Understanding Cancer: The Molecular Mechanisms, Biology, Pathology and Clinical Implications of Malignant Neoplasia

Preface
	The Molecular Mechanisms, Biology, Pathology and Clinical Implications of Malignant Neoplasia
Guide for Readers
Introduction
	Cancer: A Remarkable Entity That Thrives on Progressive Disorder
Terminology
Contents
About the Author
Defining Cancer: Comparisons of Normal Development and Cancer Formation
1 Understanding the Nature of Cancer–General Principles
	Abstract
	1.1 Cancer Pathology—Analysis of Structural and Functional Disorder
	1.2 Normal Tissue and Organ Composition: The Social Life of Cells, the Origins of Superorganisms and Emergent Behaviour
	1.3 Mechanisms of Self-assembly of Complex Organisms: Embryological Organ Formation and Its Relevance to Cancer
	1.4 Hierarchical Organisation of Multicellular Organisms
		1.4.1 The Molecular Dimension
		1.4.2 The Cellular Dimension
		1.4.3 Tissue, Organ and Whole Organism Dimensions
	1.5 Order and Disorder in Multicellular Systems: Cancerous and Non-cancerous Disease
	References
2 The Phenomenon of Inappropriate Gene Expression and Its Biological and Clinical Consequences
	Abstract
	2.1 A Fundamental Characteristic
	2.2 Defining Inappropriate Gene Expression and Its Potential Effects
	2.3 Inappropriate Gene Expression in Neoplasia
		2.3.1 Tumour Invasion and Metastasis: A Striking Example of Semi-coordinate Inappropriate Gene Expression
		2.3.2 Inappropriate Gene Expression and Cancer Metastasis Demonstrated by Experiments with Two Isogenic Cancer Cell Lines
		2.3.3 Identity of Misdirected Gene Expression Programme Causing Metastasis
	2.4 Clinical Applications
		2.4.1 Inappropriate Gene Expression and Cancer Diagnosis
	2.5 Inappropriate Gene Expression and Paraneoplastic Syndromes: Tumour—Host Interactions
	2.6 Mechanisms of Inappropriate Gene Expression and Silencing
	2.7 Conclusions
	2.8 Summary: Implications of Inappropriate Gene Expression for Clinical and Research Work
	2.9 Appendix: Refutation of the Claim That Epithelial Mesenchymal Transition (EMT) is Needed for Metastasis
	References
The Tumour “System”—Pathology and Pathophysiology of the Tumour Microenvironment
3 The Tumour System
	Abstract
	3.1 A Self-Propagating Heterogeneous Parasitic Entity
	3.2 Differences Between Cancers and Healthy Counterpart Organs and Tissues
		3.2.1 Some Basic Concepts About the Organisation of Cells and Intercellular Materials in Multicellular Organisms
	3.3 Types of Tumours—Macroscopic and Microscopic Cancer Diagnosis
		3.3.1 Macroscopic Characteristics
		3.3.2 Microscopic Features
	3.4 Histopathological Cancer Diagnosis
		3.4.1 Practical Aspects of Clinical Diagnostic Work
		3.4.2 Microscopic Features of Main Tumour Types
	3.5 Why People Die of Cancer
		3.5.1 Pathophysiological Effects of the Cancer on the Host
	3.6 The Tumour as a Parasitic Organism
	References
4 The Host Stroma and the Tumour Microenvironment
	Abstract
	4.1 Interactions Between Components of the Tumour System
	4.2 The Role of the Host Stroma in Health and in Neoplasia
	4.3 The Tumour Microenvironment
	4.4 Cancer Pathogenesis and Progression
		4.4.1 Embryological Organ Formation
		4.4.2 Cancer Formation: Sequence of Microscopic Events in the Boundary Zone Between Neoplastic and Non-neoplastic Cell Populations
		4.4.3 Differences Between Stromal Events in Wound Healing and in Early Neoplasia; Comparison of Healthy and Disorderly Reactions to Injurious Agents
		4.4.4 Specificity of Microscopic Changes in Neoplasia
		4.4.5 Implications of Stromal and Microenvironmental Changes for the Mechanisms of Carcinogenesis
		4.4.6 Invasion of Adjacent Tissues
		4.4.7 Matricellular Molecules, miRNA and Other Signalling Entities
	4.5 Specific Examples of Clinical Conditions Showing Disturbed Microenvironmental Conditions: Dysplasia Versus Neoplasia
	4.6 Why is the Histopathological Tissue Context Important?
	4.7 Small Cancers Can Regress. Cancer Screening Follow up Studies and Death Rates
	4.8 Diagnostic, Prognostic and Therapeutic Implications of Understanding the Cancer Microenvironment
	4.9 Synthesis and Conclusions
	4.10 Summary
	References
Prevalence of Cancer in Nature and History of Study of the Disease
5 The Biology and Natural History of Cancer
	Abstract
	5.1 An Ancient Disease Ubiquitous Among Multicellular Species
	5.2 Cancer in Human Populations; Geographic, Racial and Organotypic Differences
	5.3 Cancer in Domestic and Farm Animals
	5.4 Cancer in Captive Laboratory Animals
	5.5 Cancer in Wild Animals and Plants: Cancer in the Wild
		5.5.1 Mammals
		5.5.2 Registry of Tumours in Other Species
		5.5.3 Fish, Amphibians, Riverine and Lake Dwelling Species
		5.5.4 Birds
		5.5.5 Invertebrates
		5.5.6 Neoplasms in Plants
	5.6 Tumours and Evolution
	5.7 Cancer and Embryonic Development
	5.8 Summary
		5.8.1 A Cosmic Perspective
	References
6 Major Events in the History of Medical Understanding of Cancer
	Abstract
	6.1 Earliest Records—Egyptian and Greek Periods to 15th Century
	6.2 Sixteenth to 19th Centuries
	6.3 Nineteenth Century
	6.4 Twentieth and 21st Centuries
	References
Causes and Mechanisms of Cancer Formation, Invasion, Metastasis and Associated Symptoms: Clinical and Experimental Studies
7 The Behaviour of Cancers: Invasion and Metastasis I. Clinico-Pathological Aspects
	Abstract
	7.1 Hyperplasia, Atypia and the Pathological Significance of Carcinoma in Situ
		7.1.1 Diagnostic Implications
	7.2 Invasion
		7.2.1 Prognostic Implications
	7.3 Metastasis
		7.3.1 The Major Pathways of Metastasis
		7.3.2 Circulating Cancer Cells
		7.3.3 The Timing of Metastasis
		7.3.4 Kinetic Sequence of Events in Metastasis
		7.3.5 Patterns of Metastasis
		7.3.6 The Histological Structure of Metastases Reflects Their Tissue of Origin
		7.3.7 Instability of the Metastatic Process
		7.3.8 Is Metastasis Restricted to Tumours?
		7.3.9 The Clinical Effects of Metastasis
		7.3.10 Summary of the Current State of Clinical and Pathological Knowledge about of Human Cancer Metastasis
	References
8 The Behaviour of Cancers: Invasion and Metastasis II. Experimental Analysis of Mechanisms
	Abstract
	8.1 Paradoxical Aspects of the Phenomenon of Cancer Metastasis
	8.2 Methodological and Statistical Considerations
	8.3 The Metastatic Drive of Tumour Cells—Cell Biological Aspects
		8.3.1 Clonogenicity and Clonal Evolution
		8.3.2 Cell Surface Composition
		8.3.3 Cell Surface Receptors and Cognate Ligands
		8.3.4 Proteases
	8.4 Interactions Between Cancer Cells
	8.5 Interactions Between Tumour Cells and Non-neoplastic Host Cells
		8.5.1 Further Experimental Analysis of Mechanisms Determining Organ Distribution of Metastatic Deposits and of the Dormancy of Disseminated Tumour Cells
		8.5.2 Interactions Between Tumour Cells and the Structural Constituents of the Extra-Cellular Matrix
	8.6 Genetic Basis of the Intrinsic Metastatic Drive
		8.6.1 Modulation of Gene Expression Can Affect Metastatic Behaviour
		8.6.2 Transfer of Metastatic Properties with Genomic DNA
	8.7 Summary
	Appendix: Original data relating to Metastasis Associated Gene or Nucleic Acid (MAGNA) Sequence Isolated from Human Metastatic Cells
	References
9 Causes of Cancer and Mechanisms of Carcinogenesis
	Abstract
	9.1 Types of Carcinogenic Agents
	9.2 Chemical Carcinogenesis
		9.2.1 Activation and Deactivation
		9.2.2 Tobacco Smoke
		9.2.3 The Roles of the International Agency for Research on Cancer (IARC) and the World Health Organisation (WHO)
	9.3 Solid State Carcinogenesis: Physical (Foreign Body) Agents: Asbestos, Plastics and Other Foreign Body Implants
		9.3.1 Asbestos
			9.3.1.1 Composition [20–23]
			9.3.1.2 Uses [22]
			9.3.1.3 Health Hazards
			9.3.1.4 Sources of Asbestos Fibres in the Human Environment
			9.3.1.5 Carcinogenicity of Different Types of Asbestos
			9.3.1.6 Presence or Absence of the Carcinogenic Agent in the Tissues
			9.3.1.7 Electron Microscopy and Energy Dispersive Spectroscopy
			9.3.1.8 Biopersistence/Clearance
			9.3.1.9 Dosage and Susceptibility
			9.3.1.10 Macroscopic and Microscopic Pathology of Tumours Induced by Asbestos
			9.3.1.11 Mechanisms of Asbestos-Induced Carcinogenesis
			9.3.1.12 Latent Period
			9.3.1.13 Other Asbestos-Induced Diseases—Pleural Thickening, Pleural Plaques and Asbestosis [see also 29, 105, 152]
		9.3.2 Foreign Body Carcinogenesis—Plastic Sheets
			9.3.2.1 Observations Related to Tumours Induced by Implantation of Foreign Bodies
			9.3.2.2 Biological Implications
			9.3.2.3 Clinical Implications
	9.4 Carcinogenesis by Infective Agents
		9.4.1 Types of Agents: Prevalence of Viruses, Bacteria and Parasites
		9.4.2 Infectivity and Susceptibility
		9.4.3 Mechanisms of Tumour Induction
		9.4.4 Factors Influencing Implementation or Abeyance of Viral Carcinogenesis
	9.5 Radiation
	9.6 Further Mechanistic Considerations Relevant to Carcinogens of All Types
		9.6.1 Susceptibility
		9.6.2 Initiation, Promotion and Progression
		9.6.3 Timing of Action—Relationship to Cell Division
		9.6.4 Complete Carcinogens, Co-Carcinogens and Incomplete Carcinogens
		9.6.5 Relationships Between Cancer, Inflammation and Immunity
		9.6.6 Mutations, Penetrance and Gene Networks
		9.6.7 Carcinoma In Situ and the “Field Effect”
		9.6.8 Latency
		9.6.9 Progression
		9.6.10 Regression and Recurrence
		9.6.11 The Target of Action of Carcinogenic Agents: “Stem” Cells Versus Progenitor Cells
	References
10 Paraneoplastic Syndromes
	Abstract
	10.1 Diversity of Systemic Effects of Malignancy
	10.2 Haematological and Vascular Syndromes
		10.2.1 Thrombophlebitis Migrans and Other Coagulopathies
		10.2.2 Polycythaemia and Thrombocytosis
	10.3 Cutaneous Disorders
		10.3.1 Erythema Gyratum Repens
		10.3.2 Acanthosis Nigricans
		10.3.3 Dermatomyositis
	10.4 Endocrine Disorders
		10.4.1 Cushing’s Syndrome
		10.4.2 Hypercalcaemia
		10.4.3 Hypoglycaemia and Hyperglycaemia
		10.4.4 Inappropriate Anti-Diuretic Hormone (IADH) Secretion
	10.5 Neurological Disorders
		10.5.1 General Considerations Applicable to Central and Peripheral Nervous Syndromes
		10.5.2 Syndromes Affecting the Central Nervous System
		10.5.3 Peripheral Neuropathies
	10.6 Renal Syndromes
		10.6.1 Nephrotic Syndrome
		10.6.2 Haematological and Hepatic Syndromes Caused by Renal Neoplasms
	10.7 Musculo-Skeletal Disorders
		10.7.1 Myaesthenia Gravis
		10.7.2 Arthritis, Polymyositis, Myopathies, Hypertrophic Pulmonary Osteodystrophy and Finger Clubbing
	10.8 Cachexia and Fever
		10.8.1 Cachexia
		10.8.2 Fever
	10.9 Metastasis
	10.10 Therapy
	10.11 Unifying Concepts and Conclusions
	References
Synthesis and Significance of a New Perspective on Malignancy
11 Clinical Implications of Multi-level (Scalar) Disorganisation in Cancer
	Abstract
	11.1 The Concepts of Scale and Dimension in Body Organisation and Function
	11.2 Diagnostic Implications of Multi-scale Dysfunction in Tumour Cells
		11.2.1 At the Molecular Scale
		11.2.2 At the Cellular Scale
		11.2.3 At the Tissue, Organ and Whole Organism Scale
		11.2.4 Prospects for Non-Invasive Diagnosis
	11.3 Treatment and Palliation Implications of Molecular, Cellular, and Tissue Incoordination in Tumours
		11.3.1 Clonal Dynamics and Choices of Therapeutic Strategies
		11.3.2 Therapeutic Implications of Disturbances at the Molecular Scale
		11.3.3 Manipulating the Pathophysiology of the Tumour Microenvironment to Enhance Cytotoxic Chemotherapy
		11.3.4 Contributions of Combined Therapeutic Modalities
		11.3.5 Intrinsic Body Defence Mechanisms
		11.3.6 Treatment of Systemic Effects and the Value of Palliative Care
	11.4 Public Health
		11.4.1 Aspects Related to Chemical Carcinogenesis
		11.4.2 Infectious Transmission of Cancer
		11.4.3 Cancer from Ionising Radiation
		11.4.4 Screening for Early Detection and Treatment of Cancer
	11.5 Wider Social Implications
	References
12 Understanding the Significance of Cancer in the Overall Spectrum of Disease
	Abstract
	12.1 Disease and Destiny—Biological Considerations
	12.2 Clinical Considerations
	12.3 Research Considerations
	12.4 A Parting Comment—Gazing into Infinity
	References
Index
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