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Carcinogenesis-Mechanisms-And-Manifestations.Pdf Author's personal copy CHAPTER 5 Carcinogenesis: Mechanisms and Manifestations David E. Malarkey1, Mark Hoenerhoff1, Robert R. Maronpot2 1National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA, 2Maronpot Consulting, LLC, Raleigh, North Carolina, USA OUTLINE 1. Introduction 107 2.5. Gene Regulation 127 1.1. Overview 107 2.6. Cancer Stem Cell Theory 129 1.2. Background 109 2.7. Tumor Regression 133 1.3. Initiation, Promotion, and Progression 110 3. Identifying Carcinogens 134 1.4. Preneoplasia 115 3.1. Animal Bioassays 134 1.5. Hypertrophy 116 3.2. Data Evaluation and Interpretation 136 1.6. Metaplasia and Anaplasia (Atypia) 117 3.3. Genotoxic and Non-Genotoxic Carcinogens 139 1.7. Benign vs malignant neoplasms 117 3.4. Risk Assessment 140 2. Cancer is a Genetic Disease 117 3.5. Molecular Epidemiology 141 2.1. Overview 117 4. Conclusions 143 2.2. Oncogenes, Tumor Suppressors, Apoptosis and Repair Genes 120 Acknowledgments 144 2.3. Cell Proliferation and Apoptosis 124 Suggested Reading 144 2.4. Somatic Mutation Theory 125 We foresee cancer research as an increasingly exponentially increased risk for developing logical science, in which complexities are manifesta- cancer. There is a similar window of increased tions of a small set of underlying organizing princi- susceptibility to chemically-induced neoplasms ples. (Hanahan and Weinberg, 2011) in rodents treated with either a single or chronic exposure(s) to carcinogen(s). Identifying poten- 1. INTRODUCTION tial human carcinogens in rodent bioassays has been a major focus of the field of toxicologic 1.1. Overview pathology. It is estimated that 5% of human cancers are Cancer is a major cause of debilitation and caused by viruses, 5% by radiation, and the death in humans and animals. Cancer develops remaining 90% by chemicals. Of these, an esti- as a function of age, environment, diet, and mated 30% are caused by the use of tobacco genetic makeup, whether in man or animals. As products and the rest by chemicals associated humans reach their sixth decade, they face an with diet, lifestyle, and the environment. The Haschek and Rousseaux’s Handbook of Toxicologic Pathology, Third Edition. http://dx.doi.org/10.1016/B978-0-12-415759-0.00005-4 107 Copyright Ó 2013 Elsevier Inc. All rights reserved. Haschek and Rousseaux’s Handbook of Toxicologic Pathology, Third Edition, 2013, 107–146 Author's personal copy 108 5. CARCINOGENESIS importance of chemical products in the etiology of than 100 known human carcinogens (Table 5.1) cancer is reflected in the fact that up to 8% of all and virtually all of them also cause cancer in human cancers are related to occupational chem- animals. Animal and human cancers are funda- ical exposure. All chemical carcinogens, or their mentally similar and frequently share morpho- derivatives, are highly reactive electrophiles, logical, biological, and molecular biological which have electron-deficient atoms that can react features. In fact, approximately 30% of human with nucleophilic, electron-rich sites in the cell. carcinogens were first identified in animal Deoxyribonucleic acid (DNA), in particular, is studies. Two Japanese pathologists, Yamigawa made up of an array of nucleophilic centers at and Ichikawa, are credited with the original which these DNA-damaging agents can form demonstration that a chemical could produce adducts through one or more covalent bonds. cancer in animals. With chronic exposure of the To date, approximately 6 million chemicals skin (pinna) to coal tars, rabbits developed squa- have been identified and registered with the mous cell carcinomas, some of which metasta- chemical abstracts services. Of these, more than sized. These findings in 1918 confirmed Percival an estimated 50 000 are used regularly in Pott’s strong epidemiological observations in commerce and industry. Less than 2000, however, 1775 of increased rates of cutaneous scrotal have been examined for their carcinogenic cancer in chimney sweeps and demonstrated potential. that chronic exposures were necessary for the According to the International Agency of induction of some cancers. Research on Cancer (IARC), the United States Chronic inflammation and infectious agents Environmental Protection Agency (EPA), and have also been implicated in the development the United States National Toxicology Program’s of a number of human and animal cancers. Report on Carcinogens (RoC), there are more Nobel laureates Drs Robin Warren and Barry TABLE 5.1 Classification of Carcinogens by the International Agency for Research on Cancer (IARC), United States (US) National Toxicology Program’s Report on Carcinogens (RoC), and the US Environmental Protection Agency (EPA) Classification No. of agents IARC’s 2012 classification of carcinogens Group 1 Carcinogenic to humans 108 Group 2A Probably carcinogenic to humans 64 Group 2B Possibly carcinogenic to humans 271 Group 3 Not classifiable as to its carcinogenicity to humans 508 Group 4 Probably not carcinogenic to humans 1 NTP’s 2012 Report on Carcinogens (RoC) classification “Known to be human carcinogens” 56 “Reasonably anticipated to be human carcinogens” 189 US EPA classification [Integrated Risk Information System (IRIS)]a Group A Carcinogenic to humans 14 Group B Likely to be carcinogenic to humans 91 Group C Suggestive evidence of carcinogenic potential 9 Group D Inadequate information to assess carcinogenic potential 147 Group E Not likely to be carcinogenic to humans 7 a Includes guidelines from 1986 to 2005. I. PRACTICE OF TOXICOLOGIC PATHOLOGY Haschek and Rousseaux’s Handbook of Toxicologic Pathology, Third Edition, 2013, 107–146 Author's personal copy 1. INTRODUCTION 109 Marshall were credited with determining 5. inducing angiogenesis; that infection with Helicobacter pylori was 6. activating invasion and metastasis; a common cause of gastric inflammation and 7. reprogramming energy metabolism; and ulcers in man. Some skeptical scientists were 8. evading immune destruction. not convinced until Dr Marshall developed gastritis soon after drinking a Petri dish of the bacteria. 1.2. Background In subsequent years it was shown that chronic helicobacter gastritis is associated with the It is still accepted today that cancer originates development of gastric lymphomas and carci- in a single cell and develops through the clonal nomas, and thereby Helicobacter pylori is listed proliferation of their progeny. However, the as a human carcinogen. Some of the lymphomas search for a comprehensive theory of carcinogen- appear reversible and regress after treatment esis has not been forthcoming. Investigation into with antibiotics. Certain strains of mice the two predominant and antagonistic theories: (including A/JCr and B6C3F1/N) with chronic humoralist and cellular, dominated most of the Helicobacter hepaticus hepatitis develop signifi- second half of the 19th century. cantly higher rates of liver cancer compared to The humoralist view regarded cancer as origi- uninfected controls. Helicobacter infections may nating from certain hereditary characteristics of confound interpretation of the results of cancer the individual associated with susceptibility to occurrence in animal bioassays or human epide- contract the disease. Cellular pathologists such miological studies. as Muller and Virchow, however, argued that Our understanding of cancer biology is cancer was related to a form of chronic irritation. evolving at a rapid rate. Conceptual views of This latter view was supported by experimental carcinogenesis are formed by the piece-by-piece studies in mouse skin where wounding seemed discovery of key elements of the complex biolog- to play a tumorigenic role. Over the next century, ical puzzle that this disease entails. This piece- thousands of chemicals have been shown to by-piece discovery includes early findings of transform cells in vitro and to be carcinogenic the evidence of clonal evolution of cancer, the in animals. Those that are known to be carcino- Knudsen two-hit hypothesis progression from genic in humans are many times fewer (see benign to malignant growth, discovery of onco- Tables 5.1 and 5.2). genes and tumor suppressor genes, the somatic Some of the most potent carcinogens have mutation theory, the Fearon-Vogelstein multistep been extracted from fossil fuels or are synthetic colon cancer mutation model, mutator pheno- products created by industry. However, a variety type, and the cancer stem-cell theory. of occupational causes of cancer had been docu- With the advent of new technologies in molec- mented prior to the Industrial Revolution. In ular analysis, such as gene expression profiling, 1531, Paracelsus had described the “mala metal- networks, microRNAs, gene discovery, and lorum” among miners for silver and other pathway analysis, carcinogenesis is proving to metals, including uranium. This observation be much more complex than being simply a clonal was later interpreted as radiation-induced lung evolution of a cell that sustained two genetic cancer. In 1775, Pott attributed scrotal skin “hits” by a carcinogen. The current multistep cancers to prolonged exposure to soot in model of carcinogenesis involves at least 80 chimney sweeps. A few years later, on the basis cancer gene mutations or alterations, about of this observation, the Danish Chimney Sweeps a dozen of which are “drivers” of the cancer Guild ruled that its members must bathe daily. growth processes. The hallmarks of carcinogen- No public health measure since that time has so esis (Hanahan and Weinberg, 2011) include successfully
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