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Biological Basis of Alcohol-Induced Cancer - Vasilis Vasiliou

Year 2015


Chapter 1 IntroductionChapter 2 Alcohol and Breast Cancer: Reconciling Epidemiological and Molecular Data2.1 Introduction2.2 The Biology of Breast Cancer2.3 Known Risk Factors for Breast Cancer2.4 Alcohol as a Risk Factor for Breast Cancer2.4.1 Epidemiological Studies2.4.2 Molecular Studies2.4.2.1 Estrogen Metabolism2.4.2.2 Alcohol Metabolism2.4.2.3 Folate Metabolism/Epigenetic Factors2.5 Concluding Remarks2.5.1 Multiple Risk Factors2.5.2 Epidemiological Studies2.5.3 Discrepancies Between Epidemiological and Molecular StudiesChapter 3 Genetic–Epidemiological Evidence for the Role of Acetaldehyde in Cancers Related to Alcohol Drinking3.1 Introduction3.2 General Evidence for the Carcinogenicity of Acetaldehyde3.3 Genetic–Epidemiological Evidence for the Carcinogenicity of Acetaldehyde3.3.1 Basic Difficulties in Assessing the Genetic– Epidemiological Evidence3.3.2 Upper Aerodigestive Tract Cancer3.3.3 Gastric Cancer3.3.4 Colorectal Cancer3.3.5 Pancreatic Cancer3.3.6 Liver Cancer3.3.7 Lung Cancer3.3.8 Breast Cancers3.4 Summary and ConclusionsChapter 4 Alcohol and Cancer: An Overview with Special Emphasis on the Role of Acetaldehyde and Cytochrome P450 2E14.1 Introduction4.1.1 Historic Background4.1.2 Epidemiology and Animal Experiments4.2 Specific Mechanisms of Ethanol-Mediated Carcinogenesis4.2.1 Acetaldehyde as a Carcinogen4.2.1.1 Mechanisms4.2.1.2 Genetic Aspects of Acetaldehyde Accumulation4.2.2 Alcohol and Oxidative Stress4.2.2.1 Mechanisms of ROS and Cytochrome P450 2E1 in Alcohol-Mediated Carcinogenesis4.2.2.2 The Role of CYP2E1 in Experimental Carcinogenesis4.3 CYP2E1 and Its Role in Nonalcoholic Fatty Liver DiseasesChapter 5 Implications of Acetaldehyde-Derived DNA Adducts for Understanding Alcohol-Related Carcinogenesis5.1 Introduction5.2 DNA Adducts from Acetaldehyde and Alcohol5.2.1 Other Acetaldehyde-DNA Adducts5.3 N2-Ethylidene-dG as a Biomarker of DNA Damage Resulting from Acetaldehyde Derived from Ethanol5.3.1 Experimental Studies of Acetaldehyde-DNA Adduct Formation from Alcohol Drinking in Humans5.3.2 Anatomical Considerations5.4 Why Are ALDH2-Deficient Individuals at Such Elevated Risk of Esophageal Cancer from Drinking Alcohol?5.5 Is There a “Carcinogenic” Level of Acetaldehyde?5.6 Summary and ConclusionsChapter 6 The Role of Iron in Alcohol-Mediated Hepatocarcinogenesis6.1 Introduction6.2 Health Statistics of ALD6.3 Prevalence of Iron Overload in ALD6.4 Iron Toxicity and Carcinogenesis6.5 Mechanism of Iron Overload6.6 Systemic Regulation6.7 Cellular Iron Regulation6.8 Redox Regulation of Iron Metabolism6.9 Non-hepatic Causes of Alcohol-Mediated Iron Overload6.9.1 Alcohol and Hematopoietic System6.9.2 Alcohol and Hemolysis6.9.3 Alcohol and Nutrition6.10 Hepatic Causes of Iron Overload in ALD6.11 ALD in the Context of Iron Overload6.12 SummaryChapter 7 Alcoholic Cirrhosis and Hepatocellular Carcinoma7.1 Introduction7.2 Epidemiology7.3 Pathophysiology7.3.1 Tissue Remodelling as the Priming Condition for HCC7.4 Alcohol as a Risk Factor for HCC in Non-alcoholic Liver Diseases7.4.1 Coexisting Chronic Viral Hepatitis7.4.2 Hepatitis B7.4.3 Hepatitis C7.5 Non-alcoholic Fatty Liver Disease7.6 Alcohol-Mediated Activation of Environmental Carcinogens7.7 Ethanol Metabolism and HCC7.8 Acetaldehyde7.9 Oxidative Stress7.10 Alcohol and Altered DNA Methylation7.11 Alcohol with Retinoids7.12 Host Genetics and Alcohol-Associated HCC7.13 Summary and ConclusionChapter 8 TLR4-Dependent Tumor-Initiating Stem Cell-Like Cells (TICs) in Alcohol-Associated Hepatocellular Carcinogenesis8.1 Introduction8.2 Ectopic TLR4 Activation Underlies HCV-Alcohol Synergism8.3 Identification of TLR4/NANOG-Dependent TICs8.4 TLR4 as a Putative Proto-oncogene8.5 TLR4 and TGF-β Mutual Antagonism in Liver Tumorigenesis8.6 Anabolic Metabolism and TIC Self-Renewal8.7 Conclusions and DiscussionsChapter 9 Synergistic Toxic Interactions Between CYP2E1, LPS/TNFα, and JNK/p38 MAP Kinase and Their Implications in Alcohol-Induced Liver Injury9.1 Introduction9.2 Kupffer Cells and Alcoholic Liver Disease9.3 CYP2E19.4 LPS/TNFα–CYP2E1 Interactions9.5 Pyrazole Potentiates LPS toxicity [51, 52]9.6 Pyrazole Potentiates TNFα Toxicity [53, 54]9.7 Role of CYP2E1 in Pyrazole Potentiation of LPS and TNFα Toxicity9.8 Mitochondrial Dysfunction9.9 Cyclosporine A Prevents Pyrazole Plus LPS-Induced Liver Injury [57]9.10 Activation of MAP Kinases9.11 Activation of ASK-1 and Downstream MAP Kinase Kinases9.12 Effect of N-Acetylcysteine9.13 Hepatotoxicty by CYP2E1 Plus TNFα Occurs in JNK2 but not JNK1 Knockout Mice9.14 ConclusionsChapter 10 Understanding the Tumor Suppressor PTEN in Chronic Alcoholism and Hepatocellular Carcinoma10.1 ALD and Cancer10.2 The PTEN Tumor Suppressor10.3 PTEN and ALD10.4 Posttranslational Modifications of PTEN10.5 ConclusionsChapter 11 Alcohol Consumption, Wnt/β-Catenin Signaling, and Hepatocarcinogenesis11.1 Introduction11.2 Materials and Methods11.2.1 In Vivo Model of EtOH Promotion of DEN-Induced Hepatocarcinogenesis11.2.2 Pathological Evaluation11.2.3 Immunohistochemistry11.2.4 Retinoid Extraction and LC/MS/MS Analysis11.2.5 Protein Isolation and Western Blotting11.2.6 Gene Expression11.2.7 Data and Statistical Analysis11.3 Results and DiscussionChapter 12 Alcohol and HCV: Implications for Liver Cancer12.1 Introduction12.2 Alcohol, HCV and Innate Immunity12.2.1 Antiviral Immunity in HCV Infection and Alcohol Use12.2.2 Mechanisms of Inflammation12.3 Cancer Surveillance in HCV Infection and Alcohol Use12.3.1 NK Cells12.3.2 Antigen Presenting Cells in HCV Infection12.4 Alcohol and HCV Replication, Role of Micro-RNAs12.4.1 Oxidative Stress12.4.2 Modulation of HCV Replication by Alcohol Via HSP9012.4.3 Role of Micro-RNA 12212.5 SummaryChapter 13 Application of Mass Spectrometry-Based Metabolomics in Identification of Early Noninvasive Biomarkers of Alcohol-Induced Liver Disease Using Mouse Model13.1 Introduction13.1.1 Alcohol and Alcohol-Induced Liver Disease13.1.2 The Role of PPARα in ALD13.1.3 Diagnosis of ALD13.1.4 Scope of Metabolomics13.2 Methodological Overview for Urinary Metabolomics13.2.1 Animal Model13.2.2 Step 1: Preparation of Urine Samples for UPLC-ESI-QTOFMS Analysis13.2.3 Step 2: UPLC-ESI-QTOFMS Analysis of Urine Samples13.2.4 Step 3: Data Deconvolution and Feature Extraction13.2.5 Step 4: Multivariate Data Analysis13.2.6 Step 5: Metabolic Pathway Analysis13.2.7 Step 6: Identification of Urinary Biomarkers13.2.8 Step 7: Quantitation of Urinary Metabolites13.2.9 Effect of Genetic Background on Metabolomic Signatures13.3 Animal Study Design13.4 Results and Discussion13.4.1 PCA Analysis of Metabolomic Data13.4.2 Metabolic Pathway Analysis13.4.3 Identification and Quantitation of Metabolites13.4.4 Potential Use of Metabolic Signature in Detection of Alcohol Intake and ALD Susceptibility13.4.5 Effect of Genetic Background on Metabolic Signatures13.4.6 The Biochemical Origin of ALD Biomarkers13.5 Summary and Future DirectionsChapter 14 Alcohol Metabolism by Oral Streptococci and Interaction with Human Papillomavirus Leads to Malignant Transformation of Oral Keratinocytes14.1 Ethanol, Bacteria, Human Papillomavirus, and Oral Cancer14.2 Ethanol Metabolism by Oral Streptococci14.2.1 Selection of a Representative Strain14.2.2 Construction of adh Mutants in S. gordonii V201614.2.3 Acetaldehyde Production by S. gordonii V2016 adh Mutants14.2.4 Alcohol Dehydrogenases of S. gordonii V201614.2.5 Absence of ALDH in S. gordonii V201614.2.6 Substrate Specificities of S. gordonii ADHs14.2.7 ADH/ALDH Profiles Vary Among Strains of Oral Streptococcus14.2.8 Effect of adh Deletions on Bacterial Growth in Medium Containing Ethanol or Acetaldehyde14.3 Ethanol Metabolism by Oral Streptococci Increases Bacterial Adhesion, HPV Entry, and HPV-Mediated Malignant Transformation of Oral Keratinocytes14.3.1 Ethanol Metabolites Production by Bacteria and Toxicity to Keratinocytes14.3.2 Ethanol Exposure Promotes Attachment of Streptococci to HOK14.3.3 Ethanol Metabolism by Oral Streptococci Promotes HPV 16 Entry into HOK14.3.4 Malignant Transformation of HOK Cells14.4 Possible Study Limitations14.5 SummaryChapter 15 Genetic Polymorphisms of Alcohol Dehydrogense-1B and Aldehyde Dehydrogenase-2, Alcohol Flushing, Mean Corpuscular Volume, and Aerodigestive Tract Neoplasia in Japanese Drinkers15.1 Endoscopy and Esophageal Iodine Staining of Screening Japanese Alcoholic Men for Upper Aerodigestive Tract Neoplasia15.2 ALDH2 Genotype and Alcohol Metabolism15.3 ALDH2 Genotype and Squamous Cell Neoplasia in the UADT15.4 The Simple Flushing Questionnaire15.5 Mass-Screening for SCC of the UADT by Means of Health-Risk Appraisal Models15.6 ADH1B Genotype, Alcohol Metabolism, and SCC of the UADT15.7 The ADH1B*1/*1 and ALDH2*1/*2 Genotype Combination and SCC in the UADT15.8 ADH1B and ALDH2 Genotype and Liver Disease in Japanese Alcoholic Men15.9 Gastric Cancer in Japanese Alcoholic Men15.10 Colonoscopic Screening of Japanese Alcoholic Men for Colorectal Neoplasia15.11 Association Between a High Mean Corpuscular Volume and Increased Risk of Aerodigestive Tract Neoplasia in Japanese Alcoholic Men15.12 ConclusionsChapter 16 Acetaldehyde and Retinaldehyde-Metabolizing Enzymes in Colon and Pancreatic Cancers16.1 Introduction16.2 Acetaldehyde: A carcinogen16.3 Opposing Effects of Retinoic Acid on Cancer Cell Proliferation16.4 ALDHs and Cancer Stem Cells16.4.1 Colorectal Cancer16.4.2 Pancreatic Cancer16.5 SummaryChapter 17 Alcohol, Carcinoembryonic Antigen Processing and Colorectal Liver Metastases17.1 Introduction17.2 Disease Impact: CRC and Liver Metastases17.2.1 Colon Carcinoma, Alcohol Comorbidity, and Metastasis17.2.2 Colorectal Liver Metastases17.3 The Carcinoembryonic Antigen, Colon Adenocarcinoma, and Liver Metastasis17.3.1 CEA and Colorectal Cancer17.3.2 CEA and Liver Metastasis17.3.3 Contribution of Liver Cell CEA Degradation in CRC Liver Metastasis17.3.3.1 Kupffer Cell Metabolism of CEA17.3.3.2 Hepatocellular CEA Processing17.4 The Role of Alcohol in CEA Processing and Potential to Promote CRC Liver Metastasis17.4.1 Effect of Alcohol on Liver Cells17.4.1.1 Effect of Alcohol on Kupffer Cells17.4.1.2 Alcohol-Mediated Defects to the Hepatocyte ASGPR and Asialo-CEA Processing17.5 SummaryChapter 18 Alcohol Consumption and Antitumor Immunity: Dynamic Changes from Activation to Accelerated Deterioration of the Immune System18.1 Introduction18.2 Animal Model of Chronic Alcohol Consumption and B16BL6 Melanoma Inoculation18.2.1 Alcohol Administration18.2.2 Tumor Inoculation18.3 Chronic Alcohol Consumption Inhibits B16BL6 Melanoma Lung Metastasis in an IFN-γ Signaling Pathway-Dependent Fashion18.4 Effects of Chronic Alcohol Consumption on T Cells: Induction of T Cell Activation Through Homeostatic Proliferation in the Steady State and Acceleration of T Cell Dysfunction in Melanoma-Bearing Mice18.5 Effects of Chronic Alcohol Consumption on NK Cells: Impaired NK Cell Release from the Bone Marrow and Decreased Mature NK Cells in the Periphery18.6 Effects of Chronic Alcohol Consumption on B Cells: Impaired B Cell Circulation in B16BL6 MelanomaBearing Mice18.7 Effects of Chronic Alcohol Consumption on iNKT Cells: Increased Mature iNKT Cells That Produce an IFN-γ-Dominant Th1 Cytokine Profile in the Steady State, and an IL-4 Dominant Th2-Cytokine Profile in Melanoma-Bearing Mice18.8 Immunological Basis of Chronic Alcohol Consumption on Tumor Surveillance, Progression, and the Survival of Cancer Patients18.9 Prospective and Possible Strategies for Tumor Immunotherapy in Alcoholics18.10 Overall Summary and Concluding Remarks18.11 Future Directions of Research in Alcohol and Tumor ImmunologyChapter 19 A Perspective on Chemoprevention by Resveratrol in Head and Neck Squamous Cell Carcinoma19.1 Introduction19.1.1 Head and Neck Squamous Cell Carcinoma19.1.2 Major Molecular and Genetic Predispositions in HNSCC19.1.3 Alcohol: Carcinogen or Co-carcinogen in HNSCC19.1.3.1 Alcohol Metabolism and Metabolic Enzymes19.1.3.2 Alcohol: DNA Damage and DNA Repair19.1.3.3 Alcohol Interacts with Oncogenes and Tumor Suppressor Pathways19.1.3.4 Alcohol and Nutrition19.1.4 Chemoprevention19.1.4.1 Biologic Basis of Chemoprevention19.1.5 Resveratrol as Chemopreventive Agent19.1.5.1 Resveratrol in Xenometabolism19.1.5.2 Resveratrol: As Anti-inflammatory Agent19.1.5.3 Resveratrol: Cell Growth and Death Regulatory Pathways19.1.5.4 Resveratrol: An Antioxidant19.1.5.5 Resveratrol: Interaction with DNA Polymerase, Topoisomerase, and Telomerase19.1.5.6 Resveratrol: DNA Damage and DNA Damage Repair19.1.5.7 Resveratrol: Clinical Studies19.1.6 Conclusions and Prospect of Resveratrol in HNSCCChapter 20 The Effects of Alcohol and Aldehyde Dehydrogenases on Disorders of Hematopoiesis20.1 Hematopoiesis20.2 Myelodysplasia and Acute Leukemia20.3 The Effects of Alcohol on Hematopoiesis20.3.1 Alcohol and the Risk of MDS and Leukemia20.4 ALDH and HSCs20.5 A Possible Model for Ethanol Induced Bone Marrow Damage and Development of MDS/AMLChapter 21 The Effect of Alcohol on Sirt1 Expression and Function in Animal and Human Models of Hepatocellular Carcinoma (HCC)21.1 Introduction21.2 Materials and Methods21.3 Results21.4 Discussion21.5 ConclusionChapter 22 Transgenic Mouse Models for Alcohol Metabolism, Toxicity, and Cancer22.1 Introduction22.2 Clinical Significance of Human Polymorphisms of Genes Involved in Ethanol Metabolism22.3 Animal Models for Alcohol-Induced Cancer22.4 Glutathione in Alcoholic Tissue Injury22.5 Mouse Models with Genetic Deficiencies in Ethanol-Metabolizing Enzymes22.6 Mouse Models with Genetic Deficiencies in Acetaldehyde-Metabolizing Enzymes22.7 Mouse Models with GSH Deficiency22.8 Concluding RemarksChapter 23 Fetal Alcohol Exposure Increases Susceptibility to Carcinogenesis and Promotes Tumor Progression in Prostate Gland23.1 Introduction23.2 Fetal Alcohol Promotion of Prostate Cancer23.3 Fetal Alcohol, Prostate Estrogenization, and Cancer23.3.1 Evidence for an Increased Estrogen Production in the Prostate23.3.2 Connection between the Developmental Estrogenization and Prostatic Neoplasia23.4 Fetal Alcohol, Neuroimmune Axis Abnormalities, and Cancer23.4.1 Neuroendocrine–Immune System and Tumor Surveillance23.4.2 Neuroendocrine–Immune System Abnormalities and Prostatic Neoplasia23.5 ConclusionsChapter 24 Fetal Alcohol Exposure and Mammary Tumorigenesis in Offspring: Role of the Estrogen and Insulin-Like Growth Factor Systems24.1 Introduction24.2 Overview of Mammary Gland Development24.3 Role of Estrogen in Mammary Gland Development and Breast Cancer24.4 Role of the IGF System in Normal Mammary Gland Biology and Breast Cancer24.5 Cross-Talk Between the E2 and IGF Systems24.6 Evidence for Alterations in E2 and IGF Systems in Alcohol-Exposed Offspring24.7 Fetal Alcohol and Epigenetics
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