The Pathobiology of Neoplasia

Introduction: Chronology of Significant Events in the Study of Neoplasia.- 1. Classification of Neoplasms.- 1. Introduction.- 2. Non-Neoplastic Adaptive Growth Changes.- 2.1. Atrophy.- 2.2. Hypertrophy.- 2.3. Hyperplasia.- 2.4. Metaplasia.- 2.5. Dysplasia.- 3. Preneoplastic Lesions and Malformations.- 4. Anaplasia and Differentiation in Neoplasms.- 5. Pathobiologic Characteristics of Benign and Malignant Neoplasms.- 6. Nomenclature of Neoplasms.- 7. Grading and Staging of Malignant Neoplasms.- References.- 2. Chemical Carcinogenesis in Experimental Animals and Humans.- 1. Background.- 2. Metabolism of Chemical Carcinogens.- 2.1. Aromatic Compounds.- 2.2. Aliphatic Compounds.- 2.3. Miscellaneous.- 3. Classification of Chemical Carcinogens.- 3.1. Direct-Acting versus Indirect-Acting Carcinogens.- 3.2. Genotoxic versus Epigenetic Carcinogens.- 3.3. Initiators and Promoters.- 4. Structure-Activity Relationships.- 5. Relevance to Humans.- References.- 3. DNA Adducts and Carcinogenesis.- 1. General Considerations.- 2. DNA Adduct Determination and Quantitation.- 3. DNA Adducts from Specific Classes of Carcinogens.- 3.1. N-Nitrosamines.- 3.2. Aflatoxins.- 3.3. Aromatic Amines.- 3.4. Polycyclic Aromatic Hydrocarbons.- 4. Conclusions.- References.- 4. Oncogenic Viruses.- 1. Introduction.- 1.1. Purpose.- 1.2. Overview and Historic Events.- 1.3. Classification.- 2. Host Cells, Tumor Viruses, and Their Interactions.- 2.1. Host Cells.- 2.2. Tumor Viruses.- 2.3. Interactions: Proto-Oncogenes and Retro-Oncogenes.- 3. Common Pathways of Cell Transformation and Neoplasia: Unifying Features of Viral Oncogenesis.- 3.1. Virus-Induced Transformation.- 3.2. Unifying Features of Viral Carcinogenesis.- 4. Pathobiology of Oncogenic Viruses and Experimental Animal Models of Virus-Induced Human Neoplasia.- 4.1. DNA Tumor Viruses.- 4.2. RNA Tumor Viruses.- 5. Immunologic Aspects of Virus-Induced Neoplasia.- 5.1. Virus-Associated Antigens.- 5.2. Effector Mechanisms of Virus-Induced Tumor Immunity.- 6. Concluding Remarks.- References.- 5. Radiation Carcinogenesis.- 1. Introduction.- 1.1. Historic Perspective.- 1.2. Ionizing Radiation and Its Interaction with Matter.- 2. Radiation Carcinogenesis in Vivo.- 2.1. The Human Experience.- 2.2. Radiation Carcinogenesis in Animal Models.- 3. Pathology of Radiation Carcinogenesis in Vivo.- 3.1. Incidence and Morphology.- 3.2. Relative Tissue Sensitivity.- 3.3. Latency.- 4. Radiation Transformation in Vitro.- 4.1. Experimental Techniques.- 4.2. Properties of Transformed Cells.- 5. Factors Influencing Radiation Carcinogenesis or Transformation.- 5.1. Physical Factors.- 5.2. Host/Environmental Factors.- 6. Pathogenesis of Radiation Carcinogenesis.- 6.1. Multistep Process: Initiation and Promotion.- 6.2. DNA as a Critical Target.- 6.3. Oncogenes in Radiation Carcinogenesis.- 7. Conclusion.- References.- 6. The Multistage Concept of Carcinogenesis.- 1. Types of Tumorigenic Enhancement.- 2. Multistage Skin Tumorigenesis.- 3. Multistage Tumorigenesis in Nonepidermal Systems.- 3.1. Bladder.- 3.2. Liver.- 3.3. Respiratory Tract.- 3.4. Intestine.- 3.5. Mammary Gland.- 3.6. Other Nonepidermal Systems.- 4. Multistage Models of Neoplasia in Cell-Culture Systems.- 4.1. Measurement of Multistage Development of Cell Transformation.- 4.2. Measurement of Promoter-Induced Changes in Intercellular Relationships.- 4.3. Measurement of Promoter-Induced Changes in Membrane Function.- 4.4. Measurement of Changes in Cellular Differentiation.- 5. Conclusions.- References.- 7. Organ and Species Specificity in Chemical Carcinogenesis and Tumor Promotion.- 1. Introduction.- 2. Organ and Species Specificity Attributable to Metabolism.- 3. Biologic Effects of Alkylating Agents.- 3.1. Direct-Acting Compounds.- 3.2. Metabolism-Dependent Compounds.- 3.3. Molecular Targets of Alkylating Agents.- 4. Organ and Species Specificity in Tumor Promotion.- 4.1. Promotion in Squamous Epithelia.- 4.2. Promotion in Nonsquamous Epithelia.- 4.3. Dietary Factors That Promote Carcinogenesis.- References.- 8. DNA Repair Mechanisms and Carcinogenesis.- 1. Introduction.- 2. Damage to DNA.- 3. DNA Repair Systems.- 3.1. Direct Repair of Damage.- 3.2. Excision Repair.- 4. Relationship of DNA Repair to Carcinogenesis.- 4.1. Causes of Incomplete DNA Repair.- 4.2. Mechanisms for Tolerating Unrepaired DNA Damage.- 5. Summary.- References.- 9. Preneoplasia and Precancerous Lesions.- 1. Introduction.- 2. Preneoplastic and Precancerous Lesions in Experimental Animals.- 2.1. Squamous Cell Papilloma as a Precancerous Lesion in Mouse Skin Carcinogenesis.- 2.2. Precursor Lesions Associated with Hepatocarcinogenesis in the Rat.- 3. Preneoplastic and Precancerous Lesions in Humans.- 3.1. Cervical Dysplasia and Carcinoma in Situ of the Uterine Cervix.- 3.2. Adenomatous Polyps of the Colon and Rectum.- 3.3. Dysplastic Nevi.- 3.4. Liver Cell Dysplasia and Adenomatous Hyperplastic Liver Nodules.- 3.5. Other Examples of Putative Epithelial Cell Preneoplasia.- 4. Conclusions.- References.- 10. Tumor Progression and the Clonal Evolution of Neoplasia.- 1 Introduction.- 2. Structural Variation in Tumors.- 3. Foulds’ General Principles of Tumor Progression.- 4. Clonal Origins of Neoplasms in Humans and Experimental Animals.- 5. Mechanisms of Tumor Progression.- 5.1. Aneuploidy and Tumor Progression.- 5.2. Oncogenes and Tumor Progression.- 6. Conclusions.- References.- 11. Cytogenetics and Human Neoplasia.- 1. Introduction.- 2. Chromosomal Symbols, Abbreviations, and Nomenclature.- 3. Computer Data Management.- 4. Constitutional versus Acquired Chromosomal Abnormalities in Cancer.- 4.1. Constitutional Chromosomal Abnormalities.- 4.2. Acquired Chromosomal Abnormalities.- 5. Cytogenetic Dissection of a Translocation between Chromosomes 9 and 22: The Philadelphia Translocation.- 5.1. The Philadelphia Translocation Occurs in Multiple Types of Leukemia and Related Disorders.- 5.2. Biology of Cell Lineages.- 5.3. Molecular Dissection of the Ph Translocation.- 6. Cytogenetic Dissection of the Acute Nonlymphocytic Leukemias.- 6.1. The French-American-British Classification of ANLL.- 6.2. Primary Chromosomal Rearrangements and Numerical Changes.- 6.3. Cytogenetic Dissection: A New Perspective on ANLL.- 7. Cytogenetic Dissection of ALL.- 8. Other Hematologic Conditions.- 9. Comments on Chromosomal Changes in Hematologic Disorders.- 10. Chromosomal Changes in CLL and Lymphoma.- 11. Cytogenetics of Solid Tumors.- References.- 12. Genetics of Susceptibility to Mouse Skin Tumor Promotion.- 1. Introduction.- 1.1. Multistage Carcinogenesis in Mouse Skin.- 1.2. Morphologic and Biochemical Effects of Tumor Promoters in Mouse Skin.- 2. Genetic Differences in Response to Skin Tumor Promoters.- 2.1. Species Differences.- 2.2. Strain Differences.- 2.3. Inheritance of Susceptibility to Phorbol Ester Skin Tumor Promotion.- 3. Morphologic Changes in Mouse Skin Potentially Important in Determining Genetic Differences in Response to Phorbol Esters.- 3.1. Hyperplasia.- 3.2. Dark Basal Keratinocytes.- 3.3. Inflammation.- 4. Biochemical and Molecular Changes Potentially Important in Determining Genetic Differences in Response to Phorbol Esters.- 4.1. Receptor-Mediated Events.- 4.2. Phorbol Ester Metabolism.- 4.3. Other Mechanisms.- 5. Genetic Differences in Response to Stage-Specific Promoters in Mouse Skin.- 5.1. Two-Stage Promotion.- 5.2. Genetic Differences in Response to Stage-Specific Promoters.- 6. Genetic Differences in Response to Other Classes of Tumor-Promoting Agents.- 6.1. Characteristics of the Response of Mouse Skin to Different Classes of Tumor Promoters.- 6.2. Genetic Differences in Response to Different Classes of Promoters.- 7. Use of Genetic Differences to Develop Models for Studying Mechanisms of Tumor Promotion.- 8. Concluding Remarks.- References.- 13. Oncogenes.- 1. Introduction.- 2. Retroviruses and Oncogenes.- 2.1. Acute and Chronic Transforming Retroviruses.- 2.2. Acute Transforming Retroviruses and Viral Oncogenes.- 3. Cellular Proto-Oncogenes.- 3.1. Conservation among Species.- 3.2. Cellular Proto-Oncogenes as Control Elements in Normal Cell Growth and Differentiation.- 4. Tumor Formation and Mechanisms of Activation of Cellular Proto-Oncogenes.- 4.1. Overview of Mechanisms of Activation.- 4.2. Activation of Cellular Proto-Oncogenes by Retroviral Insertion.- 4.3. Mutations Activating Proto-Oncogenes.- 4.4. Amplification of Proto-Oncogenes.- 4.5. Chromosomal Translocations in the Activation of Cellular Proto-Oncogenes.- 5. Cooperation among Activated Oncogenes in Cell Transformation.- 6. Summary.- References.- 14. Activation of Oncogenes by Chemical Carcinogens.- 1. Introduction.- 2. Activation of Proto-Oncogenes by Gene Amplification and Chromosomal Translocation.- 3. Detection of Oncogenes by Gene Transfer (DNA Transfection Assay).- 4. Activation of Proto-Oncogenes by Carcinogens.- 5. Oncogene Activation in Long-Term Rodent Carcinogenic Studies.- 6. Tissue- and Carcinogen-Specific Activation of Proto-Oncogenes.- 7. Extrapolation from Rodents to Humans.- References.- 15. Alterations in Biochemical Control Mechanisms of Neoplastic Cells.- 1. Introduction.- 2. Alterations of Membrane Transport in Neoplasia.- 2.1. Acceleration of Amino Acid Uptake by Transformed Cells-Relationship to (Na+/K+)ATPase Activity.- 2.2. Alterations in (Na+/K+)ATPase in Neoplasia.- 3. Alterations in Metabolic Pathways in Transformed Cells-Enhanced Glycolysis.- 3.1. (Na+1K+)ATPase as a Major Contributor of ADP and Pi Rate-Limiting Factors for Glycolysis.- 3.2. Role of Transforming Growth Factors in Increased Glycolysis of Transformed Cells.- 3.3. Metabolic Alterations Induced by Specific Oncogenes.- 4. Cytoskeletal Alterations in Transformed Cells.- 5. Alterations in Mitochondrial Citric Acid Cycle.- 6. Alterations in Proto-Oncogenes in Neoplasia.- 6.1. The ras Oncogene, G Proteins, and Transforming Growth Factors.- 6.2. The myc Oncogene in Burkitt Lymphomas and Murine Plasmacytomas.- 7. Conclusions.- References.- 16. Membrane Alterations in Neoplasia.- 1. Introduction.- 2. Ultrastructural Membrane Pathology of Neoplasia.- 2.1. Endomembranes.- 2.2. Lysosomes and Endocytic Compartments.- 2.3. Mitochondria and Peroxisomes.- 2.4. Plasma Membrane.- 3. Functional Alterations of Endomembranes and the Plasma Membrane in Neoplasia.- 3.1 Endoplasmic Reticulum.- 3.2. Golgi Apparatus.- 3.3. Membrane Dynamics and Membrane Recycling.- 3.4. Role of Endomembranes in Oncogene Expression.- 3.5. Plasma Membranes.- 3.6. Intercellular Communication.- 4. The Cytoskeleton in Cell Transformation and Malignant Neoplasia.- 5. Membranes and Carcinogenesis.- 5.1. Endoplasmic Reticulum and Carcinogen Activation.- 5.2. Peroxisomes and Carcinogenesis.- 5.3. Lipid Peroxidation and Carcinogenesis.- 5.4. Lysosomes and Carcinogenesis.- 6. Conclusions.- References.- 17. Growth Factors and Neoplasia.- 1. Introduction.- 2. Epidermal Growth Factor.- 3. Transforming Growth Factor-?.- 4. Platelet-Derived Growth Factor.- 5. Bombesin.- 6. Fibroblast Growth Factor(s).- 7. Interleukin-2.- 8. Insulinlike Growth Factors: IGFs and Somatomedins.- 9. Nerve Growth Factor.- 10. Macrophage Colony-Stimulating Factor-1.- 11. Transforming Growth Factor-ß.- 12. Other Growth Factors.- 13. Second Messengers Mediating Growth Factor Effects.- References.- 18. Biochemical Mechanisms of Action of the Phorbol Ester Class of Tumor Promoters.- 1. Introduction.- 2. Effects of Phorbol Esters.- 3. Receptors for Phorbol Esters.- 3.1. Identification of Receptors.- 3.2. Similarities between Phorbol Ester Receptors and Protein Kinase C.- 3.3. Evidence That Protein Kinase C Is the Major Phorbol Ester Receptor.- 4. Characterization of Protein Kinase C in Vitro.- 4.1. Domains.- 4.2. Molecular Cloning.- 4.3. Substrate Specificity.- 4.4. Activators of Protein Kinase C.- 4.5. Inhibitors of Protein Kinase C.- 5. Regulation of Phorbol Ester Receptor/Protein Kinase C in Vivo.- 5.1. Translocation and Proteolytic Processing.- 5.2. Modulation of the Affinity of Receptors for Phorbol Esters.- 5.3. Modulation of the Number of Receptors.- 6. Feedback of Protein Kinase C on Other Pathways.- 6.1. Signal Transduction.- 6.2. Phosphatidylinositol Turnover.- 6.3. Cellular Responses to Growth Factors.- 6.4. Activation of Oncogenes.- 7. Concluding Remarks.- References.- 19. Biochemical Marker Alterations in Hepatic Preneoplasia Neoplasia.- 1. Introduction.- 1.1. Relationship of Markers to Different Stages in Neoplasia.- 1.2. Approaches to Evaluation of Markers.- 2. Marker Alterations in Preneoplastic and Neoplastic Liver Lesions.- 2.1. Two-Dimensional Polyacrylamide Gel Electrophoresis.- 2.2. Known Markers of Hepatocarcinogenesis.- 2.3. New Markers for Hepatocarcinogenesis.- 2.4. Specific Markers for the Neoplastic Stage.- 3. Concluding Comments.- References.- 20. Oncogene Activation and Expression during Carcinogenesis in Liver and Pancreas.- 1. Introduction.- 1.1. Activated Oncogenes versus Proto-Oncogenes.- 1.2. Proto-Oncogene Activation by Chemical Carcinogens and Ionizing Radiation.- 2. Multistage Carcinogenesis in Liver and Pancreas.- 2.1. Initiation and Promotion in Liver.- 2.2. Initiation and Promotion in Pancreas.- 3. Proto-oncogene Activation in Liver and Pancreatic Neoplasms.- 3.1. Transforming Genes Associated with Human Liver and Pancreatic Neoplasms.- 3.2. Transforming Genes in Spontaneous and Chemically Induced Liver and Pancreatic Neoplasms.- 4. Modulation of Proto-Oncogene Expression during Liver and Pancreatic Growth.- 4.1. Growth in the Liver.- 4.2. Growth in the Pancreas.- 5. Concluding Remarks.- References.- 21. Oncodevelopmental Expression and Neoplasia.- 1 Introduction.- 2. Oncodevelopmental Antigens, Proteins, and Enzymes in Malignant Neoplasms.- 3. Concepts of Stem Cells, Blocked and Partially Blocked Ontogeny, and Retrodifferentiation in Neoplastic Cell Development.- 4. Expression of Developmental Genes during Various Non-Neoplastic Conditions and in Cell Culture.- 5. Possible Mechanisms for Developmental Gene Expression in Neoplastic and Non-Neoplastic Cells of the Adult Organism.- References.- 22. Expression of Differentiated Function in Neoplasms.- 1. Embryos, Stem Cells, and Cancer Cells.- 1.1. Similarities between Normal Cells and Cancer Cells.- 1.2. Historic Considerations.- 2. Differentiated Cell Progeny Obtained from Tumor Cells.- 2.1. A Plant Tumor.- 2.2. Fish Pigment Cell Neoplasm.- 2.3. Amphibian Tumor: The Lucké Renal Adenocarcinoma.- 2.4. Neuroblastomas.- 2.5. Rhabdomyosarcoma.- 2.6. Teratocarcinomas.- 2.7. Squamous Cell Carcinoma.- 2.8. Myeloid Leukemia.- 2.9. Murine Erythroleukemia.- 2.10. Other Tumors That Differentiate.- 3. Primary Induction in the Vertebrate Embryo Compared with the Induction of Cancer Cell Differentiation.- References.- 23. Ectopic Hormone Production and Neoplasia.- 1. Introduction.- 2. ACTH, POMC-Derived Peptides, CRH.- 3. Vasopressin.- 4. Human Chorionic Gonadotropin.- 5. Parathormone (PTH) and Other Hypercalcemia-Inducing Factors.- 6. Insulinlike Hypoglycemic Factors.- 7. Growth Hormone-Releasing Factor.- 8. Other Ectopically Produced Hormones.- 8.1. Calcitonin.- 8.2. Prolactin.- 8.3. Gastrin-Releasing Peptide.- 8.4. Vasointestinal Peptide.- 8.5. Erythropoietin.- 9. Conclusion.- References.- 24. Metaplastic Transformation of Pancreatic Cells to Hepatocytes.- 1. Introduction.- 2. Animal Models.- 2.1. Hamster.- 2.2. Rat.- 2.3. Human.- 3. Characterization of the Metaplastic Cells in Pancreas.- 4. Cells of Origin.- 4.1. Hamster.- 4.2. Rat.- 5. Other Examples of Metaplasia in Gut Entoderm-Derived Tissues.- 5.1. Rat.- 5.2. Rainbow Trout.- 5.3. Human.- 6. Possible Genetic and Developmental Mechanisms Involved in Metaplasia.- 6.1. Gene Regulation of Determination.- 6.2. Role of Gene Switching in Cell Specialization.- 6.3. DNA Methylation and Gene Expression.- 7. Summary.- References.- 25. Crown Gall Neoplasms.- 1. Introduction.- 2. Pathology.- 2.1. Symptoms.- 2.2. Pathogen.- 2.3. Development of Disease.- 2.4. Genetic Organization.- 3. The Infectious Process.- 3.1. Recognition and Attachment.- 3.2. DNA Transfer.- 4. Differentiation of Crown Gall Cells.- 4.1. Phytohormone Synthesis and Differentiation.- 4.2. Opine Synthesis and Utilization.- 4.3. Reversal of the Tumorous State in Crown Gall.- 5. Summary and Conclusions.- References.- 26. Angiogenesis: Factors and Mechanisms.- 1. Tumor Vasculature.- 1.1. Background.- 1.2. Differences between Normal and Tumor Vessels.- 1.3. Relationship between Vascularization and Tumor Growth.- 1.4. Role for Growth Factors.- 2. Angiogenesis Factors.- 2.1. Introduction.- 2.2. Non-Heparin-Binding Factors: Low-Molecular-Weight Factors.- 2.3. Non-Heparin-Binding Factors: Polypeptide Factors.- 2.4. Heparin-Binding Growth Factors.- 3. Regulation of Angiogenesis.- 3.1. Actions of Angiogenesis Factors.- 3.2. Control of Availability of Angiogenic Factors.- 3.3. Role of Ischemia in Angiogenesis.- 3.4. Storage of FGF.- 4. Summary.- References.- 27 Tumor Invasion and Metastases: Biochemical Mechanisms.- 1. Multistep Cascade of Metastases.- 2. Organ Tropism for Metastases.- 3. Tumor Cell Interaction with the Extracellular Matrix.- 4. Three-Step Theory of Invasion.- 5. Tumor Cell Motility Factors.- 6. Isolation and Characterization of a Human Melanoma Autocrine Motility Factor.- 7. Transduction of the Chemical Signal in the Motile Response of Tumor Cells.- 8. Laminin Receptors.- 9. Effect of Anti-Laminin Receptor Antisera on Laminin-Mediated Haptotaxis.- 10. In Vivo Expression of Laminin Receptor in Human Tumors Correlates with Their Invasive and Migratory Capacities.- 11. RGD Recognition Receptors.- 12. Tumor Cell Proteinases.- 13. Molecular Genetics of Metastases.- 14. Conclusions.- References.- 28. Phenotypic Heterogeneity and Metastasis.- 1. Introduction.- 2. Pathogenesis of Metastasis (Mechanisms).- 2.1. Invasion.- 2.2. Lymphatic-Hematogenous Spread.- 3. Biologic Heterogeneity of a Metastatic Tumor.- 3.1. Metastatic Heterogeneity of Tumor Cells in Primary Neoplasms.- 3.2. Origin of Cellular Diversity in Malignant Neoplasms.- 3.3. Instability of Heterogeneous Tumor Populations.- 3.4. Origin of Biologic Heterogeneity in Metastases.- 3.5. Development of Intralesional Heterogeneity within Metastases.- 4. The Challenge of Biologic Heterogeneity of Neoplasms.- 4.1. Effect of Tumor Cell Heterogeneity on Chemotherapy.- 4.2. Antigenic and Immunogenic Heterogeneity.- 5. Summary.- References.