|Year : 2020 | Volume
| Issue : 2 | Page : 77-83
Cancer aetiology and progression: The crucial link between genome, epigenome and metabolome
Salihu Ismail Ibrahim1, Fakhradden Yahya Muhammad2
1 Department of Biochemistry, Federal University Dutse, Dutse, Nigeria
2 Department of Medicine, Muhammad Abdullahi Wase Teaching Hospital, Kano, Nigeria
|Date of Submission||26-Jan-2020|
|Date of Decision||22-Feb-2020|
|Date of Acceptance||11-Jun-2020|
|Date of Web Publication||9-Oct-2020|
Dr. Salihu Ismail Ibrahim
Department of Biochemistry, Federal University Dutse, Dutse
Source of Support: None, Conflict of Interest: None
Genomic and metabolic profiles of cancer cells differ significantly from normal cells. Cancer cells utilise nutrients with an impaired metabolic process to maintain their high metabolic demands to adapt and proliferate. Metabolic rewiring in cancer cells has profound effects on the regulation of gene expression and vice versa. Genomic and metabolomic interactions are highly intertwined in both normal and cancer cells. Genomic components affect the metabolomic activities by modulating the expression of genes that regulate the metabolome. Inversely the metabolome, in turn, coordinates and provide a favourable microenvironment for genomic expression of metabolome regulating enzymes. The review aims to understand the link between genomic and metabolomic processes, their point of interaction, shared process, including dependent and independent networks in understanding cancer aetiology and progression. We systematically searched PubMed, Hinari, Google scholar and Nature journals to identify potentially relevant articles. We included reports that met the following criteria: (1) current knowledge on the cause of cancer as explained by genetic mutation, and (2) examine to what extent the mutation is determined by the metabolome. We also reviewed epigenetic aberration as hallmark of cancer aetiology. We discussed that the interaction between the genomic and metabolomic components is indispensable for the normal metabolic processes. Anything that alters the interplay of these processes will definitely cause impairment in the interaction and overall compromise in the entire genomic, metabolic, and cellular processes. Understanding the complex interaction between genome, epigenome, and metabolome is crucial to gain a greater insight into unravelling cancer pathogenesis and in the onset and progression of cancers and the potential of designing novel therapeutic strategies.
Keywords: Cancer, genome, metabolome, mutation, nutrition
|How to cite this article:|
Ibrahim SI, Muhammad FY. Cancer aetiology and progression: The crucial link between genome, epigenome and metabolome. Niger J Basic Clin Sci 2020;17:77-83
|How to cite this URL:|
Ibrahim SI, Muhammad FY. Cancer aetiology and progression: The crucial link between genome, epigenome and metabolome. Niger J Basic Clin Sci [serial online] 2020 [cited 2021 Jan 18];17:77-83. Available from: https://www.njbcs.net/text.asp?2020/17/2/77/297599
| Introduction|| |
Cancer is a disease that arises from the transformation of normal cells into tumour cells in a multistage process believed to be caused by the interaction between a person's genetic predisposition and three categories of external agents, which includes: physical, biological, and chemical agents that result in a mutation. Among the various agents, tobacco use is the most important risk factor for cancer and is responsible for approximately 22% of cancer deaths. Cancer-causing infections, such as hepatitis and human papillomavirus, are responsible for up to 25% of cancer cases in low- and middle-income countries.
Cancer has many causes that promote uncontrolled cell division leading to an overgrown group of cells called a tumour and the spread of tumour cells throughout the body to form new tumours, a process called metastasis. Genetic mutations play a major role in the development of certain types of cancers. Mutations have been associated with specific genes that may predispose individuals to develop certain cancers. Such examples are oncogenes that normally carry out basic cellular functions, generally related to the regulation of cell division. However, several types of events can change a proto-oncogene into an oncogene. One of the main ways in which proto-oncogenes can be changed into their cancer-causing (oncogenic) state is by mutation. Mutation can be spontaneous or environmentally induced, which occurs in a proto-oncogene of a single cell, which then undergoes multiple cell divisions to form a tumour. Tumour cells respond to their microenvironment, which can include hypoxia and malnutrition, and adapt their metabolism to survive and grow. In hypoxia, glucose utilisation through the pentose phosphate pathway can be promoted by direct modification of metabolic enzymes by reactive oxygen species or glycosylation. Glycogen accumulates in various cancer cell lines and hypoxic tumors, and inhibition of glycogen breakdown results in p53-induced senescence due to high levels of reactive oxygen species.
Many hypotheses and theories, such as the somatic mutation theory and tissue organisation field theory, have been proposed to explain the origin of cancer cells and how they develop, such as their heterogenetic morphology, increased proliferation, metastatic capacity, and invasive behaviour. One such prominent and most widely accepted theory is the somatic mutation theory, where it is believed that cancers are caused by gene mutations in a cell.
| Mutation and Cancer|| |
The mutation theory started with the formulation of the idea that cancer cells developed from the body's own cells. This was later followed by one plausible explanation given by Bauer that cancers were likely caused by mutations. The discovery of the three-dimensional structure of DNA by Watson and Crick supports the credence to the concept that damage to DNA molecules can lead to mutation and cancer. In 1969, Ashley went further to state that cancer may be the result of just 3–7 mutations. Since then, studies have proposed the different number of possible mutations that are necessary to cause a normal cell to change into a cancer cell. One of such studies is the large-scale sequencing studies by Greenman et al., which showed that the prevalence and signature of somatic mutations in human cancers are highly variable [Table 1].
A new paradigm shift has occurred to somatic mutation theory, where it was recognised that not just one, but several mutations are required to cause cancer in a cell. Mutations have increasingly been perceived as the causal event in the origin of the vast majority of cancers, even as clinical data show little support for this theory.
The mutation theory emphasises the dominant role of the genomic component to explain carcinogenesis. However, recent clinical studies suggest that carcinogenesis requires more than mutations in order for cancer to develop. Somatic mutations are continuously being questioned as drivers of carcinogenesis,, and some cancers have been reported to be not associated with any mutation., For example, it was found in a study with three ependymoma brain tumours subtypes that not all cancers are caused by mutation, one subtype creates a new tumour-driving gene, another lacks tumour-driving mutations but has aberrant epigenetic modifications, and a third shows neither gene mutations nor epigenetic aberrations., In another different yet similar study, thousands of mutations were found in cancer-relevant genes, including cancer-driver genes, in normal eyelid epidermis that rarely develops cancers. Normal tissues have been reported to display massive genetic changes, including changes in cancer-initiating and cancer-driving genes, but do not develop into cancer. Somatic mutations occur in the genomes of all dividing cells, both normal and neoplastic. However in cancer, the somatic mutation has been classified into 'driver' mutations which confer a growth advantage on the cell in which they occur and are causally implicated in the development of cancer and 'passenger' mutations which have been reported to be biologically neutral and do not confer growth advantage to cancer cells. It has been postulated that only a small number of driver mutations lead to cancer while the remaining passenger mutations play no causal role in carcinogenesis.,,
It has been reported that an increase in the intrinsic mutation rate to be the driving force of tumorigenesis where it was postulated that most sporadic tumours start to grow with a normal mutation rate and probably continue to do so as successive mutations occur which provide a selective advantage and lead to clonal expansion [Figure 1]. Although some tumours will acquire a mutator phenotype before they present clinically, it is not necessary to invoke an increased mutation rate to explain cancer, even in tumours that carry multiple mutations. The process of tumorigenesis is a form of evolution: mutation and selection are the essential components of this process. The relative importance of these components remains controversial.
The mutator phenotype hypothesis postulates that an initial mutator mutation generates further mutations, including mutations in additional genetic stability genes, resulting in a cascade of mutations throughout the genome. Mutator phenotype can result from mechanisms other than mutations in critical genes. Profound effects on the evolution of tumour cells, including increased mutagenesis, can be caused by processes such as aberrant gene expression or DNA methylation. Tomlinson and Bodmer have presented a mathematical model indicating that an increase in mutation rate is not essential for tumour development and that clonal selection followed by clonal expansion can account for thousands of mutations in colon cancer cells. They conclude that an increase in mutation rate in tumours is an epiphenomenon and is not responsible for tumour progression. Although many assumptions in their model differ from those embodied in the mutator phenotype hypothesis, the major difference is the 5000 division cycles undergone by normal colonic stem cells. Importantly, in tissues other than colon or skin, stem cells are unlikely to undergo that many divisions and thus would not accumulate large numbers of mutations. Although the lack of measurements of mutation rates in stem cells, the observed increase in mutation frequencies in human kidney tubule cells during the human life span is at most 5-fold.
It remains to be determined whether the acquisition of a mutator phenotype underlies tumour progression and when the enhancement in mutation rate occurs during the life of tumours. In order for a mutator phenotype to be necessary for tumour progression, it would have to occur early and result in the accumulation of large numbers of random mutations. The existence of multiple mutations in cancer cells has important implications. The presence of large number of random mutations in a tumour cell population provides abundant, diverse genetic variants for the selection of mutants that specify the cancer phenotype. It may be possible to stratify tumours based on the frequency of random mutations in the genome; tumours with fewer mutations may be less likely to become resistant to chemotherapeutic agents.
The question is if mutations exclusively cause cancer, then how can we explain the existence of cancer without mutation and mutation without cancer as reported in previous studies? One plausible explanation is that genes may carry the potential to cause cancer, but epigenetic and metabolic conditions determine the expression of that gene into a cancerous mutation. The metabolic condition may determine the state of epigenetic conditions, which in turn may dictate how genes are expressed. Many experiments have clearly shown that cells exposed to a non-physiological environment such as toxic agents, inflammation,, low pH,, hypoxia, infection, irradiation, and others can induce significant genetic, metabolic, morphological and cell behaviour changes that can initiate alteration of the epigenetic micro environment in a negative way that can result in cancer development. It is well known from several studies that cancer cells are surrounded by massive environmental changes,, which can have a great impact on cancer development.
| Epigenetic of Cancers|| |
Metabolic and epigenetic conditions and nutritional status are fundamental aspects of cellular adaptation to the environment. The human genome is dynamically regulated by the metabolome. Alterations in the genome, epigenome or metabolome may drive aberrant gene expression, which in turn, may contribute to tumour development and progression. Epigenetic dysfunction can have profound effects on the regulation of gene expression. Epigenetic regulation of gene expression can be highly plastic and responsive to various environmental factors.,, Epigenetic dysfunction modifies metabolism by directly affecting the expression of metabolic enzymes and altering the signal transduction cascades involved in the control of cell metabolism [Figure 2].
The cell's environment is perfectly balanced for the cell's metabolic, molecular and nutritional processes. If the cell's precisely and perfectly balanced processes become disturbed irreversibly, then the cell will be forced to undergo a functional and/or structural adjustment by creating a new equilibrium point that may be detrimental to the overall cellular processes, once this new equilibrium point becomes established within the cell. The new established equilibrium condition will disrupt previous dependent cellular processes and override the existing regulatory processes, resulting in the disruption of primarily ordered cellular processes, thereby creating a new cellular order.
The cell exchanges nutrients between intra and extracellular environments, because of that capability, the cell can maintain normal physiological processes under certain and specific conditions. Under these exclusive conditions, a cell controls and provides optimal reaction conditions for the synthesis of essential and degradation of harmful waste metabolites generated during metabolic processes. The structural order and the functionality of proteins, enzymes are highly dependent on conditions such as pH, electrolyte concentration and temperature., The functional and physical interaction of these enzymes and proteins with pH, temperature, ions and other metabolites determines physiological or pathological outcomes. For example, varying pH levels may have a direct effect on the activity of many enzymes and proteins due to the presence of ionisable residues in the catalytic site of most enzymes. Changes in pH levels may result in a conformational change in enzyme structure, leading to an alteration in substrate accessibility to the catalytic site and, ultimately, loss of function of the enzyme. It has long been known that the microenvironment in tumors of both animals and humans is acidic as compared with that in normal tissues because of elevation in anaerobic as well as aerobic glycolysis in tumours.,,,,, Tumour acidosis may result from the accumulation of H+ ions as an initial consequence of alterations in the pH of the cytosolic compartment of cells, which cannot withstand acidification, and gives rise to the delicate balance between the intracellular pH (pHi) and the extracellular pH (pHe) which trigger various adaptations to maintain an optimal pH balance at the same time determine the new behavior of cells in an acidic environment.
| Metabolome and Cancer|| |
Cancer cells have high metabolic demands, and they utilise nutrients with an altered metabolic programme to support their high proliferative rates and adapt to the hostile tumour microenvironment. Cancer cells have been shown to have high rates of glucose consumption and production of lactate despite bioavailability of sufficient oxygen for complete oxidation of glucose, a process termed the Warburg effect.
Changes in the expression levels of metabolic enzymes, expression of alternative enzyme isoforms or mutations in genes encoding metabolic enzymes have all been implicated in altering the metabolism of tumours. Oncogenic and tumour suppressor pathways that drive cancer development have been shown to promote these metabolic features, which are, therefore, stably propagated throughout tumour development. This has raised hopes that metabolic enzymes comprise good targets for cancer therapy., High-glucose catabolism in mitochondria through pyruvate carboxylase has also been observed in human glioblastoma tumours of diverse genetic backgrounds.
It has long been known that tumours can be acidified by the induction of hyperglycemia by administration of excess glucose.,, Cancer cells could metabolize glucose via glycolysis to generate lactate, instead of oxidative phosphorylation (OXPHOS), even in the presence of normal oxygen levels.,,, Cancer cells exhibit high rates of glucose fermentation to lactate even when growing in aerobic conditions, a phenotype known as aerobic glycolysis or the Warburg effect. Glucose has been reported to be the main source of lactate generation in cancer cell metabolism. Cancer cells convert most incoming glucose to lactate., Clinical studies showed that a high level of lactate was a strong prognostic indicator of increased metastasis and poor overall survival.,,,, Lactate and proton together prevented cancer cells from glucose deprivation-induced death. Lactate and proton are important for cancer cells to survive through harsh conditions. Lactic acidosis exhibited multifaceted roles in skewing macrophages, inhibiting the function of cytotoxic T-cells, altering cancer cell metabolism,, promoting tumour angiogenesis, and inducing chromosomal instability.
Glutamine, as well as glucose has been reported to be one of the most important nutrients to be metabolized more abundantly than other non-essential amino acids. Glutamine metabolism not only provides a source for the synthesis of macromolecules, such as lipids, proteins, and nucleotides, but also supports nicotinamide adenine dinucleotide phosphate production and anaplerosis in proliferating tumor cells.
It can clearly be seen that cancer cells need a stable microenvironment favorable for growth and proliferation to continue dividing and invading new territories. It can be speculated that before cancer initiates and develops in a particular tissue it has to create the favourable environment by acidifying that environment, as acidification will force many non-acid-dependent processes to a stop, thereby favouring cancer machinery to initiate, develop and invade. Apart from metabolising glucose, cancer cells are addicted to glutamine. By means of a process known as glutaminolysis, cancer cells could divert a major fraction of glutamine to replenish the tricarboxylic acid cycle.,, Hence, glutaminolysis supplies biosynthetic precursors for nucleotides, proteins and glutathione biosynthesis in tumorigenesis.,
Metabolic rewiring in cancer has profound effects on the regulation of gene expression. Although metabolite profiles might have little impact on the genetic level, it appears that they have a fundamental role in epigenetic regulation of gene expression. Epigenetics refers to heritable changes in gene expression, which are not a consequence of alterations in the DNA sequence. Epigenetic regulation of gene expression can be highly plastic and responsive to various environmental clues.,, Epigenetics, which principally involved the chemical modification of DNA and histones, represents an innate mechanism that links nutritional status to gene expression [Figure 3]. As such, metabolic rewiring could hijack the epigenome machinery in cancer cells to transmit a mitogenic gene expression profile.,, Reciprocally, epigenetic deregulation in cancer mediates, at least in part, to the altered expression of genes involved in cellular metabolism. Accelerated glycolysis in cancer contributes to histone acetylation via citrate and acetyl CoA. Histone acetylation in cells is regulated by glucose flux in a dose-dependent manner and elevated glycolysis in cancer is associated with global histone hyperacetylation. An increased contribution of acetate to acetyl-coA and histones has also been observed in mouse liver cancer models, orthotopically implanted human GBM tumours in mice, as well as human patients, which could reflect an increased presence of hypoxic regions in these tumours.
| Conclusion|| |
Understanding the interplay between genomic and metabolomic modulators may serve as a potential factor to target the mechanism of cancer initiation, development and progression. New approach to cancer therapy is required in order to take into consideration of the potential impact of the tumor microenvironment and metabolism. Recent cancer metabolism studies in higher organisms are uncovering the influence of metabolic interactions with the environment.
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Conflicts of interest
There are no conflicts of interest.
| References|| |
GBD 2015 Risk Factors Collaborators. Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks, 1990-2015: A systematic analysis for the Global Burden of Disease Study 2015. Lancet 2016;388:1659-724.
Plummer M, de Martel C, Vignat J, Ferlay J, Bray F, Franceschi S. Global burden of cancers attributable to infections in 2012: A synthetic analysis. Lancet Glob Health 2016;4:e609-16.
Anastasiou D, Poulogiannis G, Asara JM, Boxer MB, Jiang JK, Shen M, et al
. Inhibition of pyruvate kinase M2 by reactive oxygen species contributes to cellular antioxidant responses. Science 2011;334:1278-83.
Yi W, Clark PM, Mason DE, Keenan MC, Hill C, Goddard WA 3rd
, et al
. Phosphofructokinase 1 glycosylation regulates cell growth and metabolism. Science 2012;337:975-80.
Favaro E, Bensaad K, Chong MG, Tennant DA, Ferguson DJ, Snell C, et al
. Glucose utilization via glycogen phosphorylase sustains proliferation and prevents premature senescence in cancer cells. Cell Metab 2012;16:751-64.
Virchow R. Die Cellular Pathologie Inihrer Begründungauf Physiologische Undpathologische Gewebelehre. Berlin: Von August Hirschwald Verlag; 1858.
Bauer KH. Mutationstheorie der Geschwulst-Entstehung. Berlin: Julius Springer Verlag; 1928.
Watson JD, Crick FH: Molecular structure of nucleic acids; a structure for deoxyribose nucleic acid. Nature 1953;171:737–78.
Cobb M. 1953: When genes become “information”. Cell 2013;153:503-6.
Ashley DJ. The two “hit” and multiple “hit” theories of carcinogenesis. Br J Cancer 1969;23:313-28.
Greenman C, Stephens P, Smith R, Dalgliesh GL, Hunter C, Bignell G, et al
. Patterns of somatic mutation in human cancer genomes. Nature 2007;446:153-8.
Rosenfeld S. Are the somatic mutation and tissue organization field theories of carcinogenesis incompatible? Cancer Inform 2013;12:221-9.
Versteeg R. Cancer: Tumours outside the mutation box. Nature 2014;506:438-9.
Mack SC, Witt H, Piro RM, Gu L, Zuyderduyn S, Stütz AM. et al
. Epigenomic alterations define lethal CIMP-positive ependymomas of infancy. Nature 2014;506:445-50.
Parker M, Mohankumar KM, Punchihewa C, Weinlich R, Dalton JD, Li Y, et al
. C11 or f95-RELA fusions drive oncogenic NF-κB signalling in ependymoma. Nature 2014;506:451-5.
Martincorena I, Roshan A, Gerstung M, Ellis P, VanLoo P, McLaren S, et al
. High burden and pervasive positive selection of somatic mutations in normal human skin. Science 2015;348:880-6.
Kan Z, Jaiswal BS, Stinson J, Janakiraman V, Bhatt D, Stern HM, et al
. Diverse somatic mutation patterns and pathway alterations in human cancers. Nature 2010;466:869-73.
Lawrence MS, Stojanov P, Polak P, Kryukov GV, Cibulskis K, Sivachenko A, et al
. Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature 2013;499:214-8.
Imielinski M, Berger AH, Hammerman PS, Hernandez B, Pugh TJ, Hodis E, et al
. Mapping the hallmarks of lung adenocarcinoma with massively parallel sequencing. Cell 2012;150:1107-20.
Tomlinson IP, Novelli MR, Bodmer WF. The mutation rate and cancer. Proc Natl Acad Sci 1996;93:14800-3.
Loeb LA, Loeb KR, Anderson JP. Multiple mutations and cancer. Proc Natl Acad Sci U S A 2003;100:776-81.
Loeb LA. A mutator phenotype in cancer. Cancer Res 2001;61:3230-9.
Perou M, Sorlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, et al
. Molecular portraits of human breast tumours. Nature 2000;406:747-52.
Laird PW, Jaenisch R. The role of DNA methylation in cancer genetic and epigenetics. Annu Rev Genet 1996;30:441-64.
Tomlinson I, Bodmer W. Selection, the mutation rate and cancer: Ensuring that the tail does not wag the dog. Nat Med 1999;5:11-2.
Martin GM, Sprague CA, Epstein CJ. Replicative life-span of cultivated human cells. Effects of donor's age, tissue, and genotype. Lab Invest 1970;23:86-92.
Tsutsui T, Tamura Y, Suzuki A, Hirose Y, Kobayashi M, Nishimura H, et al
. Mammalian cell transformation and aneuploidy induced by five bisphenols. Int J Cancer 2000;86:151-4.
Tayama S, Nakagawa Y, Tayama K. Genotoxic effects of environmental estrogen-like compounds in CHO-K1 cells. Mutat Res 2008;649:114-25.
Kamp DW, Shacter E, Weitzman SA. Chronic inflammation and cancer: The role of the mitochondria. Oncology (Williston Park) 2011;25:400-10, 413.
Marusawa H, Jenkins BJ. Inflammation and gastrointestinal cancer: An overview. Cancer Lett 2014;345:153-6.
Takeshi M. Low phleadsto sister-chromatid exchange and chromosomal aberrations, and its clastogenicity is S-dependent. Mutat Res 1995;334:301-8.
Gatenby RA, Gillies RJ. Hypoxia and metabolism: Opinion- A microenvironmental model of carcinogenesis. Nat Rev Cancer 2008;8:56-61.
Fang JS, Gillies RD, Gatenby RA. Adaptation to hypoxia and acidosis in carcinogenesis and tumor progression. Semin Cancer Bio 2008;18:330-7.
Castello G, Scala S, Palmieri G, Curley SA, Izzo F. HCV-related hepatocellular carcinoma: From chronic inflammation to cancer. Clin Immunol 2010;134:237-50.
Nishisgori C. Current concept of photocarcinogenesis. Photochem Photobiol Sci 2015;14:1713-21.
Hanahan D, Weinberg RA. Hallmarks of cancer: The next generation. Cell 2011;144:646-74.
Gatenby RA, Gillies RJ. Why do cancers have high aerobic glycolysis? Nat Rev Cancer 2004;4:891-9.
Jaenisch R, Bird A. Epigenetic regulation of gene expression: How the genome integrates intrinsic and environmental signals. Nat Genet 2003;33 Suppl: 245-54.
Feil R, Fraga MF. Epigenetics and the environment: Emerging patterns and implications. Nat Rev Genet 2011;13:97-109.
Herceg Z, Vaissière T. Epigenetic mechanisms and cancer: An interface between the environment and the genome. Epigenetics 2011;6:804-19.
Wirth AJ, Platkov M, Gruebele M. Temporal variation of a protein folding energy and scape in the cell. J Am Chem Soc 2013;135:19215-21.
Uversky VN. Functional roles of transiently and intrinsically disordered regions within proteins. FEBSJ 2015;282:1182-9.
Song CW, Lyon JC, Luo Y. Intra- and extracellular pH in solid tumors: Influence on therapeutic response. In: Teicher BV, editor. Drug Resistance in Oncology. New York: Marcel Dekker; 1993. p. 25-51.
Song CW, Park HJ, Ross BD. Intra- and extracellular pH in solid tumors. In Teicher BV, editor. Antiangiogenic Adnets in Cancer Therapy. Totowa: Humana Press; 1998. p. 51-64.
Rhee JG, Kim TH, Levitt SH, Song CW. Changes in acidity of mouse tumors by hyperthermia. Int J Radiat Oncol Biol Phys 1985;10:393-9.
Wike-Hooley JL, Haveman J, Reinhold HS. The relevance of tumour pH to the treatment of malignant disease. Radiother Oncol 1984;2:343-66.
Webb SD, Sherratt JA, Fish RG. Mathematical modelling of tumour acidity: Regulation of intracellular pH. J Theor Biol 1999;196:237-50.
Warburg O. Warburg on the origin of cancer. Science1956;123:309-14.
Pavlova NN, Thompson CB. The emerging hallmarks of cancer metabolism. Cell Metab 2016;23:27-47.
Galluzzi L, Kepp O, Vander Heiden MG, Kroemer G. Metabolic targets for cancer therapy. Nat Rev Drug Discov 2013;12:829-46.
Elia I, Schmieder R, Christen S, Fendt SM. Organ-specific cancer metabolism and its potential for therapy. Handb Exp Pharmacol 2016;233:321-53.
Marin-Valencia I, Yang C, Mashimo T, Cho S, Baek H, Yang XL, et al
. Analysis of tumor metabolism reveals mitochondrial glucose oxidation in genetically diverse human glioblastomas in the mouse brain in vivo
. Cell Metab 2012;15:827-37.
Gerweck LE, Rhee JG, Koutcher JA, Song CW, Urano M. Regulation of pH in murine tumor and muscle. Radiat Res 1991;126:206-9.
Ward KA, DiPette DJ, Held TN, Jain RK. Effect of intravenous versus intraperitoneal glucose injection on systemic hemodynamics and blood flow rate in normal and tumor tissues in rats. Cancer Res 1991;51:3612-6.
Vaupel PW, Okunieff PG. Role of hypovolemic hemoconcentration in dose-dependent flow decline observed in murine tumors after interperitoneal administration of glucose or mannitol. Cancer Res 1988;48:7102-6.
Kim JW, Dang CV. Cancer's molecular sweet tooth and the Warburg effect. Cancer Res 2006;66:8927-30.
Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: The metabolic requirements of cell proliferation. Science 2009;324:1029-33.
Fernandez-de-Cossio-Diaz1, J and Vazquez, A. Limits of aerobic metabolism in cancer cells. Sci Rep 2017;7:13488.
DeBerardinis RJ, Cheng T. Q's next: The diverse functions of glutamine in metabolism, cell biology and cancer. Oncogene 2010;29:313-24.
Paschen W, Djuricic B, Mies G, Schmidt-Kastner R, Linn F. Lactate and pH in the brain: Association and dissociation in different pathophysiological states. J Neurochem 1987;48:154-9.
Walenta S, Salameh A, Lyng H, Evensen JF, Mitze M, Rofstad EK, et al
. Correlation of high lactate levels in head and neck tumors with incidence of metastasis. Am J Pathol 1997;150:409-15.
Schwickert G, Walenta S, Sundfør K, Rofstad EK, Mueller-Klieser W. Correlation of high lactate levels in human cervical cancer with incidence of metastasis. Cancer Res 1995;55:4757-9.
Brizel DM, Schroeder T, Scher RL, Walenta S, Clough RW, Dewhirst MW, et al
. Elevated tumor lactate concentrations predict for an increased risk of metastases in head-and-neck cancer. Int J Radiat Oncol Biol Phys 2001;51:349-53.
Wu H, Ding Z, Hu D, Sun F, Dai C, Xie J, et al
. Central role of lactic acidosis in cancer cell resistance to glucose deprivation-induced cell death. J Pathol 2012;227:189-99.
Zhang W, Guo C, Jiang K, Ying M, Hu X. Quantification of lactate from various metabolic pathways and quantification issues of lactate isotopologues and isotopmers. Sci Rep 2017;7:8489.
Colegio OR, Chu NQ, Szabo AL, Chu T, Rhebergen AM, Jairam V, et al
. Functional polarization of tumour-associated macrophages by tumour-derived lactic acid. Nature 2014;513:559-63.
Haas R, Smith J, Rocher-Ros V, Nadkarni S, Montero-Melendez T, D'Acquisto F, et al
. Lactate regulates metabolic and pro-inflammatory circuits in control of t cell migration and effector functions. PLoS Biol 2015;13:e1002202.
Chen JL, Lucas JE, Schroeder T, Mori S, Wu J, Nevins J, et al
. The genomic analysis of lactic acidosis and acidosis response in human cancers. PLoS Genet 2008;4:e1000293.
Sonveaux P, Végran F, Schroeder T, Wergin MC, Verrax J, Rabbani ZN, et al
. Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice. J Clin Invest 2008;118:3930-42.
Végran F, Boidot R, Michiels C, Sonveaux P, Feron O. Lactate influx through the endothelial cell monocarboxylate transporter MCT1 supports an NF-kB/IL-8 pathway that drives tumor angiogenesis. Cancer Res 2011;71:2550-60.
Dai C, Sun F, Zhu C, Hu X. Tumor environmental factors glucose deprivation and lactic acidosis induce mitotic chromosomal instability – An implication in aneuploid human tumors. PLoS One 2013;8:e63054.
Reitzer LJ, Wice BM and Kennell D. Evidence that glutamine, not sugar, is the major energy source for cultured HeLa cells. J Biol Chem 1979;254:2669-76.
DeBerardinis RJ, Mancuso A, Daikhin E, Nissim I, Yudkoff M, Wehrli S, et al
. Beyond aerobic glycolysis: Transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis. Proc Natl Acad Sci U S A 2007;104:19345-50.
Dang CV. Glutaminolysis: Supplying carbon or nitrogen or both for cancer cells? Cell Cycle 2010;9:3884-6.
Jin L, Alesi GN, Kang S. Glutaminolysis as a target for cancer therapy. Oncogene 2016;35:3619-25.
Wise DR, DeBerardinis RJ, Mancuso A, Sayed N, Zhang XY, Pfeiffer HK, et al
. Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction. Proc Natl Acad Sci U S A 2008;105:18782-7.
Hensley CT, Wasti AT, DeBerardinis RJ. Glutamine and cancer: Cell biology, physiology, and clinical opportunities. J Clin Invest 2013;123:3678-84.
Wong CC, Qian Y, Li X, Xu J, Kang W, Tong JH, et al
. SLC25A22 promotes tumorigenicity and metastasis of KRAS-mutant colorectal cancer by regulating intracellular aspartate biosynthesis. Gastroenterology 2016;151:945-60.
Gupta V, Gopinath P, Iqbal MA, Mazurek S, Wellen KE, Bamezai RN. Interplay between epigenetics & cancer metabolism. Curr Pharm Des 2014;20:1706-14.
Johnson C, Warmoes MO, Shen X, Locasale JW. Epigenetics and cancer metabolism. Cancer Lett 2015;356:309-14.
Muñoz-Pinedo C, González-Suárez E, Portela A, Gentilella A, Esteller M. Exploiting tumor vulnerabilities: Epigenetics, cancer metabolism and the mTOR pathway in the era of personalized medicine. Cancer Res 2013;73:4185-9.
Cluntun AA, Huang H, Dai L, Liu X, Zhao Y, Locasale JW. The rate of glycolysis quantitatively mediates specific histone acetylation sites. Cancer Metab 2015;3:10.
Liu XS, Little JB, Yuan ZM. Glycolytic metabolism influences global chromatin structure. Oncotarget 2015;6:4214-25.
Comerford SA, Huang Z, Du X, Wang Y, Cai L, Witkiewicz AK, et al
. Acetate dependence of tumors. Cell 2014;159:1591-602.
Mashimo T, Pichumani K, Vemireddy V, Hatanpaa KJ, Singh DK, Sirasanagandla S, et al
. Acetate is a bioenergetic substrate for human glioblastoma and brain metastases. Cell 2014;159:1603-14.
Schug ZT, Peck B, Jones DT, Zhang Q, Grosskurth S, Alam IS, et al
. Acetyl-CoA synthetase 2 promotes acetate utilization and maintains cancer cell growth under metabolic stress. Cancer Cell 2015;27:57-71.
[Figure 1], [Figure 2], [Figure 3]