS1754 did not affect the tumor volume but could decrease
blood vessel formation and VEGF expression. Our results suggest that
extracellular adenosine, through the activation of A2BAR, enhances the
migratory and invasive capacity of GSCs in vitro under hypoxic conditions.
Targeting A2BAR can be an effective therapy for GBM recurrence.post-print556 K
Newcastle Disease Virus (NDV) Oncolytic Activity in Human Glioma Tumors Is Dependent on CDKN2A-Type I IFN Gene Cluster Codeletion.
Glioblastoma (GBM) is the most aggressive and frequent primary brain tumor in adults
with a median overall survival of 15 months. Tumor recurrence and poor prognosis are related to
cancer stem cells (CSCs), which drive resistance to therapies. A common characteristic in GBM is
CDKN2A gene loss, located close to the cluster of type I IFN genes at Ch9p21. Newcastle disease
virus (NDV) is an avian paramyxovirus with oncolytic and immunostimulatory properties that has
been proposed for the treatment of GBM. We have analyzed the CDKN2A-IFN I gene cluster in
1018 glioma tumors and evaluated the NDV oncolytic e ect in six GBM CSCs ex vivo and in a mouse
model. Our results indicate that more than 50% of GBM patients have some IFN deletion. Moreover,
GBM susceptibility to NDV is dependent on the loss of the type I IFN. Infection of GBM with an
NDV-expressing influenza virus NS1 protein can overcome the resistance to oncolysis by NDV of type
I-competent cells. These results highlight the potential of using NDV vectors in antitumor therapies.post-print3309 K
DNA sequences within glioma-derived extracellular vesicles can cross the intact blood-brain barrier and be detected in peripheral blood of patients
Tumor-cell-secreted extracellular vesicles (EVs) can cross the disrupted bloodbrain
barrier (BBB) into the bloodstream. However, in certain gliomas, the BBB
remains intact, which might limit EVs release. To evaluate the ability of tumor-derived
EVs to cross the BBB, we used an orthotopic xenotransplant mouse model of human
glioma-cancer stem cells featuring an intact BBB. We demonstrated that all types of
tumor cells-derived EVs−apoptotic bodies, shedding microvesicles and exosomes−
cross the intact BBB and can be detected in the peripheral blood, which provides a
minimally invasive method for their detection compared to liquid biopsies obtained
from cerebrospinal fluid (CSF). Furthermore, these EVs can be readily distinguished
from total murine EVs, since they carry human-specific DNA sequences relevant
for GBM biology. In a small cohort of glioma patients, we finally demonstrated
that peripheral blood EVs cargo can be successfully used to detect the presence of
IDH1G395A, an essential biomarker in the current management of human gliomaWe are grateful for the financial support from the ‘Fondo de Investigaciones Sanitarias’ (FIS) (PI10/01069 and PI14/00077) and the ‘Miguel Servet Program’ (CP11/00147) from the ‘Instituto de Salud Carlos III’ (AAS), RTC-2015-3846-1 from Ministerio de Economía
y Competitividad and FEDER fund
SOX2(+) Cell Population from Normal Human Brain White Matter Is Able to Generate Mature Oligodendrocytes
Peer reviewe
Bevacizumab dose adjustment to improve clinical outcomes of glioblastoma.
Background
Glioblastoma (GBM) is one of the most aggressive and vascularized brain tumors in adults, with a median survival of 20.9 months. In newly diagnosed and recurrent GBM, bevacizumab demonstrated an increase in progression-free survival, but not in overall survival.
Methods
We conducted an in silico analysis of VEGF expression, in a cohort of 1082 glioma patients. Then, to determine whether appropriate bevacizumab dose adjustment could increase the anti-angiogenic response, we used in vitro and in vivo GBM models. Additionally, we analyzed VEGFA expression in tissue, serum, and plasma in a cohort of GBM patients before and during bevacizumab treatment.
Results
We identified that 20% of primary GBM did not express VEGFA suggesting that these patients would probably not respond to bevacizumab therapy as we proved in vitro and in vivo. We found that a specific dose of bevacizumab calculated based on VEGFA expression levels increases the response to treatment in cell culture and serum samples from mice bearing GBM tumors. Additionally, in a cohort of GBM patients, we observed a correlation of VEGFA levels in serum, but not in plasma, with bevacizumab treatment performance.
Conclusions
Our data suggest that bevacizumab dose adjustment could improve clinical outcomes in Glioblastoma treatment.post-print1360 K
Ceramide Composition in Exosomes for Characterization of Glioblastoma Stem-Like Cell Phenotypes.
Glioblastoma (GBM) is one of the most malignant central nervous system tumor types.
Comparative analysis of GBM tissues has rendered four major molecular subtypes. From
them, two molecular subtypes are mainly found in their glioblastoma cancer stem-like cells
(GSCs) derived in vitro: proneural (PN) and mesenchymal (MES) with nodular (MES-N) and
semi-nodular (MES-SN) disseminations, which exhibit different metabolic, growth, and
malignancy properties. Many studies suggest that cancer cells communicate between
them, and the surrounding microenvironment, via exosomes. Identifying molecular
markers that allow the specific isolation of GSC-derived exosomes is key in the
development of new therapies. However, the differential exosome composition
produced by main GSCs remains unknown. The aim of this study was to determine
ceramide (Cer) composition, one of the critical lipids in both cells and their cell-derived
exosomes, from the main three GSC phenotypes using mass spectrometry-based
lipidomics. GSCs from human tissue samples and their cell-derived exosomes were
measured using ultra-high-performance liquid chromatography-quadrupole time-of-flight
mass spectrometry (UHPLC/Q-TOF-MS) in an untargeted analysis. Complete
characterization of the ceramide profile, in both cells and cell-derived exosomes from
GSC phenotypes, showed differential distributions among them. Results indicate that
such differences of ceramide are chain-length dependent. Significant changes for the C16
Cer and C24:1 Cer and their ratio were observed among GSC phenotypes, being different
for cells and their cell-derived exosomes.post-print4713 K