Data are means±SEM. (A) Hexokinase-II protein is detected in all VHL PH/PGL but is hardly detectable in RET, NF1 and SDH samples. 3D). Now Warburg's theory is enjoying a resurrection. Aliquots of the RNA were analyzed by electrophoresis on a Bioanalyser 2100 (Agilent Technologies) and quantified using Nano Drop ND-1000 (Labtech). The different mutations are localized in three distinct clusters: SDH (grey), VHL (white) and RET/NF1 (black). In ref. Inactivation of SDH also leads to HIF stabilization, through the inhibition of their hydroxylation by prolyl-4-hydroxylases, necessary for their recognition by pVHL [15], [16]. Contributed reagents/materials/analysis tools: JB CB FT LA RL PFP APGR. INSERM, unit 970, Paris, France, Microarray analysis in the 68 inherited tumors revealed a modest but significant decrease of TIGAR mRNA expression (0.7 fold, Welch T-test p<0.05) in VHL vs non-VHL tumors (Fig. Yes QCCR activity was also slightly lower in SDH and VHL tumors, but the difference was much smaller (1.3 and 1.8-fold lower, respectively, than in NF1 and RET tumors) and was not statistically significant (Fig. [16] and reviewed in ref. AP-HP, Hôpital Européen Georges Pompidou, Service d'Hypertension artérielle, Paris, France, Affiliation The Warburg Effect and Mitochondrial Uncoupling. From his observations, Warburg concluded that the mitochondria were dysfunctional [8,9]. (A) Unsupervised hierarchical clustering analysis of the 68 samples according to the expression of 200 genes. The Warburg Effect has been documented for over 90 years and extensively studied over the past 10 years, with thousands of papers reporting to have established either its causes or its functions. J. Mol. Reducing the glucose in the media to physiological levels will give a truer picture of the complex metabolic processes at work. The observation that cancer cells produce lactate in an environment of oxygen sufficiency (aerobic glycolysis) is a central theme of cancer metabolism known as the Warburg effect. Clustering were performed using Ward linkage and (1-Pearson coefficient of correlation) as inter-individual distance (R package cluster). https://doi.org/10.1371/journal.pone.0007094.g006. This rapid fermentation of glucose by tumors, even in the presence of ample oxygen, was the first biochemical trait assigned to cancer and is known as the Warburg effect. Abstract. Likewise, we found that lactate dehydrogenase (LDH), which catalyses the last step of anaerobic glycolysis and can be used as an indicator of glycolytic activity [4], was twice as active in all VHL tumors (p<0.01) than in NF1 and RET PH/PGL. To evaluate the link between hypoxia and Warburg effect, we studied mitochondrial electron transport, angiogenesis and glycolysis in pheochromocytomas induced by germ-line mutations in VHL, RET, NF1 and SDH genes. Warburg [4] i… The Warburg effect has been confirmed in previous studies including those of DeBerardinis et al. Why do cancers have high aerobic glycolysis? INSERM, unit 676, Hôpital Robert Debré, Paris, France, Affiliations A low complex II activity correlated with a high vascular density (n = 18; r = −0.71; p<0.001). AP-HP, Hôpital Cochin, Service d'Anatomie pathologique, Paris, France, Affiliation Uncontrolled proliferation is one of the essential characteristics of cancer. A review of cancer metabolism. Advances in research techniques since then have shown the mitochondria in cancer cells to be functional across a range of tumour types. 18F-FDG is transported into cells by glucose transporters (GLUTs) and phosphorylated by hexokinase (HK) to 18F-FDG-6-phosphate (18F-FDG-6-P). The more actively proliferating cells in the periphery may perhaps use the lactate excreted in the hypoxic region and oxidise it [57], leading to a symbiotic relationship between the hypoxic and aerobic cell populations. Previous studies have shown that high levels of glucose in the culture media can significantly reduce levels of mitochondrial respiration, with reduced glucose conditions showing much higher rates of mitochondrial respiration, as cells use other substrates for cellular ATP production [39,40]. However, looking to the future, the role of aerobic glycolysis needs further elucidation, as it is not a consistent feature in all cancers. The genetic testing identified a germ-line RET mutation in three patients, an SDHB mutation in five patients, an SDHD mutation in two patients, an SDHC mutation in one patient and a VHL missense mutation in 12 patients. Find Other Styles. In summary, we have sought here to revisit the Warburg effect and review its significance in cancer based on recent advances in our knowledge and understanding of the complex biology underlying this disease. In contrast, the two increased genes were strongly upregulated. 2A). The Warburg effect has been confirmed in previous studies including those of DeBerardinis et al. The Warburg effect, characterized by increased glucose uptake and lactate production, is a well-known universal across cancer cells and other proliferating cells. Collège de France, Paris, France, The common feature of this altered metabolism is the increased glucose uptake and fermentation of glucose to lactate. (B) Lactate dehydrogenase is increased in tumors harboring a VHL mutation as compared to SDH, RET and NF1 tumors. Data are means±SEM. https://doi.org/10.1371/journal.pone.0007094.g003. Data are means±SEM, represented as relative to NF1 expression values. For one patient (P6), vascular density could not be evaluated because of an anarchic vascular architecture. The lactate secreted by the astrocytes then fuels the neurons, which use oxidative phosphorylation to generate ATP [54]. In contrast to normal differentiated cells, which rely primarily on mitochondrial oxidative phosphorylation to generate the energy needed for cellular processes, most cancer cells instead rely on aerobic glycolysis, a phenomenon termed "the Warburg effect." Under high glucose conditions, this property of cancer cell lines will be held back by glucose inhibition of mitochondrial respiration. The authors suggest that rather than an increase in glycolysis being the main cause of malignant tumour growth, it is the efficiency of mitochondrial energy conversion that is the key metabolic factor. [10], where cells were incubated under oxygenated conditions in 10 mM C-13-labelled glucose. There was no difference in HIF-1α mRNA levels between the different types of tumors studied. We found an overall decrease in subunits of complexes I to IV in tumors from SDH and VHL patients. Michelle Potter and Emma Newport were supported by Williams fund (http://www.williamsfund.co.uk/). Rare Adrenal Cancer Network-Corticomédullosurrénale Tumeur Endocrine, Institut National du Cancer, Paris, France, Affiliations This tumour is less than 10% cancer cells, and the remaining cells are stromal/inflammation cells [47]. Although PET imaging is undeniably an extremely useful and an important clinical technique, there can be issues with the interpretation of the image. First postulated by Pavlides et al. Otto Heinrich Warburg demonstrated in 1924 that cancer cells show an increased dependence on glycolysis to meet their energy needs, regardless of whether they were well-oxygenated or not. In the present study, we were unable to detect p53 in PH/PGL samples using a standard immunohistochemistry protocol. Increasing levels of CO 2 have been shown to stimulate the rate of photosynthesis, eliminate the oxygen inhibition of photosynthesis (Warburg effect), and decrease glycolate formation in isolated spinach chloroplasts. Even in the presence of sufficient oxygen, cancer cells produce about 60% of their ATP through glycolysis instead of oxidative phosphorylation. The Von Hippel-Lindau (VHL) gene is inactivated in 80% of sporadic RCC, and was thus suspected to mediate this phenomenon. were supported by the Association Française contre les Myopathies and the Association contre les Maladies Mitochondriales. 3C). Warburg hypothesis; This disambiguation page lists articles associated with the title Warburg effect. First, we performed HIF-1α and HIF-2α immunohistochemistry to evaluate pseudohypoxia in inherited PH/PGL tissues (Fig. We demonstrated here that FOXE1 repressed Warburg effect by inhibiting the expression of the glycolytic enzyme hexokinase 2 (HK2), a key mediator of aerobic glycolysis, in CRC cells. PLOS ONE promises fair, rigorous peer review, Ponceau staining confirmed equivalent loading of each sample and membranes were then blocked in 5% milk in TBST buffer, and probed with the primary antibody. We performed MXI-1 and c-Myc immunohistochemistry (data not shown) and analyzed MXI-1 and PGC1-β mRNA expression by microarray, but such experiments led to negative results. The microenvironment of cancer is ever changing, and cancer cells can and do vary in their metabolic phenotype even within the same tumour mass [56]. We therefore studied the expression and activity of other complexes of the respiratory chain. Recent studies arguing that cancer cells benefit from this phenomenon, termed the Warburg effect, have renewed discussions about its exact role as cause, correlate, or facilitator of cancer. This work is part of the national program Cartes d'Identité des Tumeurs ® (CIT) funded and developed by the Ligue Nationale Contre le Cancer.P.B. A hypoxia-inducible transcription factor (HIF)-dependent decrease in SDHB protein expression has also been described, specifically in SDH- and VHL-related PH/PGL. Analyzed the data: JF JJB LV AdR XJ PR APGR. https://doi.org/10.1371/journal.pone.0007094.t003. 1B and C). 7, Table 1). Beyond cancer, the WE plays an important role in many other cell types involved in immunity, angiogenesis, pluripotency, and infection by pathogens (e.g., malaria). For each patient, we obtained two or three frozen samples and two paraffin-embedded specimens prepared for routine pathological analyses. Université Paris Descartes, Faculté de Médecine, Paris, France, Sci. The NDUFA4L2 transcript was also strongly overexpressed in PH/PGL harboring SDH and VHL mutations. This is described as aerobic glycolysis and, in cancer, often termed the “Warburg effect” after Otto Warburg who first observed it almost 100 years ago . Université Paris Descartes, Faculté de Médecine, Paris, France, Affiliations In addition, Fantin et al. In oncology, the Warburg effect is a form of modified cellular metabolism found in cancer cells, which tend to favor a specialised fermentation over the aerobic respiration pathway that most other cells of the body prefer. Yes https://doi.org/10.1371/journal.pone.0007094, Editor: Joseph Najbauer, City of Hope Medical Center, United States of America, Received: May 7, 2009; Accepted: August 20, 2009; Published: September 18, 2009. Expression profiles are shown as a heat map indicating high (red) and low (blue) expression according to a log2-transformed scale. RET and NF1 tumors). Tumourigenic cells oxidise glucose by fermentation and generate lactate and adenosine triphosphate even in the presence of oxygen (Warburg effect). After more than 80 years from the revolutionary discoveries of Otto Warburg, who observed high glucose dependency, with increased glycolysis and lactate production regardless of oxygen availability in most cancer cells, the ‘Warburg effect’ returns to the fore in neuronal cells affected by Alzheimer’s disease (AD). An increase in HIF-2α mRNA expression has previously been reported in VHL PH/PGL [13]. Affiliations Another study by Schulz et al. Loss of TIGAR expression thus appeared preferentially in VHL-related PH/PGL (p = 0.025). The exact reasons behind the metabolic switch are not known, but likely reasons include: (i) sustaining high proliferative rates in hypoxia [27] and (ii) evading apoptosis as a result of reduced mitochondrial function [28]. [44]. Collège de France, Paris, France, Once inside the cell, 18F-FDG-6-P cannot be further metabolised through the glycolytic pathway and due to its high polar nature becomes trapped. Here, we show that PH/PGL susceptibility genes influence the complex cellular balance between angiogenesis, electron transport and glycolysis, which are regulated by two master genes, HIF and p53. We confirmed that TIGAR protein was absent from 7/8 VHL-PH/PGL samples analyzed, but was present in 9/12 non-VHL samples. This is considerably higher than plasma glucose, which lies between 4 and 6 mM. Activities of cytochrome c oxidase (COX; complex IV), succinate cytochrome c reductase (SCCR; complexes II+III), quinol cytochrome c reductase (QCCR; complex III) and lactate dehydrogenase were measured spectrophotometrically using a pseudo dual-wavelength Cary 50 spectrophotometer (Varian, Melbourne, Australia) [40]. The phenomenon of aerobic glycolysis, termed the Warburg effect, has been observed in a variety of other tumour types, including colorectal cancer [3], breast [4], lung [5] and glioblastoma [6,7]. Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. With the exception of 3 patients, cytoplasmic expression of TIGAR was systematically associated with the presence of p53 in the nucleus of tumor cells. The Na+/H+-antiporter is upregulated in tumourigenic cells resulting in release of lactate- and … The Warburg hypothesis (/ ˈ v ɑːr b ʊər ɡ /), sometimes known as the Warburg theory of cancer, postulates that the driver of tumorigenesis is an insufficient cellular respiration caused by insult to mitochondria. Nelly Burnichon, Affiliations Otto Heinrich Warburg demonstrated in 1924 that cancer cells show an increased dependence on glycolysis to meet their energy needs, regardless of whether they were well-oxygenated or not. They described a relatively higher expression of HIF-2α than HIF-1α in VHL tumors and a reverse pattern in SDH tumors. SDHB, C and D genes encode three of the four subunits of succinate dehydrogenase (SDH), a mitochondrial enzyme, which catalyzes the oxidation of succinate into fumarate in the tricarboxylic acid (TCA) cycle, and feeds electrons to the ubiquinone pool in the respiratory chain. ], Michelle Potter, Emma Newport, Karl J. Morten; The Warburg effect: 80 years on. (B) Principal component analysis of the 68 samples according to the expression of 200 genes. Lactate was discovered in the late 1700s and was traditionally thought of as a waste product of glycolysis. Microarray evaluation of HIF-1α (B) and HIF-2α (C) expression between SDH, VHL, RET and NF1 tumors. Immunohistochemistry revealed a mild to strong nuclear p53 labeling, and the cystoplasmic expression of TIGAR in the majority of RET, NF1 and SDH tumors. The expression profile of these 38 probe sets was used to perform a clustering of the 68 tumors and led to the division of patients into two clusters (Fig. The Warburg effect (WE), or aerobic glycolysis, is commonly recognized as a hallmark of cancer and has been extensively studied for potential anti-cancer therapeutics development. Modern anti-cancer therapies targeting the epigenetic machinery awaken retroelement expression, inducing anti-viral responses that eliminate tumors through mechanisms not completely understood. Article Transcriptional Regulation of the Warburg Effect in Cancer by SIX1 Graphical Abstract Highlights d SIX1 is a key transcription factor involved in the Warburg effect d SIX1 potentiates the Warburg effect via HBO1 and AIB1 d SIX1 glycolytic function is directly repressed by microRNA- 548a-3p d The miR-548a-3p/Six1 axis regulates the Warburg effect and tumor growth Back in the lab at the Kaiser Wilhelm Institute, Warburg discovered that thin slices of tumors produced lactate much more rapidly than normal tissue. Biochem Soc Trans 15 October 2016; 44 (5): 1499–1505. However, using tyramide signal amplification, we were able to reveal p53 expression in tumor tissues. INSERM, unit 970, Paris, France, The Warburg effect is not a universal feature of cancer, and similarly the reverse Warburg is not universal in all tumours. Both MCF-7 and MDA-MB-231, when co-cultured with fibroblasts, show reduced mitochondrial function in fibroblasts with increased activity in the cancer cell lines. Paris-Cardiovascular research Center at HEGP, Paris, France, Interestingly, this gene was identified as the first gene up-regulated in a transcriptome analysis of hypoxic neuroblastoma cells, another neural-crest derived tumor that shares a number of features with PH/PGL [27]. These data were interpreted as tumourigenicity being dependent on high levels of energy derived from glycolysis. Glucose is a crucial molecule in energy production and produces different end products in non-tumourigenic- and tumourigenic tissue metabolism. Complex II+III electron transfer activity was abolished in SDH and substantially lower in VHL samples than in NF1 and RET tumors (Fig. Together, these phenomena concur to the observed decreased electron transport and increased glycolysis. Increases in glycolysis have been linked to invasiveness, with changes in glycolysis identified in several studies [29,30]. Calibration bar: 50 µm. We then used CD34 immunohistochemistry to evaluate the vascular density in PH/PGL samples (Fig. The Warburg Effect. In 2000, Hanahan and Weinberg published a highly cited review article identifying six cancer hallmarks [25]. PLoS ONE 4(9): Recently, however, a team of … 3,4 The Warburg effect allows dividing cells to use intermediate glucose metabolites to double their biomass and suppress apoptosis. Although hard to generalise in solid tumours with a hypoxic core, perhaps the Warburg effect most probably predominates with reduced oxygen levels driving the cells to make the most of all available glucose. 5 This phenomenon was first discovered by Otto Warburg in the 1920s and was called aerobic glycolysis. Paris-Cardiovascular research Center at HEGP, Paris, France, Contributed equally to this work with: FOXE1 bound directly to the promoter region of HK2 and negatively regulated its transcription and thus prohibiting cell proliferation. (C) Mean values for genes expression between SDH, VHL, RET and NF1 tumors. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. broad scope, and wide readership – a perfect fit for your research every time. The Authors declare that there are no competing interests associated with the manuscript. 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