Cancer Handbook

Intestinaltype Gastric Cancer

The most common form of stomach cancer in high-risk populations is a gland-forming tumour that arises in the pyloric antrum and is preceded by the appearance of mucosal glands that resemble those in the intestine -- a condition called intestinal metaplasia. The tumours that develop in the intestinalized mucosa are termed intestinal-type gastric cancers. Intestinal-type tumours account for almost two-thirds of the gastric cancers in the high-risk areas of northeast Asia, central America and...

Microscopic Features Histological Patterns and Cytological Variants Ultrastructure and Special Techniques

Liver Hyperplasia Schistosomiasis Egg

The main microscopic characteristic of hepatocellular carcinoma is its resemblance to the normal liver, both in its plate-like growth pattern separated by sinusoids and its cytological appearances Figure 4 . Certain architectural and cytological variants have been recognized in the World Health Organisation classification Ishak et al., 1994 which are helpful for diagnosis but have no other, i.e. clinical or biological, significance. The commonest architectural pattern is the plate-like or, as...

Human Herpesvirus8 HHV8KSHV

Before the HIV epidemic, Kaposi sarcoma showed a greater geographical variation in incidence than almost any other cancer. It was as common in parts of sub-Saharan Africa, such as Uganda and eastern Zaire, as colon cancer is in Europe and the USA, representing up to 9 of all cancers in men. Kaposi sarcoma was also endemic, although much rarer, in countries around the Mediterranean, particularly Italy, Greece and the Middle East, but was almost nonexistent elsewhere in the world, except in...

Smad And Nonsmad Signalling

The only characterized signalling effector pathway, initiated by activated TGF-,3 receptors, is provided by the Smads (Piek et al., 1999 Itoh et al., 2000 Massague, 2000 Massague et al., 2000). The Smads, a family of structurally related proteins, are directly activated by the receptors and then translocate into the nucleus to act as ligand-dependent transcriptional regulators of target genes. The Smads are structurally related to each other in two domains, an N- or MH1 domain which corresponds...

The Messengers Wnt Genes

Wnt genes were first identified independently by researchers in two different fields. Wnt-1 (first called int-1) was identified as a preferred integration site for mouse mammary tumour virus (Nusse and Varmus, 1982). Insertion of the mouse mammary tumour virus in regions surrounding the Wnt-1 gene led to its inappropriate activation and breast cancer. Wingless (wg), the fly counterpart of Wnt-1, was identified in the Nobel Prize-winning screen of Nusslein-Volhard and Weischaus (1980) as a...

Further Reading

General and Applied Toxicology, 2nd edn, Vol. 2. Part 5 Genetic Toxicology, Carcinogenicity and Reproductive Toxicology. (Macmillan, London). Cartwright, A. C. and Matthews, B. R. (eds) (1997). International Pharmaceutical Product Registration, Aspects of Quality, Safety and Efficacy. Ch. 14, Mutagenicity (Ellis Horwood, Chichester). EU (1998). Testing of Medicinal Products for their Mutagenic Potential. The Rules Governing Medicinal Products in the European...

Basal Cell Carcinoma

Basal cell carcinoma by far is the most frequent of all cutaneous cancers. Like squamous cell carcinoma, basal cell carcinomas are slow-growing tumours that rarely metastasize. They also have a tendency to occur at sites subject to chronic sun exposure and in lightly pigmented people. Other predisposing factors include ionizing radiation, chronic scarring and arsenical exposure. As with squamous cell carcinoma, the incidence of basal cell carcinoma increases sharply with immunosuppression and...

Normal Upper Respiratory Tract

Motore Termico Disegno

The nose warms, humidifies and filters air via hairs and conchae (turnbinates) (Figure 1). These cause alterations in airflow, trapping particles larger than 6 p.m in diameter in nasal mucus. The nasal sinuses are collections of air cells called the frontal, sphenoidal, maxillary and ethmoid sinuses. The inner nasal cavity and sinuses, with their ostia in the lateral nasal walls, are lined by ciliated, pseudostratified columnar epithelium. A type of mucus cell called the goblet cell appears in...

References

Mesenchymal reprogramming of adult human epithlelial differentiation. Differentiation, 65, Andreasen, P., et al. (1997). The urokinase type plasminogen activator system in cancer metastasis a review. International Journal of Cancer, 71, 1-22. Anzano, M. A., et al. (1983). Sarcoma growth factor from conditioned medium of virally transformed cells is composed of both type alpha and type beta transforming growth factors. Proceedings of the National Academy of Sciences...

Tyrosine Kinases And Cancer

The functions listed in Table 2 are important because they include many of the cellular behaviours which are modified in neoplastic transformation of cells (Nicolson, 1976). Thus, the phenotypic changes in tumour cells correspond closely to the functions regulated by tyrosine kinases in cells. However, the relationship of tyrosine kinases and human cancer is not so simple. Formation of diagnosable human tumours appears to require about five genetic changes in a single cell lineage. Contrary to...

Hepatitis B Virus HBV

HBV is one of a group of viruses known as Hepadnaviruses which affect humans (HBV) and certain animals such as the woodchuck (WHV), ground squirrel (GSHV) and duck (DHV). All of these cause liver disease acute and chronic hepatitis, cirrhosis and hepatocellular carcinoma, in their respective hosts. In humans, transmission is mainly via blood or blood products, contaminated instruments, male homosexual contact and, most important, from mother to infant at birth. HBV is a partly double-stranded...

The Kinase Superfamily

Tyrosine kinases are members of a much larger family of protein kinases (Hunter, 1998), which can be categorized by two classifications, one based on specificity for the target amino acid and the other on structure and cellular localization. The major specificity classes are the serine or threonine-specific (Ser Thr) kinases and the tyrosine-spe-cific (Tyr) kinases which catalyse the phosphorylation of serine and threonine or tyrosine residues, respectively. In addition, a few mixed function...

Tumour Staging

It is essential to have a uniform standardized system for classifying the extent of disease (staging) in order to compare therapeutic intervention and estimate outcome. One of the most widely used staging systems to describe the anatomic extent of neoplastic diseases has been developed by The American Joint Committee on Cancer (AJCC) (American Joint Committee on Cancer, 1997) in cooperation with the TNM Committee of the International Union Against Cancer. For most organs, the size of the tumour...

The Natural History Of The Epidemiological Identification Of A Cancer Cause

The formulation of aetiological hypotheses is usually based on the examination of existing data. These data may represent the results of studies in experimental animals, e.g. the occurrence of papillary carcinoma in the bladder of mice after exposure to tobacco tar encouraged investigators to examine whether an association between tobacco smoking and bladder cancer also existed in humans. In other instances, the data may refer to 'unusual' or 'interesting' cases reported in the clinical...

ECM Proteins

The ECM proteins comprise a large family of glycoproteins. These large proteins are often comprised of several distinct subunits. For example, laminin, which is composed of a-, ft- and 7-chains, and has a molecular mass of over 106kDa, has up to three variants of each of these chains. The final composition of laminin is tissue specific. For example, laminin 5 is found in basement membranes associated with epithelia and endothelium, while laminin-2 is preferentially found in muscle (for a...

The Tumour Vasculature Is Disorganized

The vascular tree of tumour vessels appears 'chaotic' and 'disorganized.' Tumour vessels are also hyperpermeable ('leaky') owing to a discontinuous endothelium and lack of pericytes. Morphologically the vessels appear highly tortuous. The tumour vasculature is formed in two ways by co-opting pre-existing vessels and by induction of new vessels by angiogenesis. In addition, every tumour induces its own characteristic vascular bed which is different for each tumour type. As a result of persistent...

Secondary tumours Liver form at new sites

Individual cells within the primary tumour upregulate production of specific proteases, which gives the cell the ability to degrade ECM or basement membrane. Cells then break away from the primary tumour and begin to migrate. Migrating cells adhere to connective tissue and invade dermal tissue. Cells thus enter the vascular system by migrating between endothelial cells and moving through blood vessels. Lastly, tumour cells reach secondary sites where conditions...

Angiogenesis Inhibitors Encrypted within Larger Proteins

Similarly to PEX, several other endogenous angiogenesis inhibitors have been characterized which are all fragments of larger molecules. These inhibitors are formed by pro-teolytic breakdown of their parent molecules. The first of these inhibitors was identified as early as 1985 and is a 29-kDa fragment of fibronectin. It has been shown to inhibit endothelial cell proliferation. Fibronectin itself is an abundant molecule which has no such inhibitory function. More recently discovered endogenous...

Kinetic Parameters During Tumour Growth

Why does tumour growth slow down Well, the net rate of growth is defined by the relationship between the rate of cell production - the birth rate - and the rate of cell death or other modes of loss, the cell loss rate. In the earlier phases of growth, as seen in the early exponential part of the curve in Figure 3, most cells are growing exponentially thus every cell which divides contributes two cells to the population, with effectively no cell loss. What defines the rate at which the...

Heterocyclic Amines

Humans have used heat for cooking foods for over 500 000 years. Widmark (1939) reported carcinogenic activity of a solvent extract of broiled horse meat, with induction of mammary tumours in mice by painting on the skin. Production of mutagens by heating meat and fish was established in the 1970s by the use of bacterial mutagenesis assays (Sugimura et al., 1977). Methanol extracts from charred parts of grilled sun-dried sardine, beefsteak and hamburger were found to contain mutagens. Subsequent...

Antiproliferative Activity via Signal Transduction Pathways

Much is now known about the biochemical control mechanisms involved in regulating cell growth and development. Cells respond to signals from extracellular stimuli via a complicated network of highly regulated events collectively referred to as signal transduction pathways. Stimulation of these pathways results in changes in transcriptional activity. While normal cells respond appropriately to extracellular stimuli, many precancerous and cancerous cells have lost this ability and display...

Angiogenesis

Tumours also exhibit extensive vascularization which increases as the tumour grows (Folkman, 1992). This outgrowth of new blood vessels is termed angiogenesis and is not seen in normal adult animals except in the cases of wound healing and pregnancy, where new tissues such as placenta are formed. In the absence of new blood vessels, a tumour is able to grow to a maximum size of approximately 1 mm in diameter, the distance that oxygen and nutrients are able to diffuse into the tumour (Kurschat...

Nonneoplastic and Preneoplastic Lesions

Many tumours arise from preneoplastic lesions, not themselves neoplastic, which were previously regarded as hyperplasias, which involve changes in many cells and therefore by definition polyclonal. However, such lesions are often clonal proliferations themselves. Extremely relevant is the growing recognition that mutations in important genes such as p53 are found in tissues such as squamous epithelium preceding any dysplastic change, such as sun-exposed normal epidermis. Clones of...

Tumour Classification

All tumour classification schemes are by their nature artificial and arbitrary as biological processes are generally continua. Yet specific landmarks can often be used to define boundaries not only in the spectrum from benign to malignant but also through the grades of malignancy and among the types of tumours. For example, the presence of stromal invasion is a critical parameter that separates carcinoma in situ of the cervix, a lesion with no metastatic potential, from an invasive cervical...

Integration And Recommendation

It is very clear that genotoxic substances in the diet are related to human cancer development. Laboratory data offer particularly strong support. In this chapter, information on genotoxic carcinogens in the diet and the significance of other nutritional factors have been concisely summarized. Carcinogenesis is due to the accumulation of multiple genetic changes in a cell, implying multiple steps. Each step could be caused by exposure to a minute amount of a genotoxic substance in the diet....

Human Papillomaviruses HPV

The papillomaviruses are double-stranded DNA viruses. About 100 subtypes have been distinguished to date, many of which can infect humans, and at least as many again await formal characterization. Several specific subtypes have been associated with cancer in humans. Indeed, more cancers are attributable to HPV infection than to any other transmissible agent (Table 1). Most of these are cervix cancers, but other anogenital tumours and cancers at distant sites may also be caused by HPV. After...

Exogenous Antigenotoxins

Aflatoxin Biosynthesis Pathway

Exogenous antigenotoxins can be divided into synthetic and naturally occurring substances present in food or food constituents or additives. Most antigenotoxins are taken up via consumption of food, and more especially from fruit and vegetables as part of the diet. Recently however, synthetic antigenotoxins such as nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin, indomethacin, sulindac and oltipraz have been recognized. Also food supplements in the form of tablets containing...

Carcinogenblocking Activities Antimutagenicity

Inhibition of carcinogen uptake into cells, inhibition of carcinogen formation or activation, carcinogen deactiv-ation or detoxification, preventing carcinogen binding to DNA, and enhancing the level or fidelity of DNA repair are all carcinogen-blocking activities and potential chemo-preventive mechanisms (Wattenberg, 1978 Kelloff et al., 1995b). (See the chapter on Antigenotoxins and Cancer.) Table l Mechanisms for chemoprevention with possible molecular targetsa Table l Mechanisms for...

Mechanistic Assays

Agents not previously tested are put first into mechanistic assays to determine their potential range of chemopre-ventive activities (Table 2). Many of the mechanistic endpoints are described above in relation to characterizing various classes of chemopreventive agents. The battery of assays used is continually evolving and is designed to address various specific activities associated with general Table 2 Representative assays of chemopreventive mechanisms3 B(a)P-DNA adduct formation...

Markers Of Internal Dose The Example Of Haemoglobin And Dna Adducts

Engine exhaust, tobacco smoke and other complex mixtures contain several groups of carcinogenic compounds, including arylamines, polycyclic aromatic hydrocarbons (PAHs) and nitrosamines, many of which are able to POPULATION EXPOSED TO TOBACCO SMOKE OR AIR POLLUTION POPULATION EXPOSED TO TOBACCO SMOKE OR AIR POLLUTION Polycyclic aromatic hydrocarbons (PAHs) in smoke or air Polycyclic aromatic hydrocarbons (PAHs) in smoke or air CARCINOGEN REACTS WITH DNA OR PROTEIN, LEAVING A CHARACTERISTIC...

Table 9 Aspects of chemoprevention at major cancer target sites3

Age > 50 years familial history of prostate cancer high serum testosterone high-fat diet high red meat consumption population geographical background (highest incidences in Canada and northwest Europe) prostatitis, genetic polymorphisms (e.g. in SRD5A2, gene for steroid 5-reductase) low micronutrient levels (e.g. selenium, carotenoids, vitamin D) Steroid 5-reductase inhibitors (e.g. finasteride) retinoids (e.g. 9-c s-retinoic acid) RAMBA antiproliferatives (e.g. DFMO, DHEA analogues)...

Table 9 Continued

Males, age> 55 years, cigarette, pipe, and cigar smoking occupational exposures to aromatic amines metabolic polymorphism slow N-acetyltransferase phenotype chronic cystitis or urinary tract infections coffee drinking chlorinated tap water Anti-inflammatories (e.g. sulindac, Piroxicam, aspirin, ibuprofen) antiproliferatives (e.g. DFMO) retinoids (e.g. fenretinide) Alcohol and tobacco use poor diet (e.g. lacking fresh fruit and vegetables) chronic gastro-oesophageal reflux disease (GERD) for...

Known And Suspected Occupational Carcinogens

The International Agency for Research on Cancer (IARC) has established, within the framework of its Monographs programme, a set of criteria to evaluate the evidence for carcinogenicity of specific agents. The IARC Monographs programme represents one of the most comprehensive efforts to review cancer data systematically and consistently, and is highly reputed in the scientific community (IARC, 1972-2000). It also has an important impact on national and international occupational cancer control...

Precursors of Skin Cancer Dysplastic Moles and Actinic Solar Keratoses

Precursor Skin Cancer

Although some skin cancers appear to develop 'de novo'' in normal skin, many others are preceded by proliferations termed atypical or dysplastic. These lesions have already begun to lose normal responsiveness to control mechanisms that determine the order and uniformity typical of normal skin and benign proliferations. ln terms of malignant melanoma, the association of pigmented 'moles' (naevocellular naevi) with malignant melanoma was made over 160 years ago. However, it was not until 1978...

Tumours of the Nasopharynx Clinical Features

Most nasal tumours cause nasal obstruction, occasionally epistaxis and facial pain, irrespective of their histology. These are benign exophytic tumours with no association with human papillomavirus (HPV) and are seen in the oropharynx, larynx and trachea. They are covered by a bland, stratified, keratinizing squamous epithelium lining a fibrovascular core. The ciliated columnar epithelium lining most of the nasal and paranasal cavity is called the Schneiderian membrane. The commonest tumour...

Introduction

There has been increasing evidence of familial predisposition to cancer since the classic model of hereditary retinoblastoma was outlined (Knudson, 1971). The notion that some cancer is hereditary has long been held by more than just a few diehard clinicians. The earliest reports of cancer families date back more than 180 years to a large cluster of breast cancer in the wife and family of a French physician named Broca and the cluster of gastric cancer in Napoleon's family. Despite the...

Formulation Of Aetiological Hypotheses

The reasoning leading to the generation of aetiological hypotheses follows, explicitly or implicitly, a set of rules which focus on difference, agreement, concomitant variation and analogy (MacMahon and Trichopoulos, 1996). According to the rule of difference, when both a particular set of factors and the incidence of a particular cancer differ between two populations, one or more of these factors will likely contribute to the occurrence of the disease. When the difference in incidence is...

Cellular Adhesion

Normal tissue morphology and organ architecture are tightly regulated by a communication reciprocity between the tissue cells and the extracellular matrix (ECM) and or basement membrane. Adhesion is more than just anchoring -- it is dynamic solid phase signal transduction (Fashena and Thomas, 2000). Receptors sensing changes in the cell-ECM state provide extracellular signals, which trigger corresponding intracellular signal transduction pathways that regulate proliferation, differentiation and...

The International Conference on the Harmonization of Technical Requirements for Registration of Pharmaceuticals for

ICH Guidance S1A The Need for Long-term Rodent Carcinogenicity Studies of Pharmaceuticals 1. Carcinogenicity studies are performed for any pharmaceutical expected to be used clinically for 6 months on a daily basis or those that will be used repeatedly in an intermittent manner to treat a chronic or recurrent condition. 2. Carcinogenicity studies are performed when there is cause for concern. This can include evidence of geno-toxicity, a similarity to known carcinogens (e.g. SAR), the presence...

Figure 1 Phylogenetic tree of HPVs based on DNA sequence homology of a 384bp fragment of the E6 ORF The clinical

Hpv Structure Representation

Genome are located on one DNA strand (Figure 3) (Shah, 1990). The properties of the proteins encoded by the two late ORFs, L1 and L2, have been described in the previous section. The El proteins, molecular weights (MW) 68-85 kDa, are essential for viral replication and in this role they are similar to the SV40 large T-antigen. They are phosphoproteins with DNA-dependent ATPase and ATP-dependent helicase activities. The 5' portion of the El ORF can sometimes be translated as a smaller protein...

THE Husl RadlRad9 Sliding Clamp And Radl7 Clamploader Model

Husl, Radl, Rad9 and Rad 17 are components of a so-called 'Rad checkpoint' DNA damage response system that is conserved from yeast to humans. Although the role of these molecules in mammalian cells is not yet clear, recent evidence suggests a provocative model for their molecular mode of function (Rauen et al. (2000) and references cited therein). Husl, Radl and Rad9 form a heterotrimer complex that resembles PCNA in structure Table 2 Eukaryotic polymerases and their fidelity in replication of...

Preinvasive Lesions

The field cancerization hypothesis states that multiple cells form independent tumours, since carcinogenic exposure affects multiple cells in the field (Slaughter et al., 1953), and predicts that second primary or synchronous tumours arise from independent genetic events. Thus 11 of individuals with oral cancer had multiple upper aerodigestive tract tumours, and multiple invasive foci are associated with overlying areas of in situ squamous carcinoma in these lesions. There is now genetic...

Multistep Carcinogenesis Models Land and Weinberg Modei

At about the same time that Knudson proposed the two-hit hypothesis, Weinberg and Barrett independently suggested models of carcinogenesis based on the activation of a series of oncogenes. Weinberg suggested that the activation of two or more oncogenes is required for tumorigen-esis and that the right combination must be activated in Mutagenizing event unrepaired DNA damage Mutated gene retained in progeny cells Figure 2 Acquisition of tumorigenic phenotype and clonality. Once a cell has...

Treatment Oesophagus Squamous Cell Carcinoma

Surgical treatment of SCC is most likely to be successful when the tumour is confined to the lining of the oesophagus or when the invasive tumour is limited to the most superficial portion of the oesophageal wall. The extent of the tumour may be estimated through the use of endo-scopic sonography, which uses echoes of ultrasonic pulses at the time of endoscopy to measure the depth of tumour penetration into the oesophageal wall and to identify metastases into the regional lymph nodes. This...

Telomerase For The Development Of In Vitro Models Of Cancer Progression

The introduction of telomerase into some normal human cells resulted in bypass ofM1 and immortalization. After a doubling of their normal lifespan, these immortalized cells maintain a normal diploid karyotype and DNA damage and cell cycle checkpoints remained fully intact, suggesting that normal cells immortalized with telomerase do not develop additional cancer-associated changes. In cells expressing the Simian virus 40 Large T antigen for long periods of time followed by the introduction of...

Interaction of ER with Compressors

Unlike coactivators, only very few corepressors of ER action have been reported to date. These include NCoR (nuclear receptor corepressor also called RIP13), SMRT (silencing mediator for retinoid and thyroid receptor, also termed TRAC2), REA (repressor of oestrogen receptor activity), SHP (short heterodimer partner) and BRCA-1 (breast cancer susceptibility gene). Repression of ER activity can occur in the absence of hormone or when an antagonist is bound to the receptor. The corepressors NCoR...

Conclusions

The last 10 years has seen an enormous advance in our understanding of cancer and its familial elements. A great deal of this knowledge derives from the study of rare cancer-predisposing syndromes. This research is not esoteric because the cloning of these genes will benefit not only the small proportion of people who suffer from these conditions but also those who suffer from the common cancers occurring in these syndromes. Gene therapy, which could be directed at replacing the function of a...

Extracellular Matrix Degradation During Invasion

Proteolytic modification of the cell surface and the extracellular matrix is believed to be an essential component of invasion (Liotta et al, 1980), both neoplastic and physiological. The major enzymes that degrade the ECM and cell-associated proteins are (1) the matrix metalloproteinases (MMPs), a family of secreted and membrane anchored proteinases, (2) the adamalysin-related membrane proteinases, (3) the bone morphogenetic protein 1 type metallo-proteinases and (4) tissue serine proteinases...

Gastric Cancer

There are several forms of hereditary gastric cancer in which the genetic makeup of the patient and the patient's family strongly favour the development of gastric cancer. Germ-line mutations account for a small proportion of familial gastric cancer clusters, some of which may also be influenced by environmental factors. The hereditary non-polyposis colon cancer (HNPCC) syndrome is an autosomal dominant disease that carries an increased risk of stomach and colon cancer. It results from a...

Interpretation Of Results

Comparative trials have shown that false-positive and false-negative results in relation to cancer predictivity can be generated by each genotoxicity test. Experimental conditions such as the limited capacity of the in vitro metabolic activation system can lead to false-negative results in in vitro tests, whilst culture conditions such as changes in pH and high osmolality are known to cause false-positive results in in vitro mammalian assays. Guidelines for testing new chemical entities require...

Study Design and Analysis

The design of rodent carcinogenicity studies for pharmaceuticals is essentially the same as the design employed for industrial and environmental chemicals and US National Toxicology Program (NTP) rodent carcinogenicity studies. Male and female rats and mice are divided randomly into one or two control and three treatment groups of 50-70 animals per group per species. Historically, the highest dose in the studies analysed generally approximates the maximum tolerated dose (MTD) in the test...

Signal Transducer and Activator of Transcription STAT

The STATs (signal transducers and activators of transcription) constitute a family of signal transduction proteins that are activated in the cytoplasm by the binding of extracellular polypeptides to transmembrane receptors and which then regulate the transcription of immediate-response genes. Following their obligatory tyrosine phosphorylation, induced by a cytokine ligand, STATs dimerize, translocate to the nucleus and bind directly to response elements present in the promoters of target genes...

Definitions

The amount of energy deposited in biological tissue, and therefore the types of changes seen in cells, depend on the nature of the radiation (Table 1). Ionizing radiation refers to those types of radiation that produce the ejection of an orbital electron from an atom or molecule and result in the formation of an ion pair. The ionization potential of most molecules in biological materials is 10-15 electronvolts (eV), so in order to be ionizing, the radiation must be able to impart at least that...

The DNA Damageinduced Gi Checkpoint

After DNA is damaged, other checkpoint controls delay entry into the next phase of the cell cycle. One such major checkpoint is at the G1 to S transition, which prevents cells from beginning DNA synthesis until the damaged DNA is repaired. Several proteins, in particular p53, have been implicated in this checkpoint mechanism (Figure 5). Individuals who are mutated in the ataxia telangiectasia gene, ATM, are very sensitive to X-rays and have a high incidence of tumorigenesis. In response to DNA...

Small Intestine

The epithelium of the small intestine provides another example of a self-renewing tissue which has been studied for many years. The tissue organisation of the small intestine is different from that described for the haematopoietic system, being highly polarized and structured. However, the regulation mechanisms are equally complicated and largely unknown at present. In the small intestine, epithelium covers finger-like projections called villi and flask-shaped crypts located at the base of the...

Epidemiology

Nearly all ATL patients carry antibodies against HTLV-1 proteins. These antibodies are easily detected by indirect immunostaining of cells infected with HTLV-1, by an enzyme-linked immunosorbent assay (ELISA), by a particle-agglutination assay or by Western blotting. Some populations of healthy adults also carry HTLV-1 antibodies and these sero-positive persons are defined as the viral carriers. In fact, HTLV-1 can be detected in such individuals using the polymerase chain reaction (PCR). In...

Epsteinbarr Virus Ebv History Definition and Classification

A relevant point to note about EBV (or HHV-4) is that it is almost ubiquitous in the adult human population, with the great majority of individuals carrying antibodies to the virus. Infection of B lymphocytes by EBV is mediated through interaction of a viral envelope glycoprotein with the receptor for the C3d complement component, CD21 (CR2), although, notably, EBV can infect epithelial cells that lack this receptor. The average age of seroconversion to this virus differs markedly in various...

Figure 2 Examples of carcinogenic polycyclic aromatic hydrocarbons

Cycad nuts, pyrrolizidine alkaloids and ptaquiloside in various plants (see the chapter Dietary Genotoxins and Cancer). Although most of the aforementioned chemicals require metabolic activation in order to exert their carcinogenicity, there are many examples of chemical carcinogens whose structure incorporates inherently reactive functional groups. Such chemicals are direct-acting carcinogens (see Figure 3). In each case, the reactivity of the key functional group enables the chemical to...

Haematopoietic System

The hierarchical organisation of the continually renewing cells in the bone marrow has been extensively studied. All mature blood cells in the body are derived from a small number of stem cells that reside in the bone marrow in a process called haematopoiesis. Over 1011 new cells are produced daily to maintain homeostasis since the majority of mature blood cells are short-lived. In addition, normal daily cell replacement must also be sporadically increased to fight infection or to compensate...

The Molecular Basis of Cell and Tissue Organisation Glycoprotein spikes

Figure 7 Schematic structure of a herpesvirus. (From IARC, 1997, p. 34.) Figure 7 Schematic structure of a herpesvirus. (From IARC, 1997, p. 34.) when dealing with a large and complicated genome. Out of the 100 or so genes encoded by EBV, many of which are still poorly characterized, latent functions, as derived from data mainly drawn from EBV gene expression in B lymphocytes, consist of a small number of species only. These include six discrete EBV nuclear antigens (EBNAs), three discrete...

Immunological Considerations

One of the dominant characteristics about EBV is its adaptation to allow for persistence in its host(s), and gene expression, even in the presence of a functional immune system. EBV co-replicates with host DNA, and EBNA-1, required for latent replication, is tolerated, not eliminated, although there are epitopes for class I and class II HLAs in the viral antigen (Khanna et al., 1999). The dominant feature in this protein that allows for its tolerance appears to be the repetitive (IR3) sequence...

Historical And Current Patterns On Occupational Cancer Risks

Exposures encountered at the workplace are a substantial source of cancer, as has been known for over 200 years (Pott, 1775). Occupational cancers were initially detected by clinicians. From early findings of Pott of scrotal cancer among chimney sweeps in 1775 to Creech and Johnson's identification of angiosarcoma of the liver among vinyl chloride workers in 1974, unusual cancer patterns among persons with unusual occupations amounted to sufficient evidence to judge that the occupational...

Telomeres Are The Divisional Clock

The existence of an internal divisional clock was first suggested in 1965 by Leonard Hayflick, who demonstrated that cells maintained in culture have a finite capacity to proliferate. In 1972, Olovnikov suggested that erosion of the chromosome ends could lead to the loss of essential genes and an exit from the cell cycle. Harley et al. introduced a modification of the Olovnikov theory, proposing a telomere-based mechanism to account for the process of 'cellular ageing' (Harley et al., 1990)....

Metabolism Of Chemical Carcinogens

Many chemicals require metabolic activation in order to exert their carcinogenic potential. The pioneering studies of Elizabeth and James Miller showed that metabolic activation of azo dyes led to their covalent binding to cellular macromolecules. They went on to show with the model carcinogen 2-acetylaminofluorene that hydroxyla-tion of the amide nitrogen generated a metabolite that was more carcinogenic than the parent molecule. Subsequently it was found that these primary products of...

Chemicals Can Induce Mutations

The interaction of a chemical with DNA is not, in itself, a mutagenic event. The interaction of a xenobiotic with DNA can lead to mutagenesis due to attempts by the cell to repair the damaged DNA or during replication of the damaged DNA. Either way, a mistake may be made in which an inappropriate base is inserted or is lost (or a series of bases are inserted or are lost) from the region of DNA, with the consequence that a mutation is acquired, which is heritable. If the mutation occurs in a...

Dimethylnitrosamine

The nitrosamines are another extensively studied family of chemical carcinogens. Dimethylnitrosamine, representative of this family, is hepatotoxic, mutagenic and carcinogenic, causing kidney tumours with acute exposure and liver tumours after chronic exposure (Magee et al., 1976). Additionally, tumours of the stomach, oesophagus and central nervous system are found. Again, cytochrome P450 enzymes are central to the metabolic activation of dimethylnitrosamine, involving -demethylation to...

Vinyl chloride

Vinyl chloride is a simple halogenated allyl compound that is extensively used in the plastics industry, being the starting point for a number of polymer syntheses, particularly the manufacture of poly(vinyl chloride). A gas at room temperature and therefore usually stored as a liquified gas under pressure, the use of the material in an industrial setting is substantial and numerous workers have suffered well-documented accidental occupational exposure, for example being overcome by vinyl...

Dna Damage By Carcinogens

A property common to many chemical carcinogens is that they, or one or more of their metabolites, are DNA reactive. Cellular responses to DNA damage in mammalian cells include DNA repair, cytotoxicity, apoptosis, mutagenesis and transformation to malignancy. These processes are either fundamental to maintaining the integrity of the cell or they set the cell on a path to mortality or malignancy. Thus the study of reactions between carcinogens and DNA, and the biological consequences of these...

Mechanisms Of Tumour Induction

The mechanisms by which tobacco causes cancer can best be illustrated by considering the relationship between cigarette smoking and lung cancer, because it is here that the most information is available. The overall framework for discussing this information is illustrated in Figure 4 (Hecht, 1999). Carcinogens form the link between nicotine addiction and cancer. Nicotine addiction is the reason why people continue to smoke. While nicotine itself is not considered to be carcinogenic, each...

MMR Apoptosis and Chemotherapy Resistance

In addition to its role in DNA repair, the MMR system seems to signal the presence of DNA damage to the apoptosis-initiating system, which may be why MMR-defective tumour cells tend to have increased resistance to DNA-damaging drugs such as cisplatin (see reviews by Li (1999) and Jiricny and Nystrom-Lahti (2000)). Treatment of a mixture of MMR-proficient and deficient cells with cisplatin resulted in enrichment of the MMR-deficient population (Fink et al., 1998). Moreover, cisplatin resistance...

The Dna Replication Checkpoint

DNA damage during S phase normally causes temporary arrest of DNA replication. Proteins required for this checkpoint include ATM, Mre11, Rad50 and NBS1. Genetic defects occur in ATM (ataxia telangiectasia), NBS1 (Nijmegen breakage syndrome) and Mre11 (ataxia telangiectasia-like disorder) (see the chapter Inherited Predispositions to Cancer). In all three syndromes, DNA damage (e.g. by ionizing radiation) fails to arrest replication and leads to extensive chromosome damage (Petrini, 2000)....

Units of Dose and Activity

Radiation exposure is usually expressed either as energy incident on a surface or energy absorbed per gram of tissue. For ionizing radiation (Table 2), the gray (Gy) is the Syst me Internationale (SI) unit of dose that is most often used. It is equal to 1 J kg An older term still in use is the rad, which is equal to 0.01 Gy. For ionizing radiation, the unit of absorbed dose does not take into account the differences in efficiency with which one type of radiation might act. Therefore, to...

Squamous Cell Carcinoma

Squamous cell carcinoma is the most common tumour arising on chronically sun-exposed sites. As such, it is typically detected on facial, extremity and trunk skin of older people. Except for lesions that develop on the lower legs, these tumours have a higher incidence in men than in women. Industrial carcinogens (tars and oils), chronic ulcers and draining osteomyelitis, old burn scars, ingestion of arsenicals, ionizing radiation and in the oral cavity tobacco and betel nut chewing,...

Mushroom Hydrazines

The cultivated edible mushroom Agaricus bisporus contains agaritine, -N- y-l( + and its decomposition products. Three hydrazine derivatives (the N'-acetyl derivative of 4-hydroxymethylphenylhydrazine, 4-methylphenylhy-drazine hydrochloride and the tetrafluoroborate form of 4-(hydroxymethyl) benzenediazonium ion), derived from agaritine, are carcinogenic in mice. Moreover, uncooked cultivated Agaricus bisporus itself is carcinogenic in mice (Toth and Erickson, 1986). Agaritine is also present in...

Modulating Checkpoints

Several novel potential therapies are being developed The loss of G2 cell cycle checkpoints can increase tumour-cell sensitivity to chemotherapy. Furthermore, these cells often cannot take refuge at the G1 checkpoint owing to the loss of p53 or other G1 checkpoint molecules, whereas Figure 7 Potential therapies. Several potential therapies described in the text are illustrated. Figure 7 Potential therapies. Several potential therapies described in the text are illustrated. cells with the normal...

Table 5 Cytogenetic and molecular alterations in fatty tumours

Round cell liposarcoma Atypical lipomatous tumours Lipoma Lipoblastoma Spindle cell and t(12 16)(ql3 pll) t(12 22)(ql3 pl2) (rare) t(12 16) Ring and giant chromosomes, often with abnormalities of 12q13-q15 Abnormalities of 12q, 6p,13q 8q rearrangements Aberrations of 16q and or 13q Table 6 Translocations used in the diagnosis of sarcomas involved Available Table 6 Translocations used in the diagnosis of sarcomas with the previous morphological classification schemes. Of the common types of...

Checkpoints Mutations And Cancer

The general sequential organisation and duration of the cycle are preserved in cancer, but checkpoint controls are defective (Pardee, 1989 Hartwell and Kastan, 1994). Modifications in cancers are found at many levels of growth regulation, some of which have already been mentioned. The main defect is misregulation of growth initiation at the R point. Furthermore, since checkpoints ensure that mutations are kept low in normal cells, defective checkpoints increase the mutation rate in cancer cells...

Breast Cancer

Breast cancer is now known to occur as part of a high penetrance predisposition such as in LFS, and in BRCA1 2 families, but may also be caused by mutations in genes such as ATM and PTEN which confer a risk of < 50 . Breast cancer has long been known to have a familial tendency, as discussed earlier, and there is a profusion of supporting literature. Evidence from meticulous epide-miological studies shows that 4---5 of breast cancer is due to a dominant cancer gene with high penetrance and a...

Molecular Biology Of The Cycle Signalling Molecules

Comparisons of growth of mammalian cancer and normal cells in culture revealed in 1974 that the basis of cancer's deranged growth control is located in Gi phase, shortly before initiation of DNA synthesis (Pardee, 1989). In the same year, genetic studies of the cycle were intiated research with cycle-controlling yeast mutants led to the discovery of numerous cycle-regulatory genes (Hartwell and Kastan, 1994). Biochemistry and molecular biology soon followed, with the identification of new genes...

Pyrrolidine Alkaloids

Mutagenic and carcinogenic pyrrolizidine alkaloids are distributed in a variety of plant species. Humans are exposed to some of them in foods and herbal remedies. Petasitenine is present in coltsfoot, Petasites japonicus Maxim, the young flower stalks of which have been used as a food and a herbal remedy in Japan. Senkirkine, also having an otonecine moiety, is present in another kind of coltsfoot, Tsussilago farfara L., the dried buds of which are taken as a herbal remedy for coughs in China...

Telomerase Inhibition In Cancer

Several lines of evidence support the notion that inhibition of telomerase may be an effective anti-cancer strategy. As mentioned previously, telomerase is present in most human malignancies. Although the introduction of certain viral oncoproteins or the abrogation of tumour-suppressor genes may confer an extended lifespan, in the absence of a mechanism for telomere maintenance, these cells eventually reach a period of crisis and undergo widespread cell death. Telomerase is a challenging...

Tumour Induction In Laboratory Animals

Experimental studies evaluating the ability of cigarette smoke and its condensate to cause cancer in laboratory Table 7 1995 US cancer deaths caused by cigarette smoking. (From Shopland, 1995.) Gender Site and ICD disease 1995 cancer deaths Smoking attributable Estimated deaths category expected risk ( ) due to smoking Total excess deaths due to cigarette animals have collectively demonstrated that there is sufficient evidence that inhalation of tobacco smoke as well as topical application of...

Evidence For The Biological Significance Of Dna Adducts

While it is widely assumed that the formation of DNA adducts is an early and obligatory event in the process by which many carcinogens initiate tumours, it is by no means a sufficient event, and the long delay between carcinogen treatment and tumour appearance precludes a direct cause-and-effect demonstration. Nevertheless, it is the case that inhibition of DNA adduct formation will decrease the incidence of tumours formed subsequently, and increasing the adduct levels generally leads to a...

Chemistry Of Tobacco Smoke

When cigarette tobacco is burned, mainstream smoke and sidestream smoke are generated (IARC, 1986 Hecht, 1998b). Mainstream smoke is the material drawn from the mouth end of a cigarette during puffing. Sidestream smoke is the material released into the air from the burning tip of the cigarette plus the material which diffuses through the paper. The material emitted from the mouth end of the cigarette between puffs is sometimes also considered as sidestream smoke. The mainstream smoke emerging...

Epidemiological Studies Evaluating Cancer Causation

In theory, the best empirical evidence regarding causation should come from randomized trials in humans. Studies in humans do not face the pitfalls inherent in the reasoning by analogy from animal to human data, whereas randomization allows control for distorting influences by both known and unsuspected confounding factors in addition, doubleblind designs minimize the potential for several types of bias. Indeed, therapeutic clinical trials are also aetiolo-gical studies exploring the causation...

Inert Chemical Carcinogens

Some chemicals are carcinogenic even in the absence of chemical reactivity their physical presence in tissues can be enough to form a tumour. Implantation of certain plastics and fibres into animals can induce sarcomas, usually at the site of implantation. It is the physical size and nature of the material that appear to be important for the development of cancer and not the chemical composition (Brand et al., 1975). Although rodents are susceptible to these agents, other species are resistant,...

Benzo[apyrene78dihydrodiol910oxide Figure 11 The metabolic activation of benzo[apyrene P450 cytochrome P450 EH epoxide

Of different oxidized metabolites including epoxides, phenols, diols, dihydrodiols and their conjugated products, particularly with glutathione, glucuronic acid and sulfate. The genetic toxicity of the PAHs is based around the formation of their epoxides (Sims et al, 1974). For example, with benzo a pyrene, cytochrome P-450-1 family enzymes can generate a series of epoxides around the different rings of the molecule, some of which are known to be more carcinogenic than others. Electronically,...

Why Molecular Epidemiology

Epidemiology is the study of health and disease in populations, and of their determinants. The term molecular epidemiology may sound like an oxymoron, since it encompassess such different entities as molecules and populations. The aim of molecular epidemiology is to overcome some of the limitations of conventional epidemiology by linking research in the laboratory with research in free-living populations. In fact, rather than introducing an opposition between conventional and molecular...

Nitrosamines and Nitrosatable Mutagens and Carcinogen Precursors

Sodium nitrite has been used as a food preservative and colouring substance in meat. Severe liver disease was encountered in sheep fed a diet containing fishmeal preserved with nitrite and subsequently the toxic principle was identified as N-nitrosodimethylamine (Sakshaug et al., 1965). Vegetables are a major source of nitrite. Nitrite is also produced from nitrate by bacteria in the oral cavity. Under gastric acidic conditions, nitrite reacts with secondary amines to produce mutagenic and...

Chemicals and Drugs

Hundreds of chemicals - some purely experimental, others industrial - can produce liver tumours in rodents but epidemiological studies have shown that few, if any, are relevant to humans. Those that have caused most concern are nitrites, hydrocarbons, solvents, organochlorine pesticides and polychlorinated biphenyls (International Agency for Research on Cancer, 1972-1999). Tumours that develop after the administration of high doses of chemicals in short-term animal experiments may represent...

Cancer Development And Tissue Organisation

The chapter Overview of Oncogenesis will discuss the mechanisms involved in carcinogenesis in detail, but briefly the process is thought to involve a number of steps. First, a cell experiences a mutation that may or may not influence its immediate behaviour. This cell may then be more susceptible to subsequent mutations and, over time, gradually accumulate enough damage such that the normal control or 'braking' mechanisms is perturbed. This gradual accumulation of mutations is therefore known...

Chemicals Can Damage

As discussed above, the metabolism of chemical agents to reactive species is a common feature of carcinogenicity. Once bioactivated (often via proximal carcinogens or intermediate chemicals formed on the way to the creation of the ultimate carcinogen), for most classical chemical carcinogens, some form of DNA damage is the norm. Because of this DNA-damaging activity, such agents are known as genetic or genotoxic carcinogens. However, this is not the case for all chemical carcinogens and some...

Table 1 Some representative carcinogens their active metabolites and sites of modification of DNA

(PhIP) 3,N4-Cytosine, 1,N6-adenine, 3,N2-guanine more biologically important than others. This is still a matter of debate, with some suggestions that adenine adducts formed by PAHs are more consequential than guanine adducts, even though benzo a pyrene forms very few of the former. Others have proposed that unstable, depurinating adducts are more important than stable adducts in causing mutations from which tumour initiation proceeds, although this theory has been challenged. Substitution at...

Radiolabeled Compounds

Because only a very small proportion of an applied dose of a carcinogen becomes bound to DNA in the exposed cells or tissue, very sensitive methods of detection are required to study DNA adduct formation in vivo. Most of the early work on adducts was done using radiolabelled carcinogens and, although other methods now provide comparable or greater sensitivity, the method still has its uses. With compounds labelled either with 3H or 14C, at a position of the molecule where the isotope will not...

Dna Adduct Dosimetry

From a number of animal studies, it has been demonstrated that at chronic low doses, there is a linear relationship between the amount of carcinogen administered and the level of DNA adducts that results (Poirier and Beland, 1992). Adducts can be lost from DNA by depurination and by DNA repair, and can be diluted by DNA replication and cell division, so if the exposure is chronic, a steady-state level will be attained typically this takes about 1 month of dosing. Where exposure is acute or of...

Microwave and RF Radiation

Studies on microwave and RF radiation and cancer have included analyses of a wide variety of different populations, including radar laboratory workers, foreign service workers, military personnel and electrical workers (National Research Council, 1997 Moulder et al., 1999 National Institute of Environmental Health Sciences, 1999). In addition, there have been a number of animal studies that have looked at the effects of exposure. For many of the epidemiological studies, there is no precise...

Histone deacetylation and chromatin compaction

Figure 5 Model for the epigenetic inactivation of DNA transcription. A schematic representation of transcriptionally active open chromatin with acetylated histones is shown at the top. Cytosine methylation of the normally unmethylated promoter region is followed by recognition and binding by MeCP2 (methyl CpG protein). MeCP2 recruits HDAC (histone deacetylase) and other corepressor proteins that function to locally deacetylate histones followed by condensation of the chromatin the result is...

Highthroughput Screening

Chemical synthesis techniques are creating millions of new compounds and to cope with the vast numbers of tests required an approach termed high-throughput screening is being developed. A new branch of chemistry, called combinatorial chemistry, has emerged which allows chemists to take a number of relatively simple molecules and to combine them in every single possible permutation and in turn combine the products of these combinations. The result is a huge number new compounds which must be...

Intervention And Chemoprevention Of Cancer Treatment Of Carcinogenesis

Carcinogenesis is a several years to decades long process expressed in progressive genetic changes and corresponding increasingly severe tissue damage (Figure 1). Cancer prevention is intervention in this process before invasive disease develops, when it is potentially reversible, often asymptomatic, easier to control medically and associated with less morbidity. During the last half century, our understanding of carcinogenesis has grown enormously owing largely to technology allowing...

Precancerous Changes in the Liver Screening and Prevention

Cirrhosis itself is a precancerous condition but the magnitude of the risk varies with aetiology, i.e. it is high with HBV and HCV but low with alcohol. Sustained proliferation of liver cells consequent upon chronic hepatitis B and C or the daily ingestion of a hepatoxic agent such as alcohol over many years seems to be the most likely mechanism of carcinogenesis as it predisposes the cell to accumulate DNA abnormalities. Proliferation prevents the repair of any damage to DNA and it is then...