Alcohol and Cancer : Proceedings of the Third International Conference

Following the Third Alcohol and Cancer Conference, this volume compiles the most up-to-date research on the role of alcohol consumption in carcinogenesis, from epidemiology to pathology metabolism and stem cells. More specifically, it delves into the effects of alcohol consumption and thyroid cancer, CD133+ progenitor cells, carcinogenic iron accumulation, developmental morphogens, and cancer-inducing epigenetic changes. __Alcohol and Cancer: Proceedings of the Third International Conference__ is a timely update to __Biological Basis of Alcohol-Induced Cancer__, which followed the Second Alcohol and Cancer Conference, compiling cutting-edge research from graduate students, young scientists, and researchers. It is ideal for graduate students and researchers in oncology, hepatology, epigenetics, and alcohol consumption. Preface 5 Contents 7 Contributors 9 Chapter 1: Alcohol Consumption and Risk of Thyroid Cancer: A Population Based Case-Control Study in Connecticut 13 1.1 Introduction 14 1.2 Materials and Methods 15 1.3 Results 16 1.4 Discussion 20 References 24 Chapter 2: Roles of Cytochrome P450 in Metabolism of Ethanol and Carcinogens 27 2.1 Introduction to Cytochrome P450 (P450) 28 2.2 P450 2E1 30 2.3 Ethanol Oxidation by P450 2E1 32 2.4 Source of Oxidative Stress Due to P450 2E1 in Tissues 34 2.5 Roles of Mitochondrial P450s 35 2.6 Future Questions 40 References 43 Chapter 3: Glutathione and Transsulfuration in Alcohol-Associated Tissue Injury and Carcinogenesis 48 3.1 Introduction 49 3.2 GSH Biosynthesis, Metabolism and Function 50 3.3 The Transsulfuration Pathway 52 3.4 Glutathione and Transsulfuration in Alcohol-Related Non-Cancerous Diseases 53 3.5 Alcohol-Mediated Carcinogenesis 55 3.6 GSH and Transsulfuration in Cancer Biology and Alcohol-Related Cancers 56 3.7 Concluding Remarks 58 References 59 Chapter 4: Fatty Liver Disease and Hepatocellular Carcinoma: The Pathologist’s View 65 4.1 Introduction 65 4.2 Epidemiology 66 4.2.1 ALD-related HCC 66 4.2.2 NAFLD-related HCC 67 4.3 Pathogenesis 68 4.3.1 ALD-related HCC 68 4.3.2 NAFLD-related HCC 69 4.4 Diagnosis 69 4.5 Histopathology 70 4.5.1 ALD-related HCC 70 4.5.2 NAFLD-related HCC 72 4.6 Management 73 4.7 Epilogue 74 References 75 Chapter 5: Alcoholic Liver Disease Accelerates Early Hepatocellular Cancer in a Mouse Model 80 5.1 Introduction 80 5.2 New Model of HCC in Mice with Alcoholic Liver Disease 81 5.3 Liver Damage, Histology and Tumor Characteristics 81 5.4 Role of Inflammation in HCC 83 5.5 Markers of Stemness and Carcinogenesis 84 5.6 MicroRNA-122 84 5.7 Summary and Relevance to Human Disease 85 References 87 Chapter 6: Chronic Ethanol Consumption and Generation of Etheno-DNA Adducts in Cancer-Prone Tissues 89 6.1 Introduction 90 6.2 Etheno-DNA Adducts: Formation and Significance 90 6.3 Etheno-DNA Adducts in ALD and NAFLD: The Role of CYP2E1 Induction and Inflammation 93 6.4 Etheno DNA Adducts (εdA) in Alcohol Consuming Rodent Models and ALD Patients 95 6.5 Etheno DNA Adducts in Animal Models of NASH with and Without Additional Alcohol Administration and in NASH Patients 96 References 97 Chapter 7: Role of TGF-β in Alcohol-Induced Liver Disease 101 7.1 Background and Significance 102 7.2 Overview of TGF-β Signaling 102 7.3 Modulation of TGF-β Signal Transduction 103 7.4 Alcohol Induced TGF-β Signaling 105 7.5 Defective TGF-β Signaling in Cirrhosis and Hepatocellular Carcinoma 106 7.6 The Role of TGF-β in Genomic Stability and Stem Cell Disorder Beckwith-Wiedemann Syndrome 107 References 109 Chapter 8: NANOG-Dependent Metabolic Reprogramming and Symmetric Division in Tumor-Initiating Stem-like Cells 113 8.1 Introduction 113 8.2 Synergistic Risk Factors for Alcohol-Associated HCCs 114 8.3 Genesis of TICs Induced by Alcohol Exposures 115 8.4 TLR4/NANOG-Dependent TICs Give Rise to Tumors 115 8.5 Metabolic Reprogramming and TIC Self-Renewal 115 8.6 Cell Fate Determinant NUMB and Oncogenesis in TICs 116 8.7 Conclusions and Discussions 117 References 118 Chapter 9: Diet Supplementation with Soy Protein Isolate, but Not the Isoflavone Genistein, Protects Against Alcohol-Induced Tumor Progression in DEN-Treated Male Mice 122 9.1 Introduction 123 9.2 Materials and Methods 124 9.2.1 In Vivo Mouse Model of DEN-EtOH Liver Tumor Promotion 124 9.2.2 Tumor Pathology 125 9.2.3 Biochemical Analysis of Liver Injury and Inflammation 125 9.2.4 Analysis of Ceramide-Sphingosine Signaling 126 9.2.5 Hepatocyte Proliferation and β-Catenin Signaling 126 9.2.6 Data and Statistical Analysis 126 9.3 Results and Discussion 127 References 131 Chapter 10: ALDH1L1 and ALDH1L2 Folate Regulatory Enzymes in Cancer 134 10.1 Introduction 134 10.2 Folate: Overview 135 10.3 Interactions Between Alcohol Consumption and Dietary Folate: Implication for Cancer 136 10.4 ALDH1L1 Role in Cancer 138 10.5 Role of Mitochondrial ALDH1L2 Enzyme in Cancer 140 10.6 Effect of Ethanol on ALDH1L1/L2 Genes and Proteins 142 10.7 Conclusion 143 References 144 Chapter 11: Developmental Morphogens & Recovery from Alcoholic Liver Disease 151 11.1 Summary 155 References 155 Chapter 12: Suppressed Fat Mobilization Due to PNPLA3 rs738409 -Associated Liver Damage in Heavy Drinkers: The Liver Damage Feedback Hypothesis 158 12.1 Introduction 159 12.2 Health Statistics of ALD 159 12.3 Genetic Confounders: (Role of PNPLA3) 160 12.4 Discovery of the PNPLA3 Polymorphism rs738409 and Its Role in ALD 161 12.5 Role of PNPLA3 rs738409 in Alcoholic Cirrhosis/Advanced Fibrosis 164 12.6 Role of PNPLA3 in Cancer Progression (HCC) 164 12.7 Potential Physiological Functions of PNPLA3 166 12.7.1 Enzyme Function 167 12.7.2 In Vivo Studies 168 12.8 Recent Findings from the Heidelberg Mono–Center Cohort of Heavy Drinkers – The Role of Alcohol Withdrawal 168 12.9 Evidence of Suppressed Fat Mobilization in the Heidelberg Cohort 169 12.10 Reduced Fat Mobilization Due to PNPLA3-Associated Liver Damage: The Liver Damage Feedback Hypothesis 172 12.11 Other Genetic Variations that Promote ALD 173 12.12 Conclusion and Future Perspectives 173 References 173 Chapter 13: Aldo-Keto Reductases: Multifunctional Proteins as Therapeutic Targets in Diabetes and Inflammatory Disease 178 13.1 Introduction 178 13.2 Function of AR in Cellular Responses 179 13.2.1 Inflammation 179 13.2.2 Intersection of Glucose Metabolism and Inflammatory Signaling 180 13.2.3 Oxidative Stress 181 13.3 AR and Complications of Diabetes and Chronic Hyperglycemia 182 13.3.1 Heart 183 13.3.1.1 Myocardial Ischemic Injury 183 13.3.1.2 Cardiomyopathy 184 13.3.2 Kidney 184 13.3.2.1 Nephropathy 184 13.3.2.2 Acute Kidney Injury 185 13.3.3 Peripheral Nervous System Disorders 185 13.3.3.1 Diabetic Peripheral Neuropathy 185 13.3.3.2 Cardiac Autonomic Neuropathy 186 13.3.4 Ocular Disorders 187 13.3.4.1 Uveitis 187 13.3.4.2 Diabetic Cataract 188 13.3.4.3 Diabetic Retinopathy 188 13.3.4.4 Posterior Capsule Opacification 190 13.4 Summary and Future Directions 191 13.4.1 Novel AR Inhibitors 191 13.4.2 A role for AR in Ocular Inflammation 192 13.4.3 Studies of AR as a Mediator of EMT During Development of Posterior Capsule Opacification 194 References 195 Chapter 14: Engineered Animal Models Designed for Investigating Ethanol Metabolism, Toxicity and Cancer 208 14.1 Introduction 209 14.2 Animal Models for Alcohol-Induced Cancer 210 14.3 Mouse Models with Genetic Deficiencies in Ethanol-Metabolizing Enzymes 211 14.3.1 Adh1 Global Knockout 211 14.3.2 Catalase Global Knockout 213 14.3.3 Cyp2e1 Global Knockout 214 14.3.4 Cat and Cyp2e1 Global Double-Knockout 214 14.4 Mouse Models with Genetic Deficiencies in Acetaldehyde-Metabolizing Enzymes 215 14.4.1 Aldh2 Global Knockout 215 14.4.2 Aldh1b1 Global Knockout 216 14.4.3 ApcF/FCdx2ERT2–Cre/Aldh1b1–/– Mutant 217 14.4.4 Aldh1a1 Global Knockout 217 14.4.5 Aldh1b1 and Aldh1a1 Double Knockout 218 14.4.6 Aldh1b1 and Aldh2 Global Double-Knockout 218 14.4.7 Global Aldh3a1 Single and Aldh1a1/Aldh3a1 Double Knockouts 218 14.4.8 Aldh3a1C244A and Aldh1a1C303A Knock-in Mice 219 14.5 Mouse Models with Glutathione Deficiency 219 14.5.1 Gclc Conditional (Gclcf/f) Knockout 220 14.5.2 Global Gclm (Gclm–/–) knockout 220 14.5.3 Gclm and Nrf2 Global Double-Knockout 221 14.6 Concluding Remarks 221 References 221 Author Index 227 Subject Index 268 Front Matter ....Pages i-xii Alcohol Consumption and Risk of Thyroid Cancer: A Population Based Case-Control Study in Connecticut (Huang Huang, Nan Zhao, Yingtai Chen, Nicole Deziel, Min Dai, Ni Li et al.)....Pages 1-14 Roles of Cytochrome P450 in Metabolism of Ethanol and Carcinogens (F. Peter Guengerich, Narayan G. Avadhani)....Pages 15-35 Glutathione and Transsulfuration in Alcohol-Associated Tissue Injury and Carcinogenesis (Ying Chen, Ming Han, Akiko Matsumoto, Yewei Wang, David C. Thompson, Vasilis Vasiliou)....Pages 37-53 Fatty Liver Disease and Hepatocellular Carcinoma: The Pathologist’s View (Dina G. Tiniakos, João Maurício, Helen L. Reeves)....Pages 55-69 Alcoholic Liver Disease Accelerates Early Hepatocellular Cancer in a Mouse Model (Gyongyi Szabo)....Pages 71-79 Chronic Ethanol Consumption and Generation of Etheno-DNA Adducts in Cancer-Prone Tissues (Teresa Peccerella, Tatjana Arslic-Schmitt, Sebastian Mueller, Kirstin-Berit Linhart, Devanshi Seth, Helmut Bartsch et al.)....Pages 81-92 Role of TGF-β in Alcohol-Induced Liver Disease (Wilma Jogunoori, Lopa Mishra)....Pages 93-104 NANOG-Dependent Metabolic Reprogramming and Symmetric Division in Tumor-Initiating Stem-like Cells (Keigo Machida)....Pages 105-113 Diet Supplementation with Soy Protein Isolate, but Not the Isoflavone Genistein, Protects Against Alcohol-Induced Tumor Progression in DEN-Treated Male Mice (K. E. Mercer, C. F. Pulliam, L. Hennings, M. A. Cleves, E. E. Jones, R. R. Drake et al.)....Pages 115-126 ALDH1L1 and ALDH1L2 Folate Regulatory Enzymes in Cancer (Sergey A. Krupenko, Natalia I. Krupenko)....Pages 127-143 Developmental Morphogens & Recovery from Alcoholic Liver Disease (Anna Mae Diehl)....Pages 145-151 Suppressed Fat Mobilization Due to PNPLA3 rs738409 -Associated Liver Damage in Heavy Drinkers: The Liver Damage Feedback Hypothesis (Vanessa Rausch, Sebastian Mueller)....Pages 153-172 Aldo-Keto Reductases: Multifunctional Proteins as Therapeutic Targets in Diabetes and Inflammatory Disease (Kun-Che Chang, J. Mark Petrash)....Pages 173-202 Engineered Animal Models Designed for Investigating Ethanol Metabolism, Toxicity and Cancer (Stephanie Marshall, Ying Chen, Surendra Singh, Pablo Berrios-Carcamo, Claire Heit, Nicholas Apostolopoulos et al.)....Pages 203-221 Back Matter ....Pages 223-271