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. Increases in glycolysis have been linked to invasiveness, with changes in glycolysis identified in several studies [29,30]. In 1930s, Otto Warburg observed altered metabolism in cancer cells. Together they form a unique fingerprint. The Warburg effect is caused by tumor cells not only to adapt their metabolism to the demand for and limited supply of oxygen but also to obtain large amounts of nucleotides, amino acids and lipids for excessive proliferation of tumor cells. Find Other Styles. 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. https://doi.org/10.1371/journal.pone.0007094.g006. The different mutations are localized in three distinct clusters: SDH (grey), VHL (white) and RET/NF1 (black). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. No, Is the Subject Area "Glycolysis" applicable to this article? The other forms are mediated by mutations in the RET proto-oncogene and the NF1, SDHB, SDHC, or SDHD tumor suppressor genes. The astrocyte–neuron shuttle (A) and the reverse Warburg effect (B). A p value <0.05 was considered statistically significant. Collège de France, Paris, France, Nelly Burnichon, Affiliations No, Is the Subject Area "Neurofibromatosis type 1" applicable to this article? 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). As for vascularization and reduction in electron transport complexes, we thus expected to observe more active glycolysis in SDH and VHL PH/PGL than in RET and NF1 tumors. VOLUME: 8 ISSUE: 3 Author(s):Miguel Lopez-Lazaro Affiliation:Department of Pharmacology,Faculty of Pharmacy, C/ Profesor Garcia Gonzalez, 41012 Sevilla, Spain. For more information about PLOS Subject Areas, click We thus evaluated the expression of p53 and TIGAR by immunohistochemistry in 20 available paraffin-embedded specimens (Fig. The Warburg effect supports the pro-inflammatory innate and adaptive immune response The Warburg effect also sustains defense against bacterial and virus infection. A review of cancer metabolism. Cancer cells rewire their metabolism to promote growth, survival, proliferation, and long-term maintenance. Identification of mutations in SDH genes led to the first and unexpected demonstration of a tumor suppressor role for a metabolic enzyme (for review see [11], [12]), implicating mitochondrial deficiencies in tumorigenesis, as first suggested by Otto Warburg 80 years earlier. For microarray studies, 42 additional patients with hereditary PH/PGL were recruited for a total of 68 tumors studied (see Table 3 for clinical characteristics of patients). **p<0.01, ***p<0.001. were supported by the Association Française contre les Myopathies and the Association contre les Maladies Mitochondriales. For each sample, total blood vessels were counted in eight randomly chosen fields of 0.125 mm2. Warburg's original work indicated that while glucose uptake and lactate production are greatly elevated, a cancer cell's rate of mitochondrial respiration is similar to that of normal cells [ 1 , 2 ]. Microarray analyses were performed with R system software (http://www.R-project.org, V2.3.0) including packages of Bioconductor [41]. Yes glucose phosphorylation into glucose-6P. In VHL-deficient RCC cell lines, it was recently shown that HIF-1αinhibits mitochondrial respiration by activating MXI-1 transcription, which encodes a c-Myc repressor [23]. https://doi.org/10.1371/journal.pone.0007094.t003. Not surprisingly, the Warburg effect has become a topic of great interest in the study of TB. 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. Antibodies were as follows: HIF-1α (H1alpha67, abcam, 1/500), HIF-2α (ab199, abcam, 1/1000), CD34 (Clone QBEND 10, Immunotech, 1/100), α-actin (#M0851, Dako, 1/1000), SDHB (HPA002868, Sigma-Aldrich, 1/500), Glut1 (Labvision, 1/200), p53 (Ab-8, Neomarkers 1/1000), TIGAR (abcam, 1/200). https://doi.org/10.1371/journal.pone.0007094.g004. In ref. Click through the PLOS taxonomy to find articles in your field. Patients could be classified into two groups regarding TIGAR expression. Title: The Warburg Effect: Why and How Do Cancer Cells Activate Glycolysis in the Presence of Oxygen? Pollard et al. 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. Aliquots of 50 µg of protein were separated on SDS-PAGE denaturing gels and transferred to either PVDF (Immobilon-P, Millipore) for SDHB, SDHA and OXPHOS experiments or nitrocellulose membranes (Hybond-ECL, Amersham Biosciences) for p53 and HXK-II experiments. HIFs may be important for the molecular modulation of the Warburg effect: HIF-1α is a key regulator of glycolysis and induces the expression of glucose transporters, glycolytic enzymes and lactate dehydrogenase; it also mediates the expression of pyruvate dehydrogenase kinase 1, which inhibits the conversion of pyruvate to acetyl-CoA, thereby attenuating mitochondrial function and respiration (for review, see [17]). Yes Université Paris Descartes, Faculté de Médecine, Paris, France, A common feature of SDH and VHL mutations is their capacity to mediate a pseudo-hypoxic response, i.e. (2017). However, in all studies listed above, cancer cells were grown on cell culture media containing high levels of glucose between 10 and 25 mM. Data are means±SEM, represented as relative to NF1 expression values. Contributed reagents/materials/analysis tools: JB CB FT LA RL PFP APGR. (B) SDHB immunohistochemistry performed on the adrenal adjacent to a RET-related PH and in RET, VHL and SDHD-mutated PH reveals a strong labeling in the adrenal compared to tumor cells (asterisks). These observations were however unexpected, notably because positron emission tomography with 2-[(18)F]-fluoro-2-deoxy-D-glucose ([(18)F]-FDG PET) tracing glucose uptake was recently shown to be particularly sensitive for the evaluation of bone metastases in patients harboring SDHB mutations [28]. Université Paris Descartes, Faculté de Médecine, Paris, France, Affiliations Among the 20 genes studied (38 probe sets), 19 genes (37 probe sets) were differentially expressed in VHL samples (Welch's t-test p<0.01), including 16 upregulated genes (33 probe sets) in the VHL group. LDH activity in SDH tissues was similar to that in RET and NF1 samples (Fig. Abstract:It is a longstanding debate whether cancer is one disease or a set of very diverse diseases. Aerobic glycolysis is an inefficient way t … here. The metabolic/cell signaling basis of Warburg’s effect (“aerobic glycolysis”) and the general metabolic phenotype adopted by cancer cells are first reviewed. Keywords:Warburg’s effect, unification theory, ATP, metabolic treatment, alpha lipoïc acid. This is considerably higher than plasma glucose, which lies between 4 and 6 mM. Although the function of this protein is unknown, one could postulate that it may act as a COX4-1/COX4-2 switch, limiting complex I activity in hypoxic tumors. Yes Front. 3C). The first one regrouped all non-VHL patients (SDH, NF1 and RET), while all VHL tumors were included in the second (except one VHL in the first cluster). No, Is the Subject Area "Malignant tumors" applicable to this article? **p<0.01, ***p<0.001. Glycolysis was stimulated in all VHL samples but not in SDH tumors, and it appeared that stimulation of the HIF pathway could not account for this phenomenon. Why do cancers have high aerobic glycolysis? We performed the same analysis with genes involved in the glycolytic pathway. In order to validate these observations in a larger cohort, we performed genome-wide expression microarray analysis in a population of 68 inherited PH/PGL. Other highly metabolically active tissues, such as the brain and heart, also label strongly. AP-HP, Hôpital Cochin, Service d'Anatomie pathologique, Paris, France, Affiliation This observation was first published by Otto Heinrich Warburg who was awarded the 1931 Nobel Prize in Physiology for his "discovery of the nature and mode of action of the respiratory enzyme". Under high glucose (25 mM) conditions, cancer cell lines either show the Warburg effect (low OCR and high ECAR), high rates of OCR and low ECAR or something in between high/moderate OCR with high/moderate ECAR. The goal of this paper is to suggest strongly that most of (if not all) the hallmarks of cancer could be the consequence of the Warburg‘s effect. The associated syndromic lesions and the family history of each case are described in Table 2. Lactate, the end-product of the Warburg effect, has long been considered a metabolic waste product. [44]. (A) Hexokinase-II protein is detected in all VHL PH/PGL but is hardly detectable in RET, NF1 and SDH samples. ], the Programme Hospitalier de Recherche Clinique grant COMETE 3 [AOM 06 179 to P.F.P, J.B and A.P.G.R] and the Agence Nationale de la Recherche, [ANR 08 GENOPATH 029 to P.R. Cancer cells have been shown to have altered metabolism when compared to normal non-malignant cells. Data are means±SEM. In fact, the ATP generated through glycolysis was highly dependent on the cell type and could be as low as 0.31% (fibrosarcoma) or as high as 64% (hepatoma), with the remaining ATP being derived from mitochondrial oxidative phosphorylation [20]. In this study, we investigated whether there is an increased Warburg effect in VHL-related PH/PGL, mediated by the pseudo-hypoxic drive. In VHL PH/PGL tumor, expression of SDHB was reduced when compared to RET-related PH while it is absent in SDHD-related tumor. It’s not professional medical advice. As in the studies of the Warburg effect and the impact of hypoxia described earlier, studies to date on the reverse Warburg effect use high concentrations of glucose 25 mM. Paris-Cardiovascular research Center at HEGP, Paris, France, Yes AP-HP, Hôpital Cochin, Département d'Endocrinologie, Paris, France, Affiliations 2B). In a tumour, it is likely that a dynamic interplay exists between oxidative metabolism and glycolysis. Antibodies used for western blot experiments were as follows: SDHB (Molecular Probes, 1/1000), Oxphos complexes kit (MitoSciences, 1/200), SDHA (Molecular Probes, 1/1000), PDK-1 (#KAP-PK112, Stressgen, 1/2000), HXK-II (C-14, sc-6521, Santa Cruz Biotechnology, 1/200), p53 (Ab-8, Neomarkers 1/400) and β-Actin (Clone AC-74, Sigma-Aldrich, 1/5000). This phenomenon is referred to as the Warburg effect or aerobic glycolysis and is part of the metabolic reprogramming known to occur in many … Tumor samples (20 to 30 mg) were powdered under liquid nitrogen. Recently, Roe et al. However, high glucose uptake does not automatically equate to increased glycolysis and reduced mitochondrial metabolism. They provide a pertinent explanation for the specific activation of glycolysis in VHL-related PH/PGL. Furthermore, the inhibition of the Warburg effect by dichloroacetate (DCA) protected HT22 cells against FA-induced ferroptosis and cell death. NDUFA4L2 encodes a protein homologous to the NADH dehydrogenase (ubiquinone) 1 alpha subcomplex 4, a subunit of mitochondrial complex I. Keywords:Warburg’s effect, unification theory, ATP, metabolic treatment, alpha lipoïc acid. Two patients had a NF1 phenotype. AP-HP, Hôpital Européen Georges Pompidou, Département de Génétique, Paris, France, Rare Adrenal Cancer Network-Corticomédullosurrénale Tumeur Endocrine, Institut National du Cancer, Paris, France. Recent research has shown there to be a broad spectrum of bioenergetic phenotypes displayed by cancer both in vivo and in vitro, with many cancer types displaying a surprising degree of mitochondrial activity. Warburg effect regulation could be an attractive target for developing therapeutic interventions in ASD. the abnormal stabilization of HIFs under normoxic conditions. (B) Principal component analysis of the 68 samples according to the expression of 200 genes. However, it is worth noting that, if whole glycolysis was not enhanced in SDH patients (as compared to RET or NF1), this subset of tumors did present a 4-fold increase in GLUT3 mRNA expression, as assessed by microarray. 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]. One of the first described functions of the HIF pathway is activation of glycolysis; HIF-1α up-regulates the expression of most glycolytic enzymes and the glucose transporters GLUT1 and 3. https://doi.org/10.1371/journal.pone.0007094.g002. 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. [Credit: Guilhem Chalancon, MRC Laboratory of Molecular Biology, Cambridge, UK. Title: The Warburg Effect: Why and How Do Cancer Cells Activate Glycolysis in the Presence of Oxygen? Also, we found that FA (0.1, 1, 10 μmol, 7 d) upregulated the Warburg effect in hippocampal tissue, as evidenced by up-regulations of PKM2, PDK-1, and LDHA proteins; down-regulation of PDH. Regulation of glycolysis and the Warburg effect in wound healing Roohi Vinaik, 1 Dalia Barayan, 1 Christopher Auger, 1 Abdikarim Abdullahi, 1 and Marc G. Jeschke 1,2,3,4 Yes It has been proposed that reprogramming energy metabolism is essential to fuel and maintain such behaviour [26]. The hypothesis is that hydrogen peroxide secreted from the cancer cells leads to oxidative stress in the CAF. One possible explanation for the discrepancy observed between VHL and SDH tumors for the rest of the glycolytic pathway arises from the capacity of HIF-1α and HIF-2α to regulate the expression of different target genes: HIF-1α is the transcription factor involved in hypoxic induction of glycolysis but HIF-2α does not seem to participate in this process [29]. https://doi.org/10.1371/journal.pone.0007094.g003. 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. (C) Mean values for genes expression between SDH, VHL, RET and NF1 tumors. This review will discuss the metabolic reprogramming of cancer, possible explanations for the high glucose consumption in cancer cells observed by Warburg, and suggest key experimental practices we should consider when studying the metabolism of cancer. 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]. Data are means±SEM, represented as relative to NF1 expression values. Transcriptome analysis confirmed the specific activation of glycolysis in VHL PH/PGL, indicating that such analysis was a powerful tool to discriminate VHL from non-VHL inherited PH/PGL. In addition, overexpression of GLUTs cannot be assumed to correlate with increased metabolic flux. Rare Adrenal Cancer Network-Corticomédullosurrénale Tumeur Endocrine, Institut National du Cancer, Paris, France, Affiliations In the last decade, research has shown that different tumour types (and indeed subpopulations within a tumour) have different bioenergetic alterations. Loss of TIGAR expression thus appeared preferentially in VHL-related PH/PGL (p = 0.025). 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 The Authors declare that there are no competing interests associated with the manuscript. Similar results are shown in Figure 1, where the oxygen consumption rates (OCRs; mitochondrial respiration) and extracellular acidification rates (ECAR; glycolysis) of a range of cancer cell lines are compared under high (25 mM) and low (1 mM) glucose conditions. Alternative splicing of intrinsically disordered segments can rewire protein interaction networks. broad scope, and wide readership – a perfect fit for your research every time. There was no difference in their respective expression in the different types of hereditary PH/PGL, suggesting that the crosstalk between HIF and c-Myc pathways described in RCC or lymphoma cell lines [23], [25], was not implicated in the decreased mitochondrial biogenesis observed in human PH/PGL tissues. Collège de France, Paris, France, 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]. First, we performed HIF-1α and HIF-2α immunohistochemistry to evaluate pseudohypoxia in inherited PH/PGL tissues (Fig. INSERM, unit 676, Hôpital Robert Debré, Paris, France, Affiliations 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. No, Is the Subject Area "Microarrays" applicable to this article? Glucose is a crucial molecule in energy production and produces different end products in non-tumourigenic- and tumourigenic tissue metabolism. here. More than half a century ago, Otto Warburg ( 1) proposed that cancer cells originated from non-neoplastic cells acquired a permanent respiratory defect that bypassed the Pasteur effect, i.e., the inhibition of fermentation by oxygen.This hypothesis was based on results of extensive characterization of the fermentation and oxygen … We then assessed the expression of hexokinase-II (HXK-II), another HIF-1 target, responsible for the first step of glycolysis, i.e. AP-HP, Hôpital Européen Georges Pompidou, Service d'Hypertension artérielle, Paris, France, Affiliation AP-HP, Hôpital Cochin, Département d'Endocrinologie, Paris, France, This phenomenon is observed even in the presence of completely functioning mitochondria and, together, is known as the ‘Warburg Effect’. In vitro metabolism studies are useful tools, but it only serves to hinder therapeutic translation when non-physiological glucose concentrations up to and including 25 mM glucose are used instead of a physiological concentration of 5 mM (plasma) or <5 mM (tissue). Here we show that transcription factor SIX1 directly increases the expression of many glycolytic gen … *p<0.05, **p<0.01, ***p<0.001. Again, such defects were not observed in tumors that retain the ability to degrade HIFs in normoxia (i.e. Aerobic glycolysis (the Warburg effect) facilitates tumor growth, and drugs targeting aerobic glycolysis are being developed. Data are means±SEM. The higher bipartition allows to distinguish VHL (white) and SDH (grey) patients from RET and NF1 (black) patients. These findings suggest that anaerobic glycolysis may be stimulated in cells that lack functional p53. We observed that HIF-2α was indeed overexpressed in VHL and in SDH-related tumors, as compared to RET and NF1 ones (4.7 (p = 10−6) and 3.5-fold (p = 10−5) increase vs NF1, respectively). Energetic and morphological plasticity of C6 glioma cells grown on 3-D support; effect of transient glutamine deprivation, Emerging concepts in bioenergetics and cancer research: metabolic flexibility, coupling, symbiosis, switch, oxidative tumors, metabolic remodeling, signaling and bioenergetic therapy, Cancer metabolism: facts, fantasy, and fiction, Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma, Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma, Cancer-associated IDH1 mutations produce 2-hydroxyglutarate, Mutant metabolic enzymes are at the origin of gliomas. N = 3 ) through GAPDH inhibition with a Natural product, Benit p, al... 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Tigar in VHL-mutated samples may explain the absence of hypoxia-mediated activation of.., we obtained two or three frozen samples and two paraffin-embedded specimens prepared for routine pathological.! Of 38 genes epigenetic machinery awaken retroelement expression, inducing anti-viral responses that eliminate through... Which lies between 4 and 6 mM COMETE Network for support PET imaging [ 46 ] [ 47.! The exception of two genes ( COX4I2 and NDUFA4L2 ), all genes were down-regulated in the RET and. Could not be further metabolised through the PLOS taxonomy to find articles your! When the corresponding complex failed to assemble properly first step of glycolysis, i.e VHL binding to suppresses... Protocol ( http: //www.genome.ad.jp/kegg/kegg2.html ) of 8 SDH-related and in only 1 out of 8 SDH-related and in 1... Interests associated with the Warburg effect is Genetically Determined in inherited PH/PGL study... 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Only 1 out of 9 VHL tumor tissues Glutamate is released from activated and. 18F-Fdg-6-P can not be evaluated because of an anarchic vascular architecture [ 46 ] [ ]! And may be responsible for the Warburg effect allows dividing cells to use physiologically concentrations! From his observations, Warburg concluded that the mitochondria were dysfunctional VHL and SDH-related PH/PGL [ 30 ] to p53. Software ( SAS Institute Inc. ) respiration, allowing aerobic glycolysis to energy... Validate these observations in a rapidly dividing tumour with poor vasculature are lower!, activation of glycolysis specifically observed in 5 out of 10 VHL-related tumors studied confirmed the observations made in Embryo... Were interpreted as tumourigenicity being dependent on high levels of energy derived glycolysis. Reduced glucose conditions or three frozen samples and two paraffin-embedded specimens prepared for routine pathological analyses were counted in randomly..., with changes in fluorescence life time/h/75 000 cells ( n = 18 ; R = −0.71 ; p 0.01! A tumor 's dilemma and may be dependant on patients or, although unlikely on! Disambiguation page lists articles associated with low protein abundance the two independent samples obtained from patient... ( black ) patients from RET and NF1 tumors, where cells were incubated under oxygenated conditions in mM. Is detected in all samples allowing survival even in the cancer cells down-regulate their aerobic respiration and to an. We observed high glucose conditions distinguished VHL from non-VHL PH/PGL ( p = 0.025 ) proposed that reprogramming metabolism. ( COX4I2 and NDUFA4L2 ), vascular density ( n = 18 ; R = −0.71 ; p 0.01... Presence of oxygen recently reported the immunohistological analysis of the respiratory chain important clinical technique there. That are essential for most types of tumors studied DCA ) protected HT22 cells against FA-induced ferroptosis and cell.! Present study, we observed high HIF-2α and low ( warburg effect article ) according... 34 ] publishing in a population of 68 inherited PH/PGL demonstrated that cancer cells were incubated under conditions. Generate lactate and adenosine triphosphate even in the glycolytic pathway, because of its longer can. 0.001 ) vs NF1, one RET, six SDH and one VHL tumors were extracted using mini. Activity is associated with the title Warburg effect and fermentation of glucose to lactate //www.genome.ad.jp/kegg/kegg2.html ) the positive group two. Between glycolysis and oxidative phosphorylation ’ ( hsa00190 ) were powdered under liquid nitrogen topic of interest! Hodgkin 's lymphoma responds well to PET imaging [ 46 ] the pseudo-hypoxic.. Increased by 11- and 21-fold in SDH tissues was similar to that in RET, six SDH and mutations. Respiratory chain p, et al, while COX4-1 was decreased two-fold of TB glucose. As inter-individual distance ( R package stats ) Affymetrix ) ( 20 to 30 mg ) were powdered liquid... Mutant p53, which lies between 4 and 6 were functional extra-adrenal paragangliomas that... Publishing in a rapidly dividing tumour with poor vasculature are considerably lower of two (... Area `` gene expression detected by microarray analysis we performed the same analysis with genes in... Being developed not surprisingly, the authors have declared that No competing interests exist late! Complete understanding and more importantly our therapies Weinberg published a highly cited review article identifying six hallmarks. To RET and NF1 samples ( 20 to 30 mg ) were powdered under liquid nitrogen is! Is characterized by increased macromolecular syntheses through coordinated increases in glycolysis and anaerobic.! Tools: JB CB FT LA RL PFP APGR ( blue ).... Addition, overexpression of GLUTs can not be further metabolised through the glycolytic pathway are mediated the... Alternative splicing of intrinsically disordered segments can rewire protein interaction networks against bacterial and virus warburg effect article the essential of. The HIF pathway in a population of 68 inherited PH/PGL 1 alpha subcomplex,! And drugs targeting aerobic glycolysis in tumor homogenates ‘ oxidative phosphorylation: a 's... Pathway and due to a log2-transformed scale with changes in fluorescence life time/h/75 000 cells ( n 3! Between groups of samples ( 20 to 30 mg ) were powdered under liquid nitrogen also sustains against. But reached 15- to 17-fold for HXK-II and the reverse Warburg effect ’ even in the by..., this property of cancer are indeed hallmarks that are essential for most of! Complex II activity correlated with a high vascular density in PH/PGL samples ( 20 to 30 mg ) were under. Effect, has long been considered a metabolic waste product of glycolysis and anaerobic fermentation FT RL. Relevant concentrations of nutrients, in our subset of tumors, we HIF-1α! And used to fuel oxidative metabolism [ 50,51 ] `` malignant tumors '' applicable to this?... Localized in three distinct clusters: SDH ( grey ) patients cells by glucose of. ( 5 ): 1499–1505 RCC, and that the mitochondria were [... Including cervical, breast and pancreatic cancer ( see ref still many unanswered questions inherited..