Cell Cycle
ISSN: 1538-4101 (Print) 1551-4005 (Online) Journal homepage: http://www.tandfonline.com/loi/kccy20
ccRCC is fundamentally a metabolic disorder Apostolos Zaravinos & Constantinos Deltas To cite this article: Apostolos Zaravinos & Constantinos Deltas (2014) ccRCC is fundamentally a metabolic disorder, Cell Cycle, 13:16, 2481-2482, DOI: 10.4161/15384101.2014.947225 To link to this article: http://dx.doi.org/10.4161/15384101.2014.947225
Published online: 30 Oct 2014.
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Article views: 73
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Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=kccy20 Download by: [Universite Laval]
Date: 05 November 2015, At: 21:03
EDITORIALS: CELL CYCLE FEATURES Cell Cycle 13:16, 2481--2482; August 15, 2014; © 2014 Taylor & Francis Group, LLC
ccRCC is fundamentally a metabolic disorder Apostolos Zaravinos#,* and Constantinos Deltas Molecular Medicine Research Center and Laboratory of Molecular and Medical Genetics; Department of Biological Sciences; University of Cyprus; Nicosia, Cyprus
Downloaded by [Universite Laval] at 21:03 05 November 2015
#
Current address: Division of Clinical Immunology; Department of Laboratory Medicine; Karolinska Institutet; Stockholm, Sweden
Clear cell renal-cell carcinoma (ccRCC) represents the most common RCC subtype, being exceptionally resistant to therapy and responding poorly to radiotherapy, hormonal therapy and chemotherapy1; thus urging the development of early diagnostic markers for this particular RCC subtype. Hypoxic, rapidly proliferating tumor cells predominantly exhibit a metabolic switch toward aerobic glycolysis (the Warburg effect), which is characterized by an increase in glucose catabolism to lactate at the expense of mitochondrial oxidation.2 In fact, glutamine is able of contributing to citrate and lipid metabolism by reversing the tricarboxylic acid (TCA) cycle or through the reductive carboxylation of a-ketoglutarate or even through forward cycling of glutamine carbons (Fig. 1). Lately, great interest in tumor metabolism has come again into the surface, as a growing number of reports expose the molecular link between cellular transformation and metabolism. We recently performed a meta-analysis of various publicly available gene expression datasets in order to identify the deregulated genes in ccRCC and to measure their discriminatory capability from the normal kidney. We focused our study on the top co-deregulated genes among 5 microarray data sets and investigated the canonical pathways in which they are implicated, the networks that they form and their associated functions. The deregulated expression pattern of these genes was further validated in 2 ccRCC cell lines and a patient cohort.3 Our data highlight that kidney cancer cells
manipulate more than one molecular mechanisms and a number of biological pathways to achieve their aggressive phenotype. The top co-deregulated genes were found to participate in the antigen presentation pathway and cytotoxic T lymphocyte (CTL)-mediated apoptosis of target cells, thus highlighting the importance of autoantibodies produced against tumor-associated antigens.3 However, since the majority of the top co-deregulated genes were found to participate in inositol metabolism, the pentose phosphate pathway (PPP), glycolysis/gluconeogenesis, and metabolism of fructose and mannose, emphasis was put on the notion that ccRCC is fundamentally a metabolic disorder.3 All these pathways account for higher rates of nucleic acid and protein biosynthesis and higher energy demands that aggressive tumors have. In order to synthesize new nucleotides, cells require more ribose 5-phosphates, which they produce by diverting carbon from glycolysis into either the oxidative or non-oxidative strand of the PPP. An increased glycolysis in ccRCC, as measured by high levels of lactate, was recently reported by others.4,5 Increased glycolysis has been noted among other tumor types, as well. In metastasis, the glycolytic phenotype has been hypothesized to arise as a result of transient hypoxic episodes that occur while cells travel to distant sites through the bloodstream.6 Ultimately, cells that are able to perform glycolysis and are resistant to hypoxia, are selectively favored for survival and growth and result
in successful metastasis.6 Highly expressed reactions in the metabolism of fructose and mannose principally include the conversion of D-fructose, D-fructose-1P and D-mannose into glyceraldehyde-3P (GA3P), which is a substrate of glycolysis that leads to augmented production of ATP. Most researchers studying tumor metabolism are driven by one of two general notions regarding how cellular metabolism is regulated. The first idea is that tumor metabolism is principally the result of stress imposed on cells during tumor growth. Ample evidence shows that hypoxia in the tumor microenvironment dramatically affects cellular metabolism.6 Nevertheless, glycolytic change can still appear even in the abundance of oxygen (hyperoxia) in tumors; thus leading to specific deficiencies in the biosynthesis of proteins and lipids and resulting in inefficient cellular growth and proliferation. Therefore, the cellular responses to hypoxia in tumors, together with enhanced glycolysis, assist tumor cell survival, not growth. On the other hand, tumor cell metabolic activities are considered to function primarily in order to support the abnormally elevated rates of cellular growth and proliferation, both characteristics of tumor cells. Since the required number of proteins, lipids and nucleic acids is the double in each round of cellular division, the tumor cell metabolism needs to provide for all the necessary energy and biosynthesis. Rapidly growing tumor cells need to seize
*Correspondence to: Apostolos Zaravinos; Email: [email protected] Submitted: 07/01/2014; Accepted: 07/02/2014 http://dx.doi.org/10.4161/15384101.2014.947225
www.landesbioscience.com
Cell Cycle
2481
Downloaded by [Universite Laval] at 21:03 05 November 2015
Figure 1. In aerobic proliferating cells glucose and glutamine are used to produce the necessary biomass through the tricarboxylic acid (TCA) cycle (left). In hypoxic cells, glucose is shunt to lactate resulting in rewiring of the glutamine metabolism (right). Glutamine can be used to drive the TCA cycle independently of glucose or contribute to lipid synthesis via isocitrate dehydrogenase (IDH)-mediated reductive carboxylation of a-ketoglutarate that is generated from glutamine.
nutrients and to be able to process them in the appropriate metabolic pathways, in order to convert their carbon and nitrogen to macromolecules. The Warburg effect, synthesis of fatty acids and References 1. 2.
Cheville JC, et al. Am J Surg Pathol 2003; 27:612-24; PMID:12717246 Linehan WM, et al. Nat Rev Urol 2010; 7:277-85; PMID:20448661
2482
metabolism of glutamine in the mitochondria, all happen along with cellular growth, and there’s now enough evidence to show that these pathways work together in order to produce as many 3. 4. 5.
Zaravinos A, et al. Oncoscience 2014; 1:111-82 Hakimi AA, et al. Nat Genet 2013; 45:849-50; PMID:23892664 Sudarshan S, et al. Eur Urol 2013; 63:244-51; PMID:23063455
Cell Cycle
macromolecules as possible, in those rapidly multiplying cells.7 The reversal of the Warburg effect could be a promising novel treatment for ccRCC. However, a deeper understanding of the mechanisms driving altered metabolic pathways is the key for the development of novel targeted therapies in this kidney tumor.
6. 7.
Gatenby RA, et al. Nat Rev Cancer 2004; 4:891-9; PMID:15516961 Deberardinis RJ, et al. Curr Opin Genet Dev 2008; 18:54-61; PMID:18387799
Volume 13 Issue 16
ISSN: 1538-4101 (Print) 1551-4005 (Online) Journal homepage: http://www.tandfonline.com/loi/kccy20
ccRCC is fundamentally a metabolic disorder Apostolos Zaravinos & Constantinos Deltas To cite this article: Apostolos Zaravinos & Constantinos Deltas (2014) ccRCC is fundamentally a metabolic disorder, Cell Cycle, 13:16, 2481-2482, DOI: 10.4161/15384101.2014.947225 To link to this article: http://dx.doi.org/10.4161/15384101.2014.947225
Published online: 30 Oct 2014.
Submit your article to this journal
Article views: 73
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=kccy20 Download by: [Universite Laval]
Date: 05 November 2015, At: 21:03
EDITORIALS: CELL CYCLE FEATURES Cell Cycle 13:16, 2481--2482; August 15, 2014; © 2014 Taylor & Francis Group, LLC
ccRCC is fundamentally a metabolic disorder Apostolos Zaravinos#,* and Constantinos Deltas Molecular Medicine Research Center and Laboratory of Molecular and Medical Genetics; Department of Biological Sciences; University of Cyprus; Nicosia, Cyprus
Downloaded by [Universite Laval] at 21:03 05 November 2015
#
Current address: Division of Clinical Immunology; Department of Laboratory Medicine; Karolinska Institutet; Stockholm, Sweden
Clear cell renal-cell carcinoma (ccRCC) represents the most common RCC subtype, being exceptionally resistant to therapy and responding poorly to radiotherapy, hormonal therapy and chemotherapy1; thus urging the development of early diagnostic markers for this particular RCC subtype. Hypoxic, rapidly proliferating tumor cells predominantly exhibit a metabolic switch toward aerobic glycolysis (the Warburg effect), which is characterized by an increase in glucose catabolism to lactate at the expense of mitochondrial oxidation.2 In fact, glutamine is able of contributing to citrate and lipid metabolism by reversing the tricarboxylic acid (TCA) cycle or through the reductive carboxylation of a-ketoglutarate or even through forward cycling of glutamine carbons (Fig. 1). Lately, great interest in tumor metabolism has come again into the surface, as a growing number of reports expose the molecular link between cellular transformation and metabolism. We recently performed a meta-analysis of various publicly available gene expression datasets in order to identify the deregulated genes in ccRCC and to measure their discriminatory capability from the normal kidney. We focused our study on the top co-deregulated genes among 5 microarray data sets and investigated the canonical pathways in which they are implicated, the networks that they form and their associated functions. The deregulated expression pattern of these genes was further validated in 2 ccRCC cell lines and a patient cohort.3 Our data highlight that kidney cancer cells
manipulate more than one molecular mechanisms and a number of biological pathways to achieve their aggressive phenotype. The top co-deregulated genes were found to participate in the antigen presentation pathway and cytotoxic T lymphocyte (CTL)-mediated apoptosis of target cells, thus highlighting the importance of autoantibodies produced against tumor-associated antigens.3 However, since the majority of the top co-deregulated genes were found to participate in inositol metabolism, the pentose phosphate pathway (PPP), glycolysis/gluconeogenesis, and metabolism of fructose and mannose, emphasis was put on the notion that ccRCC is fundamentally a metabolic disorder.3 All these pathways account for higher rates of nucleic acid and protein biosynthesis and higher energy demands that aggressive tumors have. In order to synthesize new nucleotides, cells require more ribose 5-phosphates, which they produce by diverting carbon from glycolysis into either the oxidative or non-oxidative strand of the PPP. An increased glycolysis in ccRCC, as measured by high levels of lactate, was recently reported by others.4,5 Increased glycolysis has been noted among other tumor types, as well. In metastasis, the glycolytic phenotype has been hypothesized to arise as a result of transient hypoxic episodes that occur while cells travel to distant sites through the bloodstream.6 Ultimately, cells that are able to perform glycolysis and are resistant to hypoxia, are selectively favored for survival and growth and result
in successful metastasis.6 Highly expressed reactions in the metabolism of fructose and mannose principally include the conversion of D-fructose, D-fructose-1P and D-mannose into glyceraldehyde-3P (GA3P), which is a substrate of glycolysis that leads to augmented production of ATP. Most researchers studying tumor metabolism are driven by one of two general notions regarding how cellular metabolism is regulated. The first idea is that tumor metabolism is principally the result of stress imposed on cells during tumor growth. Ample evidence shows that hypoxia in the tumor microenvironment dramatically affects cellular metabolism.6 Nevertheless, glycolytic change can still appear even in the abundance of oxygen (hyperoxia) in tumors; thus leading to specific deficiencies in the biosynthesis of proteins and lipids and resulting in inefficient cellular growth and proliferation. Therefore, the cellular responses to hypoxia in tumors, together with enhanced glycolysis, assist tumor cell survival, not growth. On the other hand, tumor cell metabolic activities are considered to function primarily in order to support the abnormally elevated rates of cellular growth and proliferation, both characteristics of tumor cells. Since the required number of proteins, lipids and nucleic acids is the double in each round of cellular division, the tumor cell metabolism needs to provide for all the necessary energy and biosynthesis. Rapidly growing tumor cells need to seize
*Correspondence to: Apostolos Zaravinos; Email: [email protected] Submitted: 07/01/2014; Accepted: 07/02/2014 http://dx.doi.org/10.4161/15384101.2014.947225
www.landesbioscience.com
Cell Cycle
2481
Downloaded by [Universite Laval] at 21:03 05 November 2015
Figure 1. In aerobic proliferating cells glucose and glutamine are used to produce the necessary biomass through the tricarboxylic acid (TCA) cycle (left). In hypoxic cells, glucose is shunt to lactate resulting in rewiring of the glutamine metabolism (right). Glutamine can be used to drive the TCA cycle independently of glucose or contribute to lipid synthesis via isocitrate dehydrogenase (IDH)-mediated reductive carboxylation of a-ketoglutarate that is generated from glutamine.
nutrients and to be able to process them in the appropriate metabolic pathways, in order to convert their carbon and nitrogen to macromolecules. The Warburg effect, synthesis of fatty acids and References 1. 2.
Cheville JC, et al. Am J Surg Pathol 2003; 27:612-24; PMID:12717246 Linehan WM, et al. Nat Rev Urol 2010; 7:277-85; PMID:20448661
2482
metabolism of glutamine in the mitochondria, all happen along with cellular growth, and there’s now enough evidence to show that these pathways work together in order to produce as many 3. 4. 5.
Zaravinos A, et al. Oncoscience 2014; 1:111-82 Hakimi AA, et al. Nat Genet 2013; 45:849-50; PMID:23892664 Sudarshan S, et al. Eur Urol 2013; 63:244-51; PMID:23063455
Cell Cycle
macromolecules as possible, in those rapidly multiplying cells.7 The reversal of the Warburg effect could be a promising novel treatment for ccRCC. However, a deeper understanding of the mechanisms driving altered metabolic pathways is the key for the development of novel targeted therapies in this kidney tumor.
6. 7.
Gatenby RA, et al. Nat Rev Cancer 2004; 4:891-9; PMID:15516961 Deberardinis RJ, et al. Curr Opin Genet Dev 2008; 18:54-61; PMID:18387799
Volume 13 Issue 16
