The Heterogeneity of Cancer Metabolism.

• Superior document: Advances in Experimental Medicine and Biology Series ; v.1311
• Author: Le, Anne.
• Place / Publishing House: Cham : : Springer International Publishing AG,, 2021.; ©2021.
• Year of Publication: 2021
• Edition: 2nd ed.
• Language: English
• Series: Advances in Experimental Medicine and Biology Series
• Physical Description: 1 online resource (283 pages)

Table of Contents

Intro -- Foreword -- Preface -- Acknowledgments -- Contents -- Editor and Contributors -- About the Editor -- Contributors -- Part I: Basic Metabolism of Cancer Cells -- Glucose Metabolism in Cancer: The Warburg Effect and Beyond -- 1 Introduction -- 2 The Warburg Effect -- 2.1 Otto Warburg's Early Studies of Normal Cellular Respiration -- 2.2 The Warburg Effect Is a Prominent Feature of Cancer Cell Metabolism -- 2.3 The Biochemical Nature and Clinical Significance of the Warburg Effect -- 2.4 Metabolic and Genetic Reprogramming Underlying the Warburg Effect -- 3 Heterogeneity in Glucose Metabolism -- 4 The Role of Glycogen Metabolism and Gluconeogenesis in Tumor Growth -- 4.1 Glycogen Metabolism Is Upregulated in Several Cancers -- 4.2 Upregulation of Gluconeogenic Enzymes in Cancer -- 5 Success and Failures of Targeting Glucose Metabolism for Cancer Therapy -- 5.1 Therapies Targeting Glycolysis and the Warburg Effect -- 5.2 Therapies Targeting Glycogenolysis and Glycogen Synthesis Have Shown Promising Results -- 6 Conclusion -- References -- Glutamine Metabolism in Cancer -- 1 Introduction -- 2 Characteristic Features of Glutamine Metabolism in Cancer -- 2.1 Dysregulation of the TCA Cycle -- 2.2 Glutamine Addiction -- 2.3 The Metabolic Reprogramming of Cancers Provides Them with Alternative Sources of Glutamate: Via N-Acetyl-Aspartyl-Glutamate (NAAG) and via the Glutaminase II Pathway -- 3 Targeting Glutamine Metabolism for Cancer Therapy -- 3.1 Inhibition of Glutaminolysis by GLS Inhibitors -- 3.2 Combination Therapy -- 3.3 Knockdown of c-MYC -- 3.4 Inhibition of Glutamate Dehydrogenase (GDH) -- 3.5 Inhibiting the TCA Cycle by Depleting Glutamine, α-Ketoglutarate, and Asparagine -- 3.6 Inhibiting Glutamine Uptake -- 3.7 Using Glutamine Mimetics.

4 Transaminase Upregulation and Targeting Amino Acid Synthesis for Cancer Therapy -- 5 Glutamine Metabolism in the Tumor Microenvironment -- 5.1 The Role of Glutamine Metabolism in T Cells and NK Cells -- 5.2 The Role of Glutamine Metabolism in Tumor-Associated Macrophages -- 5.3 The Role of Glutamine Metabolism in Cancer-Associated Fibroblasts -- 6 Conclusion -- References -- The Heterogeneity of Lipid Metabolism in Cancer -- 1 Introduction -- 2 Fatty Acid Synthesis Is Upregulated in Cancer -- 2.1 The Mitochondrial Citrate Transporter Protein (CTP) Protects Mitochondrial Function in Cancer -- 2.2 ATP Citrate Lyase (ACLY) Is Upregulated in Cancer -- 2.3 Multifaceted Effects of Inhibiting Acetyl-CoA Carboxylase (ACC) in Cancer -- 2.4 The First Fatty Acid Synthase (FAS) Inhibitor TVB-2640 Is in Clinical Trials for Cancer -- 2.5 Which Markers Can Predict Cancer Cell Sensitivity to Lipid Synthesis Inhibition? -- 2.6 Tumor Microenvironment Influences the Sensitivity of Cancer Cells to Lipid Synthesis Inhibitors -- 3 Targeting Fatty Acid Elongation -- 4 The Efficacy of Inhibiting Cholesterol Synthesis with Adjuvant Statins Is Variable -- 5 Fatty Acid Uptake Is Associated with Metastasis -- 6 Fatty Acid Oxidation Encompasses a Diverse Set of Molecular Mechanisms -- 6.1 Targeting FAO for Cancer Therapy May Be Achieved by Inhibiting Carnitine Palmitoyltransferase 1 -- 6.2 CPT1 Inhibitors Are Now in Clinical Trials -- 6.3 FAO for Very-Long-Chain Fatty Acids Occurs at the Peroxisome Where Peroxisome Proliferator-Activated Receptors (PPARs) Act as Ligand-Activated Transcription Factors -- 7 Conclusion -- References -- Part II: Heterogeneity of Cancer Metabolism -- The Multifaceted Glioblastoma: From Genomic Alterations to Metabolic Adaptations -- 1 Introduction -- 2 GBM Classifications and Intratumoral Heterogeneity.

2.1 GBM Subtype Classification -- 2.2 Intratumoral Heterogeneity -- 2.2.1 Liquid Biopsy as a Method for Detecting Heterogeneity and Longitudinal Tracking -- 2.2.2 Glioblastoma Stem Cell Resistance and Recurrence Are Supported Through Mitochondrial Activity and Fatty Acid Oxidation -- 3 Genomic Alterations Lead to Distinct Metabolic Changes Allowing for Targeted Therapies -- 3.1 PTEN Mutations Lead to High Rates of Glycolysis, Facilitating Survival in Harsh Microenvironments -- 3.2 EGFR Mutations Shift Cancer Cells toward a Glycolytic Phenotype and Permit Survival under Glucose-Deprived Conditions -- 3.3 p53 Mutations Result in Activation of the Warburg Effect -- 3.4 GBM Exhibits Upregulated Glutamine Metabolism Allowing for Targeted Vulnerabilities Through GLS, GS, and mTOR -- 3.5 Lipid Metabolism Dysregulation Following BRAF Mutations and EGFR Signaling Provides Clues for New GBM Therapeutic Strategies -- 3.6 GBMs Rely on the TCA Cycle and Its Reductants -- 3.7 IDH1 Mutations Lead to Oncometabolite Production and Glutamine Addiction and Act as a Prognostic Marker -- 4 Benefits of Combined Therapy -- 5 Advanced Brain Tumors (GBM) Display Distinct Metabolic Profiles Compared to Lower Grade Tumors -- 6 Conclusion -- References -- The Intricate Metabolism of Pancreatic Cancers -- 1 Introduction -- 2 Oncogenic KRAS Regulates Metabolism in Pancreatic Cancer Cells (Fig. 2) -- 2.1 Oncogenic KRAS Regulates Glutamine Metabolism -- 2.2 Oncogenic KRAS Regulates Glucose Metabolism -- 2.3 Oncogenic KRAS Upregulates Macropinocytosis and Lipid Scavenging -- 3 Other Alternative Metabolisms in Pancreatic Cancer -- 3.1 MUC1 Overexpression Leads to Increased Glucose Metabolism -- 3.2 p53 Functions Predict the Sensitivity of Pancreatic Cancer Tumors to Glycolytic Inhibition -- 3.3 Alternative Source of Glutamate in PDAC.

3.3.1 Neurotransmitter N-Acetyl-Aspartyl-Glutamate (NAAG) as a Glutamate Reservoir in Cancer -- 3.3.2 Glutaminase II Pathway Is Another Source of Glutamate in Cancer -- 4 Pancreatic Tumor Microenvironment -- 4.1 PDACs are Dependent on Autophagy -- 4.2 Stromal Interactions Create Complex PDAC Metabolic Networks -- 5 Suggested Therapy (Fig. 3) -- 5.1 Targeting Alpha-Ketoglutarate Dehydrogenase Complex Function by CPI-613 to Slow Mitochondrial Metabolism -- 5.2 Antidiabetic Drug, Metformin, Targets Pancreatic Cancer Stem Cells -- 5.3 Combined Therapy to Target Pancreatic Metabolism Heterogeneity -- 5.4 Targeting PDACs Based on Metabolic Subtype within the PDAC Tumor Microenvironment -- 5.5 Autophagy Inhibition via Hydroxychloroquine -- 6 Conclusion -- References -- The Heterogeneity of Breast Cancer Metabolism -- 1 Introduction -- 2 Aberrant Metabolic Pathways Present in Breast Cancer Contribute to Breast Cancer Heterogeneity (Fig. 1) -- 2.1 Differences in Glycolytic Upregulation Among Breast Cancer Subtypes Can Be Attributed to Glucose Transporter (GLUT) Expression -- 2.2 Choline Metabolism in Breast Cancer Is Strongly Associated with Tumor Grades -- 3 Different Roles of Estrogen in Estrogen Metabolism and ER Binding Promote Breast Cancer Tumorigenicity -- 3.1 PHGDH Overexpression in Serine Biosynthesis Fuels TCA Anaplerosis -- 4 The Clinical Applications of Metabolic Profiling -- 4.1 Breast Cancer Diagnosis and Subtyping Using Metabolomics -- 4.2 Metabolic Profiling as a Strategy for Prediction of Recurrence in Breast Cancer -- 4.3 Metabolic Fingerprinting in Breast Cancer Metastasis -- 4.4 Prediction of Response to Therapy Based on Metabolic Phenotypes -- 5 Additional Perspectives on Breast Cancer Heterogeneity -- 5.1 Spatial Pathogenesis Observed in Breast Cancer Metabolism.

5.2 Temporal Pathogenesis Observed in Breast Cancer Metabolism: Metabolic Differences Between Early Stage and Advanced Stage -- 5.3 Metabolic Heterogeneity Influences Effective Breast Cancer Drug Treatment -- 6 Conclusion -- References -- Non-Hodgkin Lymphoma Metabolism -- 1 Introduction -- 2 Lymphoma Metabolism Exhibits Multifaceted Characteristic Features Which Are Correlated to Poor Prognosis -- 2.1 Aggressive Lymphomas Exhibit the Warburg Effect -- 2.2 Lactic Acidosis Is a Result of Overproduction of Lactate and Leads to a Fatal Prognosis -- 3 Genetic Alterations Lead to Different Metabolic Phenotypes in NHL (Fig. 2) -- 3.1 Mutation of p53 Helps Cancer Cells Survive Glutamine Deprivation -- 3.2 PI3K Regulates Fatty Acid Synthesis (FAS) in Primary Effusion Lymphoma (PEL) and Other B-NHLs -- 3.3 AMPK Regulates NADPH Balance for Fatty Acid Oxidation (FAO) as a Means of Supplementing the Tricarboxylic Acid (TCA) Cycle -- 3.4 PRPS2 Couples Protein and Nucleotide Biosynthesis to Drive Lymphomagenesis -- 3.5 mTOR Activation Promotes Fatty Acid Synthesis (FAS) -- 3.6 MYC Regulates Cancer Cell Metabolism under Glucose-Deprived and Hypoxic Conditions -- 3.7 HIF-1 Acts as a Regulator in Hypoxia Adaptation and the Related Metabolic Changes -- 3.8 Understanding the PI3K/AKT/mTOR Pathway in Lymphoma Can Lead to a Variety of Treatments -- 4 Metabolic Profiling for Monitoring Tumor Progression and Guiding Treatment -- 4.1 [18F]FDG PET/CT -- 4.2 Systemic NAAG Concentrations for Tumor Growth Monitoring -- 5 Conclusion -- References -- The Heterogeneity Metabolism of Renal Cell Carcinomas -- 1 Introduction -- 2 Different Oncogenic Mutations Lead to Different Metabolic Phenotypes in RCC (Fig. 1) -- 2.1 Loss of the von Hippel-Lindau Tumor-Suppressor Gene Results in Metabolic Alterations Including Shifts Toward Aerobic Glycolysis in RCC.

2.2 Fumarate Hydratase Mutations Result in an Increase in Aerobic Glycolysis in RCC.