The Heterogeneity of Cancer Metabolism (Advances in Experimental Medicine and Biology, 1311)

This open access volume will introduce recent discoveries in cancer metabolism since the publication of the first edition in 2018, providing readers with an up-to-date understanding of developments in the field. Genetic alterations in cancer, in addition to being the fundamental drivers of tumorigenesis, can give rise to a variety of metabolic adaptations that allow cancer cells to survive and proliferate in diverse tumor microenvironments. This metabolic flexibility is different from normal cellular metabolic processes and leads to heterogeneity in cancer metabolism within the same cancer type or even within the same tumor. In this book, the authors delve into the complexity and diversity of cancer metabolism and highlight how understanding the heterogeneity of cancer metabolism is fundamental to the development of effective metabolism-based therapeutic strategies for cancer treatment. Deciphering how cancer cells utilize various nutrient resources will enable clinicians and researchers to pair specific chemotherapeutic agents with patients who are most likely to respond with positive outcomes, allowing for more cost-effective and personalized cancer treatment. This book has four major parts. Part one will cover the basic metabolism of cancer cells, followed by a discussion of the heterogeneity of cancer metabolism in part two. Part three addresses the relationship between cancer cells and cancer-associated fibroblasts, and the new part four will explore the metabolic interplay between cancer and other diseases. This new section makes the book unique from other texts currently available on the market. The second edition will be useful for cancer metabolism researchers, cancer biologists, epidemiologists, physicians, health care professionals in related disciplines, policymakers, marketing and economic strategists, among others. It may also be used in courses such as intro to cancer metabolism, cancer biology, and related biochemistry courses for undergraduate and graduate students. 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 3 Metabolic Signatures of RCC 3.1 Metabolic Differences Between Normal Renal Cells and RCC 3.2 Temporal Impact of RCC Metabolism (Fig. 2) 3.3 Intratumoral Heterogeneity of RCC (Fig. 2) 3.3.1 Gene Independence 3.3.2 Gene Dependence 4 RCC Therapy 5 Conclusion References The Heterogeneity of Liver Cancer Metabolism 1 Introduction 2 Different Oncogenic Mutations Lead to Different Metabolic Phenotypes in Primary Liver Cancer 2.1 MYC and MET Mutations Regulate Glucose and Glutamine Metabolism Differently in Primary Liver Cancer 2.2 Liver Receptor Homolog 1 (LRH-1) Regulates Mitochondrial Glutamine Metabolism 2.3 Glucose Metabolism Increased by Acetylated Phosphoglycerate Kinase 1 (PGK1) Leads to the Promotion of Cancer Cell Proliferation and Tumorigenesis in Liver 3 Metabolic Differences Between Liver Cancer Stem Cells (LCSCs) and Non-liver Cancer Stem Cells (Non-LCSCs) 4 Metabolic Signatures of Liver Cancer 4.1 Metabolism of HCC Is Different from that of Normal Liver Tissue 4.2 Oxidative Stress Signature in HCC 5 New Therapeutic Investigations Based on Metabolism Studies 6 Conclusion References Different Tumor Microenvironments Lead to Different Metabolic Phenotypes 1 Introduction 2 The Tumor Microenvironment 3 Different Tumor Microenvironments (TMEs) Lead to Different Metabolic Phenotypes 3.1 Cancer Cells Adapt to Changes in Nutrient and Oxygen Availability by Adopting Alternative Metabolic Pathways (Fig. 2) 3.2 Fatty Acid Oxidation (FAO) Is Used as a Survival Response to Glucose Deprivation 3.3 Lipid Scavenging Is Utilized to Enable Cancer Cells to Survive Periods of Tumor Regression 3.4 Persistence of Glutamine Oxidation Under Hypoxic and Glucose Deprivation Conditions 4 Nutrient Utilization Can Predict a Tumor’s Metabolic Dependencies In Vivo [38] 4.1 Inhibition of mTORC1 Decreases Energy Consumption for Cancer Cell Survival 4.2 Cancer Cells with Functionally Defective Mitochondria Employ Glutamine-Dependent Reductive Carboxylation as an Alternative to Normal Oxidative Metabolism 5 Distinct, and Often Complementary, Metabolic Processes Operate Concurrently Within a Single Tumor 5.1 Metabolic Symbiosis as a Result of Tumor Angiogenesis Inhibition Can Be Stopped by mTOR Signaling Inhibition [44] 6 Conclusion References The Intratumoral Heterogeneity of Cancer Metabolism 1 Introduction 2 Multiple Theories Explain Cancer’s Heterogeneous Nature 3 Intratumoral Metabolic Heterogeneity Follows Intratumoral Genetic Alterations 4 Epigenetics Alterations Lead to Intratumoral Metabolic Heterogeneity 5 Intratumoral Metabolic Adaptation and Heterogeneity Are Due to the Intemperate Conditions of the Tumor Microenvironment 6 Metabolic Heterogeneity Leads to Unpredictable Outcomes 6.1 Spatial Heterogeneity Provides a Survival Advantage to Tumors 6.2 Temporal Heterogeneity Provides Cancer with Short-Term Adaptive Capabilities 7 Tailored Clinical Applications and Therapies Targeting Metabolic Pathways Can Lead to Better Clinical Outcomes 8 Conclusion References Cancer Stem Cell Metabolism 1 Introduction 2 High Levels of Glycolytic Enzymes and Activities in CSCs (Fig. 2) 3 Effects of Deregulation of Glutamine Metabolism on CSCs (Fig. 2) 4 Mitochondrial Metabolism (Fig. 3) 4.1 OXPHOS 4.2 Resistance of CSCs Against ROS 5 Lipid Metabolism (Fig. 4) 6 Conclusion References Metabolism of Immune Cells in the Tumor Microenvironment 1 Introduction 2 Tumor Immunity and the Various Roles of Immune Cells 2.1 Metabolic Competition and Tumor Immunity 2.2 Antitumor T-Cell Metabolisms in the TME 2.3 Cancer Cells’ Impacts on T-Cell Metabolism in the TME 2.4 Cancer Cell-Induced Metabolically Harsh Environment Impairs T-Cell Function 3 Targeting the Metabolism of Immune Cells for Cancer Treatment 3.1 The Metabolism of the Immune Checkpoint Blockades 3.2 The Metabolism of Chimeric Antigen Receptor (CAR) T Cells 4 Conclusion References Part III: Relationship Between Cancer Cells and Cancer-Associated Fibroblasts Metabolic Relationship Between Cancer-Associated Fibroblasts and Cancer Cells 1 Introduction 2 CAFs Undergo the Reverse Warburg Effect and Provide Cancer Cells with Glycolytic Metabolites 3 The Interaction Between Cancer Cells and CAFs Helps Cancer Cells Manage the Warburg Effect 4 Loss of Stromal Cav-1 Is an Indicator of Poor Prognosis in Breast Cancers 5 miRNAs Play a Crucial Role in CAF Metabolic Reprogramming 5.1 The Role of Endogenous miRNAs in the Metabolic Reprogramming of CAFs 5.2 The Role of Exogenous miRNA in the Metabolic Reprogramming of CAFs 6 CAF-Derived Exosomes (CDEs) Can Reprogram the Metabolic Pathway of Cancer Cells 6.1 CDEs Contain miRNAs that Downregulate Oxidative Phosphorylation of Cancer Cells 6.2 Effect of CDEs on Glycolysis and TCA of Cancer Cells 6.3 Glutamine from CDEs Undergoes Mainly Reductive Metabolism that Also Results in Aberrant Lipogenesis in Adjacent Cancer Cells 7 CAF-Derived Lactate Is more Than Just a Metabolite 8 CAFs “Surrender” Their Functional Mitochondria to Prostate Cancer Cells 9 CAFs Augment Cancer Addiction to Glutamine and Its Metabolically Relevant Consequences 10 Alanine Secreted by Pancreatic Stellate Cells Supports Pancreatic Cancer Metabolism 11 CAFs Act as Lipid Synthesis Factories for Colorectal Cancer Cells 12 Reciprocal Communication Is Essential for Cancer Progression 13 Conclusion References Targeting Metabolic Cross Talk Between Cancer Cells and Cancer-Associated Fibroblasts 1 Introduction 2 Overview of the Metabolism of CAFs in Solid Tumors 3 Targeting the Metabolic Exchanges Between CAFs and Cancer Cells 3.1 Targeting the Reverse Warburg Effect via Disruption of the “Lactate Shuttle” by MCT1/MCT4 Inhibitors 3.2 Blocking the Function of CAFs by Metformin (Fig. 2) 4 Targeting the Glutamine Uptake of Cancer Cells from CAFs 5 Targeting Ketone Bodies and Ketosis in CAFs 6 Targeting Fatty Acid, a Nutrient Reservoir for Cancer Cell Growth, from Cancer-Associated Adipocytes (CAAs) 7 Conclusion References Part IV: The Metabolic Interplay Between Cancer and Other Diseases Diabetes and Cancer: The Epidemiological and Metabolic Associations 1 Introduction 2 The Epidemiological Association: Diabetes Correlates with Increased Risk for Many Types of Cancer 3 Abnormal Glucose Metabolism Serves as a Link Between Diabetes and Cancer 3.1 High Glucose Levels Lead to Hexosamine Biosynthetic Pathway (HBP) Upregulation, Contributing to Insulin Resistance in T2D and Oncogenic Mutations (Fig. 1) 3.2 Hyperinsulinemia in Diabetes Promotes Cancer Growth Through Insulin Receptors and the Subsequent Signaling Pathways (Fig. 1) 4 Obesity Leads to Insulin Resistance in Diabetes and Oxidative Stress, Which Can Lead to Cancer (Fig. 1) 5 Amino Acid Metabolism Plays Important Roles in Both T2D and Cancer 5.1 Leucine’s Regulation of Insulin Secretion and mTOR Signaling Promotes T2D Pathogenesis, Insulin Resistance, and Cancer Growth 5.2 Glutamate Regulates Insulin Secretion, Contributes to Gluconeogenesis in T2D, and Promotes Cancer Growth 5.3 Increased Methionine and Cysteine Levels in T2D Can Promote Cancer Growth 6 Exploiting the Similarities and Relationships Between Diabetes and Cancer Metabolism for Cancer Treatment (Fig. 2) 6.1 Metformin, a Drug Developed for Diabetes, Can Inhibit Cancer Growth and Proliferation 6.2 Polyphenols Prevent Diabetes and Reduce Cancer Growth 6.3 Thiazolidinediones and Their Varied Effects on Cancer 6.4 Insulin Secretagogues Can Lead to Increased Cancer Risks 7 Conclusion References Bridging the Metabolic Parallels Between Neurological Diseases and Cancer 1 Introduction 2 Glutamine Plays a Vital Role in Both Cancer Growth and Neurological Diseases 2.1 The Elevated Presence of Glutamine in Cancer and Neurological Diseases Leads to Two Distinctive Disease Progressions and Compromised Patient Survival 2.2 The Prognostic Role of Glutamate in Cancer, Schizophrenia, and Hyperammonemia 2.3 Downregulation of Glutamate Transporters Causes Excessive Extracellular Glutamate in Cancer, Hyperammonemic Diseases, and Neurodegenerative Diseases 2.4 NMDA Receptor Leads to Opposite Cell Fates in Cancer and Psychiatric Disorders Versus Neurodegenerative Diseases and Hyperammonemic Diseases 2.5 AMPAR Expression Played a Contrasting Role in Disease Progression of Cancer and Alzheimer’s Disease 2.6 The Complex Relationship Between Glutamine Metabolism and MYC Contributes Significantly to the Pathophysiology of Both Cancer and Neurodegenerative Diseases 2.7 Alpha-ketoglutaramate and Its Shared Pathway in Cancer and Hyperammonemic Diseases 3 GABA and Its Multiple Functions in Neurological Diseases and Cancer 3.1 Elevated GAD Expression Is Found in Acute Stress and Contributes to Oral Squamous Cell Carcinoma Invasiveness 3.2 GABA Levels Are Characteristic of Various Cancers and Contribute to Alzheimer’s Disease and Attention-Deficit/Hyperactivity Disorder (ADHD) 3.3 GABA Receptors Contribute to Alzheimer’s Disease Pathogenesis, Parkinson’s Disease Severity, and Cancer Invasiveness 3.4 Autoimmune Disorders’ Attack on the GABA-ergic System Correlates with Neurological Diseases and Cancers 4 NAAG and Its Versatile Role in Neurological Diseases and Cancer 4.1 NAAG Affects Both Cancer and Neurological Disease Progression via Glutamate 4.2 Targeting GCP II Is a Promising Strategy for Cancer Treatment 4.3 NAAG Inhibits GABA Release and Indirectly Affects Both Cancer and Neurological Diseases via the GABA-ergic System 5 Conclusion References Metabolic Intersection of Cancer and Cardiovascular Diseases: Opportunities for Cancer Therapy 1 Introduction 2 Glutamine Metabolism as a Prognostic and Therapeutic Target in Cancer and Cardiovascular Diseases (Fig. 1) 2.1 Alterations in Circulating Glutamine and Glutamate Levels Are Indicative of Both Cancer Proliferation and Cardiometabolic Diseases 2.2 Upregulation of Glutaminolysis in Cancer and Pulmonary Arterial Hypertension 2.3 Glutaminase Is a Treatment Target for Cancer, Hypertension, and Hyperglycemia 2.4 Glutamine Supplementation Is Implemented for Treatment of Cancer and a Variety of Cardiovascular Diseases 3 Lipid Metabolism Plays an Important Role in Cancer Proliferation and Cardiovascular Disease Progression (Fig. 2) 3.1 Fatty Acid Oxidation in Cancer and Cardiovascular Diseases 3.2 Pharmacological Inhibition of Fatty Acid Oxidation Has Proven Effective in Slowing Cancer Progression and Treating Cardiovascular Diseases 3.3 Inhibition of Fatty Acid Synthesis Has Proven Both Effective in Cancer Treatment and Protective Against Pulmonary Hypertension 4 Upregulated Tryptophan Catabolism Has Been Linked to the Progression of Cardiovascular Diseases and Enhanced Immune System Evasion in Cancer (Fig. 3) 5 Pyruvate Metabolism Abnormality Is Associated with Cardiovascular Diseases and Chemoresistance in Cancer 6 Conclusion References Correction to: The Heterogeneity of Cancer Metabolism Index This open access volume will introduce recent discoveries in the field of cancer metabolism since the publication of the first edition in 2018, providing readers with an up-to-date understanding of developments in the field. Genetic alterations in cancer, in addition to being the fundamental drivers of tumorigenesis, can give rise to a variety of metabolic adaptations that allow cancer cells to survive and proliferate in diverse tumor microenvironments. This metabolic flexibility is different from normal cellular metabolic processes and leads to heterogeneity in cancer metabolism within the same cancer type or even within the same tumor. In this book, the authors delve into the complexity and diversity of cancer metabolism and highlight how understanding the heterogeneity of cancer metabolism is fundamental to the development of effective metabolism-based therapeutic strategies for cancer treatment. Deciphering how cancer cells utilize various nutrient resources will enable clinicians and researchers to pair specific chemotherapeutic agents with patients who are most likely to respond with positive outcomes, allowing for more cost-effective and personalized cancer treatment. This book has four major parts. Part one will cover the basic metabolism of cancer cells, followed by a discussion of the heterogeneity of cancer metabolism in part two. Part three addresses the relationship between cancer cells and cancer-associated fibroblasts, and the new part four will explore the metabolic interplay between cancer and other diseases. This new section makes the book unique from other texts currently available on the market. The second edition will be useful for cancer metabolism researchers, cancer biologists, epidemiologists, physicians, health care professionals in related disciplines, policymakers, marketing and economic strategists, etc. It may also be used in courses such as intro to cancer metabolism, cancer biology, and related biochemistry courses for undergraduate and graduate students.