Part I: On the Roles of Altered Tumor Cell Metabolism in Tumor Biology
Chapter 1: Metabolic Remodeling in Bioenergetic Disorders and Cancer
1.1 Energy Metabolism, Control, and Regulation
1.2 Metabolic Remodeling in Physiology and Metabolic Disorders
1.3 Molecular Basis of the Metabolic Flexibility of Tumors
1.4 The Signaling Pathways Involved in Metabolic Remodeling
1.5 Future Directions in the Field of Energy Metabolism
Chapter 2: Tumor Cell Complexity and Metabolic Flexibility in Tumorigenesis and Metastasis
2.2 Tumor Cell Complexity
2.3 Tumor Cell Hierarchy and Differentiation Therapy
2.4 Bioenergetic Pathways of Proliferating, Self-Renewing, and Differentiating Cells
2.5 Bioenergetic Remodeling in Tumor Cells
2.5.1 Consequences of a Glycolytic Metabolism: Plasma Membrane Electron Transport
2.5.2 Genetic and Epigenetic Changes
2.5.2.1 Nuclear Mutations Affecting Energy Metabolism
2.5.2.2 Mitochondrial Mutations Affecting Energy Metabolism
2.5.2.3 Epigenetic Changes Affecting Energy Metabolism
Chapter 3: Autophagy and Tumor Cell Metabolism
3.2 Autophagy and Metabolic Adaptation
3.2.1 Autophagy and the Tumor Microenvironment
3.2.2 Autophagy and Hypoxia
3.3 Metabolism and Posttranslational Modification Regulation of Autophagy
3.3.1 Posttranscriptional Modification Regulation at the Cytoplasmic Level
3.3.2 Posttranscriptional Modification Regulation at the Nuclear Level
3.3.3 Cross Talk Between Metabolism and Autophagy
3.4 Autophagy, Metabolism, and Cancer Stem Cells
Chapter 4: Tumour Hypoxia and the Hypoxia-Inducible Transcription Factors: Key Players in Cancer Progression and Metastasis
4.2 Hypoxia-Inducible Factors
4.2.1 Hypoxic Regulation of HIF-Alpha Subunits
4.2.2 Non-Hypoxia-Driven Regulation of the HIFs
4.2.3 Posttranslational Modifications of HIF1a and HIF2a
4.2.4 Transcriptional Regulation by HIF1a and HIF2a
4.2.5 Hypoxia and HIF Activity Affect Protein Translation
4.2.6 Translational Regulation by HIF2a
4.2.7 HIF1a, HIF2a and p53
4.2.8 Effects of Hypoxia and the HIFs on the Oncogene MYC
4.2.9 Hypoxia, HIFs and microRNA
4.2.10 Hypoxic Modulation of Wnt/Beta-Catenin Activity
4.2.11 HIF1a and Notch Signalling
4.3 Tumour Hypoxia, HIF Signalling and Patient Outcome
4.4 Tumour Hypoxia and Tumour Progression
4.4.1 Tumour Hypoxia Induces Angiogenesis and Metastasis
4.4.2 Hypoxic Induction of EMT
4.4.3 Tumour Hypoxia and HIFs Promote Stem Cell Phenotype
Part II: Some Specific Regulators of Cellular Metabolism in Normal and Cancer Cells
Chapter 5: MYC Regulation of Metabolism and Cancer
5.4 Role of MYC in Cell Growth and Proliferation
5.5.1 MYC, the Warburg Effect, and Mitochondria
5.5.2 MYC and Glutamine Metabolism
5.5.3 MYC and Amino Acid Transporters and Synthesis
5.5.4 Fatty Acid Metabolism
5.5.5 MYC and Nucleotide Biosynthesis
5.5.6 MYC and Oncometabolites
5.6 MYC-Driven Metabolism and Cancer Therapy
Chapter 6: Pyruvate Kinase M2: A Metabolic Tuner
6.2 Regulation of Pyruvate Kinase M2
6.3 Canonical and Noncanonical Functions of PKM2
6.3.1 Pyruvate Kinase M2, Warburg Effect, and Cancer Cell Metabolism
6.3.2 Why the Aerobic Glycolysis?
6.3.3 Non-metabolic Functions
6.3.4 PKM2 and Epigenetics
6.4 PKM2 and Cancer Therapeutics
6.4.1 Therapeutic Modulation of PKM2 Activity
6.4.2 Non-metabolic Functions of PKM2
6.4.3 PKM2 and Cancer Diagnostics
Chapter 7: Role of the Pentose Phosphate Pathway in Tumour Metabolism
7.1 The Pentose Phosphate Pathway in Cell Metabolism
7.1.1 The Oxidative Branch of the Pentose Phosphate Pathway
7.1.2 The Nonoxidative Branch of the Pentose Phosphate Pathway
7.2 The Role of the Pentose Phosphate Pathway in Cancer Metabolism
7.2.1 Oxidative Branch of the Pentose Phosphate Pathway in Cancer
7.2.1.1 Glucose-6-Phosphate Dehydrogenase
7.2.1.2 6-Phosphogluconate Dehydrogenase
7.2.2 Nonoxidative Branch of the Pentose Phosphate Pathway in Cancer
7.3 The Pentose Phosphate Pathway as Potential Cancer Therapeutic Target
Chapter 8: Enzymes of the Tumour Metabolome in Diagnostic Applications
8.1 6-Phosphofructo-1-Kinase
8.2 Fructose-Bisphosphate Aldolase
8.4 Pyruvate Kinase (M2-PK, PKM2)
8.5 Lactate Dehydrogenase
Chapter 9: Contribution of pH Alterations to the Tumor Microenvironment
9.2 Metabolic Sources of Acidity in Tumors
9.3 Role of Glycolysis and Oxidative Phosphorylation In Vivo
9.4 Regulation of pH in Tumor Cells
9.4.1 Carbonic Anhydrases
9.4.3 Sodium-Hydrogen Exchanger
9.5 Tumor-Supportive Effects of Altered pH
9.5.2 Resistance to Cell Death
9.5.4 Modulation of Autophagy
9.5.5 Extracellular Vesicles
9.6 Targeting pH Modulation in Cancer Therapy
Part III: On the Role of Mitochondria in Tumor Metabolism
Chapter 10: Mitochondrial Mutations in Cancer Progression: Causative, Bystanders, or Modifiers of Tumorigenesis?
10.2 Sources of mtDNA Mutations in Cancer
10.3 Selection of mtDNA Mutations in Cancer
10.4 Consequences of mtDNA Mutations on Tumorigenesis and Tumor Progression
10.5 Mitochondrial Mutations and Cancer Metabolism
10.6 Cell-Systemic Consequences of mtDNA Mutations That Modify Tumor Progression
Chapter 11: The Relevance of the Mitochondrial H+-ATP Synthase in Cancer Biology
11.2 Overview of the Changes in Metabolic Pathways During Proliferation
11.3 The Bioenergetic Function of Mitochondria in Cancer Cells
11.4 The Clinical Relevance of the Bioenergetic Signature of Cancer
11.5 The H+-ATP Synthase and Tumor Suppression
11.6 IF1-Mediated Inhibition of the H+-ATP Synthase Also Propitiates Cancer Progression
Chapter 12: Canceromics Studies Unravel Tumor´s Glutamine Addiction After Metabolic Reprogramming
12.2 Tumors as Metabolic Traps for Glucose and Glutamine
12.3 Tumors Induce a Net Flux of Glutamine and Essential Amino Acids from Host Tissues
12.4 Enzymatic Imbalance in Host Glutamine Metabolism
12.5 Tumor Glutamine Catabolism: Glutaminolysis
12.6 Metabolic Versatility of Cancer Cells: Interrelationship Between Glucose Metabolism and Glutaminolysis
12.7 Glutaminase Isoenzymes and Their Opposing Roles in Tumorigenesis
12.8 GLS Isoforms: KGA and GAC
12.9 GLS2 Isoforms: GAB and LGA
Chapter 13: Essential Role of Mitochondria in Pyrimidine Metabolism
13.1 Mitochondria Are Self-Contained Sections in the Network of Metabolic Pathways
13.2 Intracellular Location and Regulation of the Enzymes of Pyrimidine De Novo Synthesis
13.3 Metabolic Channelling in UMP De Novo Synthesis: A Paradox?
13.4 The Prominent Position of Dihydroorotate Dehydrogenase in Mitochondria
13.5 Dihydroorotate Dehydrogenase and Hypoxia
13.6 The Importance of Mitochondria in the Salvage of Pyrimidines
13.7 Pyrimidine Interconversion and Catabolism in Relation to Mitochondrial Diseases
13.8 Modulation of Pyrimidine Pools for Cell Proliferation
13.9 Deoxynucleotide Pools in Mitochondria: Crucial for mtDNA
Part IV: On the New Omics of Metabolism
Chapter 14: Metabolic Fluxes in Cancer Metabolism
14.2 Metabolic Pathways and Cancer
14.2.1 Aspects of Altered Metabolism in Cancer
14.2.2 Adaptation of Cancer Metabolism to a Hypoxic Tumor Environment
14.2.3 Oncogenes and Tumor Suppressors Coupled to Metabolic Reprogramming
14.2.4 Cancer Mutations Promoting the Warburg Effect
14.3 Metabolic Flux Analysis in Studying Cancer Metabolism
14.3.1 Historical Aspects
14.3.2 Technologies Used for MFA
14.3.3 Recent Approaches for MFA Using NMR Methods
14.4 Applications of MFA in Cancer Cell Lines
14.5 Metabolic Fluxes In Vivo
Chapter 15: Targeted 13C-Labeled Tracer Fate Associations for Drug Efficacy Testing in Cancer
15.1 Materials and Methods
15.1.1 Cells and Cell Culture
15.2 RNA Ribose Stable Isotope Studies
15.3 Lipid Extraction and Analysis
15.4 Gas Chromatography/Mass Spectrometry (GC/MS)
15.5 Data Analysis and Statistical Methods
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