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...

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...

Figure 3 Signal transmission from the extracellular space to the nucleus to activate transcription via the RasMAP

Table 2 Examples of cellular functions regulated by tyrosine kinases Table 2 Examples of cellular functions regulated by tyrosine kinases tyrosine kinases are indicated in bold. FAK, focal adhesion kinase PDGFR, platelet-derived growth factor receptor IGFR, insulin-like growth factor receptor PI3K, phosphoinositide 3-kinase STAT, signal transduction and transcription. tyrosine kinases are indicated in bold. FAK, focal adhesion kinase PDGFR, platelet-derived growth factor receptor IGFR,...

YcDependent Cytokines

7c-Dependent cytokines include IL-2, IL-4, IL-7, IL-9 and IL-15. They are peptides or glycoproteins with molecular masses of 14-20 kDa. Crystal structure analysis reveals that IL-2 is an a-helical protein, lacking ft-sheet structure, with a four-fork core stabilized by a single intrachain disulfide bond. IL-4 contains six Cys residues that are all involved in intramolecular disulfide bridges. The secondary structure of IL-4 was shown to consist of a four-helix bundle with a unique...

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...

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...

Telomerase

Early studies demonstrated a significantly shorter telomere length in most cancers compared with noncancerous tissue from the same patient (Hastie et al., 1990). In culture, cancer cells generally have short but stable telomeres, suggesting that human cancers have developed strategies for the maintenance of telomeric DNA at a length above the critical threshold. In 85-95 of human cancers, this telomere stabilization is achieved by reactivation or upregulation of the ribonucleoprotein enzyme...

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...

References

Asbestos and cancer an overview of current trends in Europe. Environmental Health Perspectives, 107, Suppl. 2, 289-298. Boffetta, P. andKogevinas, M. (1999). Introduction epidemiologic research and prevention of occupational cancer in Europe. Environmental Health Perspectives, 107, Suppl. 2, 229-231. Creech, J. L. Jr and Johnson, M. N. (1974). Angiosarcoma of liver in the manufacture of polyvinyl chloride. Journal of Occupational Medicine, 16, 150-151. Doll, R. and...

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...

Assays For Telomerase

The standard method for measuring telomerase activity is a highly sensitive PCR-based assay termed the TRAP (telomere repeat amplification protocol) assay (Figure 6). In this assay, extracts are first prepared from primary tissue or cultured cells by lysing the cells with a detergent, releasing telomerase into the extract solution. An aliquot of this solution is then added to a reaction mixture containing a short primer and deoxynucleotide triphosphates (dNTPs). If telomerase is present, it...

Molecular and Genetic Factors Microsatellite Status

Sporadic MSI-H cancers are associated with a good outcome and an independent prognostic effect has been demonstrated for stage III colorectal cancer. This will explain, at least in part, the adverse effects associated with molecular and genetic changes found in non-MSI-H cancers. These include K-ras mutation, 17p and 18q loss and increased expression of COX-2 and VEGF. The classification of colorectal cancer as MSS, MSI-H and MSI-L must precede the exploration of other prognostic markers, the...

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...

Abbreviations BFUE erythroid burstforming unit CFUE erythroid colonyforming unit MegCFU megakaryocyte colonyforming

To produce myeloid progenitor cells and can also stimulate myeloid progenitor cells to produce a number of mature cell types (Dexter, 1993). Another example is granulo-cyte-macrophage colony-stimulating factor (GM-CSF) which acts on the granulocyte-macrophage progenitor cell and the eosinophil progenitor cell to produce neutrophils, macrophages and eosinophils. In contrast, some growth factors have direct effects on only one cell population, e.g. erythropoietin, which acts only on the erythroid...

Advantages and Disadvantages of Molecular Epidemiology

Conventional epidemiology, based on simple tools such as interviews and questionnaires, has achieved extremely important goals, including the discovery of the causal relationships between smoking and lung cancer or asbestos and mesothelioma. Even a difficult issue such as the relationship between air pollution and chronic disease has been successfully dealt with by time-series analysis and other methods not based on the laboratory. Therefore, the use of molecular epidemiology should be...

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...

Chromosome 14q32

Figure 7 Cancer predisposition and methylation-dependent chromatin boundary elements. The reciprocally imprinted IGF2 and H19 genes at llpl5.5 are separated by approximately 100 kb of DNA that contains a differentially methylated ICR (imprint control region). The ICR contains seven methylation-sensitive CTCF (vertebrate enhancer blocking protein) binding sites (vertical bars). CTCF proteins are blocked from binding the methylated (small circles) paternal allele but the unmethylated maternal...

Mismatch Repair Genes

Critical regulators of genomic integrity, as exemplified by mismatch repair genes, also have been implicated as tumour-suppressor genes. The microsatellite instability genes described above, MLH1 and MSH2, are important to the maintenance of genomic integrity by repairing mismatched base pairs that arise with a stable frequency during DNA replication (Kolodner and Marsischky, 1999). Mismatched base pairs are recognized and cleared by mismatch repair enzymes, and new bases are added in their...

Angiogenic Factors

In the last 20 years, many factors that have angiogenic activity have been identified. The first to be identified were the fibroblast growth factors (aFGF or FGF-1 and bFGF or FGF-2), which are now known to be pleiotrophic growth factors. Others include the transforming growth factors (TGF-a and TGF-ft), platelet-derived growth factor (PDGF), hepatocyte growth factor (HGF), granulocyte colony-stimulating factor (G-CSF), tumour necrosis factor-alpha (TNF-a), platelet-derived endothelial cell...

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...

Carcinoma of Lung

All lung carcinomas show histological heterogeneity. If one accepts that there is a common stem cell, consequently there are mixtures of squamous and adeno or small cell carcinoma. However, major heterogeneity is found in only 5 of cases. The heterogeneity explains why after chemotherapy for SCLC a squamous or ade-nocarcinoma may develop at the site of the original tumour. Synchronous tumours arise at the same time as a primary, while a metachronous one consists of a second tumour occurring...

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...

In Vitro Test Systems

In general, a substance selected on promising epidemio-logical data is tested at first using in vitro systems, since these tests are most easiest to interpret, the most readily available and the cheapest. The most common test employed is the Ames test, where the effects of added substances on bacterial mutation rates are tested (see later). Another category of in vitro tests use cell lines, which most often are derived from human or animal tumour cells, but sometimes originate from foetal cells...

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...

Retinoblastoma Rb Gene

The first tumour-suppressor gene identified was the Rb gene, which is associated with the childhood illness of retinoblastoma (Knudson, 1971). In an epidemiological study, Knudson and colleagues noticed that bilateral reti-noblastoma occurred frequently within the same family, whereas unilateral retinoblastoma did not appear to be a genetically inherited disease. In families with bilateral retinoblastoma, karyotyping techniques were used to detect homozygous loss of chromosome 13q, a defect...

Table 2 The stages of initiation promotion and progression

Cell not morphologically recognizable Single exposure to chemical is sufficient Can occur spontaneously (transitions, transversions, frameshifts) Can involve single genes Proto-oncogenes and tumour-suppressor genes can be mutated Simple genotypic changes with corresponding phenotype change Limited growth advantage over surrounding cells (Adapted from Pitot and Dragan, 1996.) Requires multiple exposure to chemical Endogenous and exogenous chemicals can promote Measurable dose-response threshold...

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...

Checkpoints and Programmed Cell Death Apoptosis

Apoptosis is a highly regulated process that eliminates physiologically unneeded cells and those that are damaged beyond repair (see the chapter Apoptosis). Activated checkpoints give time for a cell to repair its damaged DNA, but if the damage is not soon corrected the cells will initiate apoptosis. This mechanism therefore may prevent the mutations that cause cancer (Sellers and Fisher, 1999). Checkpoint genes, including p53, called 'the guardian of the genome,' are involved in causing...

Aetiology

The list of aetiological agents is long and is shown in Table 2, but some are more important than others. This is indicated in terms of the prevalence of the agent and the magnitude of the risk attached to it. The effect of most of them is to proceed from the normal state of the liver to the cancerous through cirrhosis, but the likelihood of this varies (Simonetti et al., 1991 Okuda, 1993 Akriviadis et al., 1998). Chronic hepatitis B and C account for four-fifths of cases of hepatocellular...

Oral Cavity and Major and Minor Salivary Glands 497 Table 2 TNM staging system for oral squamous cell carcinoma3

TX Primary tumour cannot be assessed TO No evidence of primary tumour T1 2 cm or less in greatest dimension T2 More than 2 cm, but not more than 4 cm, in greatest dimension T3 More than 4 cm in greatest dimension T4 (lip) Tumour invades adjacent structures such as cortical bone, inferior alveolar nerve, floor of mouth, skin of face T4 (oral cavity) Tumour invades adjacent structures such as cortical bone, muscle of tongue, maxillary sinus, skin. Superficial erosion alone of bone tooth socket by...

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...

Putative Key Tumour Genes

Studies on KSHV genes, to designate them as latent, immediate early, early and late genes, and identify those Figure 11 Phylogenetic tree of KSHV (HHV8) in relation to other herpesviruses. The comparison shows KSHV to be most closely related to the 7-herpesviruses, EBV, equine herpesvirus 2 (EHV2) and herpesvirus saimiri (HVS), its nearest relative (see Figure 5). (From IARC, 1997, p. 385.) that may play key roles in the oncogenic activity of this virus, have been initiated. Here, as with other...

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...

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...

Immunoassays

Antisera elicited against carcinogen--DNA adducts can be used in immunoassays to detect adducts in human or animal tissues. Antibodies have been raised against a variety of carcinogen-modified DNAs, including those containing adducts ofPAHs, aromatic amines, methylating agents, tamoxifen, UV radiation and oxidative damage. Immunoassays are highly sensitive but generally require more DNA for analysis than 32P postlabelling. The assay is relatively inexpensive to perform and can be automated....

Molecular Diagnostics

The first use of molecular techniques in diagnostic pathology was the determination of clonality of haemato-lymphoid proliferations and this is still a potent tool for the diagnosis of lymphomas. The immunoglobulin genes and T cell receptor genes undergo unique somatic rearrangements during lymphocyte maturation. In reactive processes there are expansions of many clones of lymphocytes but in neoplastic proliferations the tumour is descendent from a single lymphoid cell. Originally, Southern...

Dioxins

Contamination of food by dioxins, polychlorinated dibenzo- -dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs), has received much attention from the general public. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD) is recognized as the most toxic compound among 210 congeners of PCDDs and PCDFs. To aid in the interpretation of the complex database and evaluation of the risk of exposure to mixtures of structurally related PCDDs and PCDFs, the concept of toxic equivalency factors (TEFs) is...

Contents

Repair by DNA Alkyltransferase Repair of Single-Base Damage Nucleotide Excision Repair (NER) Mitochondrial DNA Repair in Mammalian Cells Recombinational Repair Repair of DNA Double-Strand Breaks (DSB) and Cross-links DNA Repair Involving RecQ-Family Helicases The Husl Radl Rad9 Sliding Clamp and Radl7 Clamp-Loader Model Multimolecular Assemblies and Nuclear Foci The DNA Replication Checkpoint malignancy. The frequency estimates for various types of DNA damage normally incurred in mammalian...

Interferons Signalling Pathway

The common pathway for IFNa 3 requires seven distinct proteins, which include two IFNa receptors, two JAKs, two STATs and the IRF-family transcription factor p48. The IFNa 3 signalling pathways are comparatively illustrated in Figure 2, but the fine details of the mechanisms are lacking because information regarding the detailed interactions that play the crucial role for the pathway remain to be elucidated. The IFNa S receptors, designated IFNRAs, are composed of a multichain structure on both...

M phase Checkpoints

Mitosis properly segregates chromosomes into the daughter cells. Accurate segregation depends on proper chromosome alignments on and attachment to the mitotic spindle, which is composed of microtubule proteins. A checkpoint ensures that this segregation process occurs correctly. As little as one double strand break in DNA, or depletion of deoxynucleotide building blocks, activates the checkpoint control and stops cells at the G2-M boundary. This control mechanism delays completion of mitosis...

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...

Mechanistic

The transfer of a signal from an extracellular factor through the membrane via a tyrosine kinase is usually performed by one of two types of mechanisms, exemplified in Figures 2b and 3a. These two mechanisms use receptor and nonreceptor tyrosine kinases. In the first mechanism (Figure 3a) the receptor tyrosine kinase is solely responsible for the transfer of signal across the membrane. In the second mechanism (Figure 2b) a nonreceptor tyrosine kinase is coupled to a transmembrane receptor...

The Prognostic Significance Of Tumour Angiogenesis

This chapter has presented evidence that tumour growth is angiogenesis dependent and in the chapter on Antiangiogenic Therapy it is shown that inhibition of tumour angiogenesis is currently one of the most exciting avenues of anti-cancer therapy. To conclude this chapter, we will review the prognostic significance of tumour angiogenesis. This encompasses primarily three areas of interest (1) analysis of the primary tumour microvessel density, (2) expression of angiogenic factors within tumours...

Integrin Cytoskeletal Connections

The observations that fl integrin subunits extend into the cytoplasm has long generated speculation that the integrin cytoplasmic domains directly interact with cytoskeletal elements to bring about the changes in clustering and cell morphology. Functional linkages are supported by an extensive literature which shows that disrupting ECM--integrin interactions with function blocking antibodies leads to significant alterations in cell shape and cyto-skeletal organisation. Similarly, directly...

Virion Structure and the Virus Life Cycle

The HB infectious virion is a 42-nm double-shelled spherical particle (originally called the Dane particle) that consists of an outer envelope composed of HBsAg and an inner core, or nucleocapsid, with its own antigens, hepatitis B core (HBcAg) and e (HBeAg), antigens, together with HBsAg, acting as markers for the presence of intact virions and infectivity. Infectious virions also contain a small (3.2-kb) circular, partially single-stranded DNA, and an endogenous DNA polymerase that can...

Other Publications

E. (1980). Statistical Methods in Cancer Research. Vol. I. The Analysis of Case-control Studies. IARC Scientific Publication No. 32, 5-338 (International Agency for Research on Cancer, Lyon). Breslow, N. E. and Day, N. E. (1987). Statistical Methods in Cancer Research. Vol. II. The Design and Analysis of Cohort Studies. IARC Scientific Publication No. 82, 1-406 (International Agency for Research on Cancer, Lyon). Hennekens, C. H. and Buring, J. E. (1987). Epidemiology...

Transcription and Replication of the Viral Genome

The subdivision of the viral genome into 'early' and 'late' regions is based on the close association existing between viral replication and squamous epithelial differentiation. Upon entry into the basal stem cells of the epithelium, viral early gene expression is activated at a very low level, leading to the temporary amplification and establishment of the DNA plasmids. Early gene expression in the basal cell layer also stimulates cell growth and, as the epithelial cells move upwards in...

Figure 5 Large calcified ovarian fibroma on abdominal Xray in a patient with Gorlin syndrome

Eight-cell stage, roughly one eighth of all the cells will have an NF2 mutation, which means that there are two different cell populations, one of which predisposes to tumours and could be transmitted to any offspring. Figure 4 MRI scan of a 26-year-old man with type 2 neurofibromatosis. The scan shows bilateral enhancing tumours in the cerebello-pontine angles and meningiomas around the brain. The risk of developing bilateral tumours by chance is 1 in 2 x 106, yet 95 of individuals with...

Initiation

A key feature of the initiation process (Table 2) is the requirement for cell replication (Pitot and Dragan, 1996). Once a chemical has damaged DNA by forming an adduct, or inducing a strand break, etc., and provided that the cell recognizes the damage, repair processes will intervene. Should the damage be misrepaired, or not recognized by the cell, then the outcome can be (1) aberrant transcription of the affected DNA if it is a structural gene lesion and on the transcribed strand, (2) altered...

A

In contrast to the cancers illustrated in Figure 23, glandular formations are not present. (a) The tumour cells diffusely infiltrate the intestinal wall. (b) Infiltration of these same cells through the deeper layer of the stomach. Table 1 World Health Organization classification of histological types of epithelial tumours of the stomach Adenocarcinoma Papillary Tubular Mucinous Adenosquamous carcinoma Squamous cell carcinoma Undifferentiated carcinoma...

The Matrix Metalloproteinases

The MMPs are a family of extracellular endopeptidases which are secreted by a variety of cells including epithelial cells, fibroblasts and inflammatory cells. Endothelial cells express MMP-1, MMP-2, MMP-9 and the membrane-associated MT-1-MMP (for a review, see Stetler-Stevenson, 1999). These endopeptidases are secreted as inactive proenzymes and need to be activated by cleavage of a pro-teolytic fragment. The substrates of the different endo-peptidases include all known components of the ECM...

Phosphoinositide 3Kinase Gamma PI3Ky

PI3Ks have been implicated in many cellular responses, including, proliferation, apoptosis, adhesion and chemo-taxis. Recently, a number of groups generated mice deficient in PBK7. All three groups observed a severe reduction (< 85 ) in chemokine-induced chemotaxis, but there was some activity left, indicating that G -7 may link to other intracellular components and induce chemotaxis. The least effected was MIP-5-induced chemotaxis (Hirsch et al, 2000). MIP-5 (also known as HCC-2 or CCL-15)...

Polycyclic Aromatic Hydrocarbons

Polycyclic aromatic hydrocarbons (PAHs), which have been identified as carcinogenic compounds in coal tar, are in fact widely distributed in our environment such as in cigarette smoke, exhaust gas and cooked foods. The presence of PAHs including benzo a pyrene in charred parts of biscuits, roasted coffee beans and broiled steak has been reported. The average levels of benzo a pyrene is 8 ng per gram of broiled steak (Lijinsky and Shubik, 1964). Benzo a pyrene is converted into the ultimate diol...

Bacteria Helicobacter pylori

Helicobacter pylori is a spiral, flagellated, Gram-negative bacteria that colonizes the human gastrointestinal tract and lives beneath the mucus overlaying gastric epithelium. It causes gastritis in all infected people and although many cases remain asymptomatic, some result in gastric or duodenal ulceration. In a very small proportion of infected individuals, H. pylori may be involved in the aetiology of gastric adenocarcinomas and the much rarer primary gastric non-Hodgkin lymphoma --- about...

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...

Introduction

Preservation of genome integrity is critical for the functional preservation of dividing cells. Genomic instability and DNA damage set the stage for carcinogenesis, both in the initiation stage and in the evolution toward Table 1 Estimated frequencies of DNA lesions normally occurring in mammalian cells Single-strand breaks Deputations Depyrimidinations Guanine-06 methylation Cytosine deamination Glucose-6-phosphate adduct Thymine glycol Thymidine glycol Hydroxymethyluracil Guanine-8...

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...

Methylenetetrahydrofolate reductase MTHFR

Folate may serve as a protective factor through influencing methylation of DNA and the size of the nucleotide pool required for DNA synthesis and repair. The polymorphic enzyme MTHFR appears to increase the risk of colorectal neoplasia in subjects with a particular genotype (TT) and a low-folate diet (Potter, 1999). Some tumour suppressor genes are silenced through hypermethylation of the promoter region. However, this mechanism applies mainly to the subset of colorectal cancers showing DNA...

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...

Quiescence

Commencing by considering normal animal cells, most of the cells within us are in a quiescent state (G0 phase). They have left their cycling during the G1 state, so in quiescent cells DNA has not yet duplicated. But quiescent cells differ from G1 cells in many other properties, in particular lacking molecules required for growth. This fact told us that the molecular switch that controls growth versus quiescence, and that is defective in cancers, is to be found in G1 phase (Pardee, 1989). Figure...

Virion and Genome Structure

KSHV, or HHV8, has morphological features typical of herpesviruses (Figure 7), consisting of 100-150 nm particles surrounded by a lipid envelope, with an internal electron-rich central core. Its DNA was assessed by pulsed-field electrophoresis as 160-170 kb, consistent with that of other 7-herpesviruses, but more uniform than that observed with EBV. Both circular and linear forms of KSHV have been identified. Larger genomes reported to exist in some tumour-derived cell lines have been shown to...

Tumour Site Concordance

Tumour site concordance of rats and mice is relatively poor. In the FDA, NTP and CPD databases only 20-30 of all compounds with positive findings produced tumour findings in at least one common site in the rat and mouse (Gold etal., 1989 Huff and Haseman 1991 Contrera etal., 1997). The lack of site specificity has been cited as part of the rationale for a reduced 2-year study protocol employing only male rats and female mice (Haseman and Lockhart, 1993 Lai et al., 1994). Since tumour site...

Overview

Tyrosine kinases regulate a large number of cellular functions via an array of signalling pathways. Most, but not all, of these pathways originate at the cell plasma membrane via transmembrane receptor tyrosine kinases or binary receptor--tyrosine kinase couples. Both the tyrosine kinases and their effector pathways are highly regulated and must be integrated both spatially and temporally into the organisation of cellular functions. Mutational activation or overexpression of tyrosine kinases...

Hepatitis C Virus HCV

The identification of HCV in 1989 by Choo and colleagues arose from an investigation of the causes of post-transfusion non-A, non-B hepatitis. It is a single-stranded RNA virus assigned to a separate genus within the family Flaviviruses (which includes yellow fever virus and dengue virus) and is completely unrelated to the HBV. To date, six major subtypes of HCV have been identified, which have different geographical distributions. Acute infection often causes only mild illness, but it is...

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...

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...

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...

Further Reading

Brambilla, C. and Brambilla, E. (eds) (1999). Lung Tumors Fundamental Biology and Clinical Management (Marcel Dekker, New York). Churg, A. and Green, F. H. Y. (1998). Pathology of Occupational Lung Disease, 2nd edn. (Williams and Wilkins, Baltimore). Colby, T. V., et al. (1995). Tumors of the Lower Respiratory Tract. Atlas of Tumor Pathology (Armed Forces Institute of Pathology, Washington, DC). Dail, D. H. and Hammar, S. P. (1988). Pulmonary Pathology, 2nd edn (Springer, New York). Gregor, R....

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...

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...

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...

Vascular Endothelial Growth Factor VEGF

VEGF was the first member to be identified of a growing family of vascular endothelial growth factors and is now referred to as VEGF-A. Other members include VEGF-B to E and placenta growth factor (PIGF-1 and 2). VEGFs are homodimeric proteins and mediate their activity through tyrosine-kinase receptors (VEGF-receptors, VEGFR1-3) which are almost exclusively expressed on endothelial cells. VEGFR-1 (flt-1, fms-like kinase-1) binds VEGF-A, VEGF-B and PIGF with strong affinity whereas VEGFR-2...

Gorlin Syndrome

Gorlin or naevoid basal cell carcinoma syndrome is another autosomal dominant condition which predisposes to malignancy. The condition is characterized by the development of multiple jaw keratocysts in the second decade and basal cell carcinomas in the third decade onwards. Gene mutation carriers also have a recognizable appearance or morphology. They have macrocephaly with bossing of the forehead and the face is usually covered with white milia. The facial features are often coarse and the...

Gross Appearance

The small intestine is approximately 500 cm in length (shorter in life owing to tone in the longitudinal muscle coat) and lacking obvious features on external examination apart from its mesentery (the duodenum is retroperitoneal). The large intestine (colon and rectum) is 150 cm in length and variably covered by peritoneum in its different regions. The longitudinal muscle is arranged in three continuous bands (taeniae coli) which fuse into a continuous sheet at the junction of sigmoid colon and...

UV Radiation

The excitations induced by UV exposure will also produce DNA base changes and breaks in the sugar--phosphate backbone. The most important alterations appear to be cyclobutanepyrimidine dimers and pyrimidine-(6,4)-pyrimidone photoproducts. Replication of DNA containing these lesions leads to C to T transitions at dipyrimidine sites. Nucleotide excision repair processes normally repair these base alterations efficiently and without error. Like ionizing radiation, UV radiation can also induce...

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...

MMR and TGF Receptor

TGF 3-RII, a receptor in the TGF 3 tumour-suppressor pathway, has a special relationship with MMR-deficient colon and stomach cancers. This relationship is due to two circumstances. First, the coding sequence of the human TGFft-RII gene contains a homopolymer tract of 10 adenines that is subject to frame-shift mutation in MMR-deficient cells. This causes premature transcript termination with loss of most of the cytoplasmic domain of the receptor. Among colon tumours, these TGFft-RII frame...

Clinical Management Initial Consultation and Diagnosis

The management of colorectal cancer begins with a process of consultation. This will vary according to the mode of presentation. The consultation may be motivated by altered bowel habit, present as an acute abdominal emergency due to obstruction or perforation or be precipitated by the diagnosis of cancer in an asymptomatic subject participating in a screening program. Regardless of the mode of presentation, frequent, clear and instructive communication is necessary to ensure the best outcome...

Sodium Chloride

A positive correlation between daily salt intake and gastric cancer incidence was noted by epidemiologists some time ago and urinary sodium chloride concentrations are well correlated with stomach cancer mortality. In experimental animal model systems, N-methyl-N'-nitro-N-nitroso-guanidine (MNNG) induces gastric cancers and this is enhanced by salt administration. High doses of salt disrupt the mucin layer covering and protecting the gastric epithelium and further damage epithelial cells by...

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...

Singlestrand Annealing

An alternative mechanism of homologous recombination repair, called single-strand annealing, is important when no sister chromatid is available. This mechanism involves resection or realignment of the broken DNA duplex to regions of homology that may be some distance from the break site. Completion of the repair then only requires DNA strand scission of ligation events. Consequently, the segment of DNA intervening between the realigned regions of homology is deleted, which makes this repair...

P53

The p53 protein is involved in sensing DNA damage and regulating cell death (Marx, 1993). In normal cells, when DNA damage is sensed by p53, the cell cycle is arrested to permit DNA repair. Upon completion of this process, the cell progresses through the mitotic cycle. If repair fails to occur, p53 initiates the process of apoptosis, or programmed cell death. Thus, normal cells with genetic defects die. If p53 is not present in the cell (via gene deletion) or is mutated to be nonfunctional, DNA...

Oncogenic Activation Of The Wnt Pathway

Tumour formation results from the loss of control over cell proliferation. This occurs through mutations that produce oncogenes with a dominant gain of function or inactivate tumour suppressor genes through recessive loss of function mutations. Both types of mutations lead to defects in regulatory pathways that normally control cell proliferation. Recently, it has become clear that components of the -Catenin accumulates, leading to hyperactivation of target genes Gain of function i 33 37 41 45...

Flavonoids

Numerous kinds of flavonoids are present in plants. Among those, quercetin and its glycosides are the most common flavonoids, distributed in vegetables and fruits. Their daily intake by humans is estimated to be more than 100 mg per person. Many flavonoids including quercetin, kaempferol and isorhamnetin show mutagenicity in Salmonella with and without metabolic activation systems, but this is not the case with their glycoside compounds, which require digestion by glycosidase for mutagenic...

TRAFs

The cytoplasmic domain of TNFR2 does not contain a death domain. In fact, under many circumstances, TNFR2 signalling can induce proliferation. This is thought to be mediated by the direct interaction of the intracellular signalling intermediate, TRAF2, with the cytoplasmic tail of TNFR2, which leads to the activation of NF-kB. In cells which respond to TNFR2 signals by proliferating, no caspase activation is observed, and presumably no interaction of TRAF2 with TRADD. However, in cells which...

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...

Structure And Function Of ycDependent Cytokines And Receptors

Members of the cytokine haematopoietic superfamily often share a common receptor subunit while retaining their own private receptor subunits. One well-documented example is that five cytokines, IL-2, IL-4, IL-7, IL-9 and IL-15, form one group, which is characterized by utilizing the common 7 chain (7c) as a receptor subunit. The common 7c subunit was initially cloned as the 7 chain of the IL-2R complex. Soon it was discovered that this 7 subunit also participates functionally in the receptors...

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...

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...

A BRCAlassociated Genome Surveillance Complex BASC

BRCA1 has several protein-binding domains, and may be associated with large multiprotein complexes in the nucleus, including the DNA repair-related proteins MSH2, MSH6, MLH1, ATM, BLM and the Rad50 Mre11 Nbs complex (Wang et al., 2000a,b). The exact structure and function of these complexes is still not clear, however, because it has been difficult to demonstrate specific direct binding in cells (Jun Qin, personal communication). BRCA1-based multimolecular foci perhaps assemble in alternative...

Entry into S Phase

Increased cyclin D and E overcome inhibition of cdk activity, and pRb is phosphorylated. This releases E2F and activates genes involved in initiating S phase, including enzymes of DNA synthesis. An example is DNA polymerase, whose transcription is regulated at Gi S phase by a complex of proteins that contains pRb-like pi07, cyclin A and kinase. It is worth noting that most major cell cycle processes are catalysed by large complexes composed of many proteins. Progression through S phase depends...

The Next Cycle Licensing for DNA Synthesis

A process named licensing permits only one DNA replication per cycle. DNA synthesis cannot be reinitiated until after mitosis is completed. pRb is a critical determinant in preventing DNA reduplication. Perhaps related is the breakdown and reformation during mitosis of the membrane around the nucleus. This permits interaction of molecules from the nucleus and cytoplasm. Degradation of cyclin B by proteasomes is necessary for the start of S phase in the following cycle. Licensing can be...

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...

Motility

Translocation of individual cells across tissue boundaries is a necessary component of invasion. Cell motility and migration are not unique to tumour cells. This process is essential for normal immune cell function and for embryological development, organogenesis and gastrulation. Deregulation and persistence of motility may distinguish carcinoma cells from their normal epithelial counterparts (Nabeshima et al., 1997). The direction of tumour cell motility is controlled by a multitude of...

MMR and Colon Cancer

For reasons unknown, MMR defects are associated mainly with cancer of the colon (predominantly right colon), endo-metrium and ovary. MMR is most closely associated with HNPCC, the most common cancer predisposition syndrome 70 of HNPCC kindred have germ-line mutations in one of the MMR-associated genes. About 60 of the mutations are in hMLHl and about 35 in hMSH2 (Jiricny and Nystrom-Lahti, 2000 http www.nfdht.nl). Tumours of HNPCC kindred with mutations in hMSH2 or hMLHl have strong mutator...

Prospects For Cancer Prevention

In the future, new technology and molecular biomarkers (of exposure, effect and susceptibility) promise to revolutionize the practice of cancer prevention and provide new tools for screening and prevention of occupational cancer. Lung cancer remains the leading cause of death from cancer, and recent developments have generated substantial interest in the use of spiral computed tomography (CT) to screen for lung cancer. The use of lung cancer biomarkers to identify the early clonal phase of...

General Organisation

The gastrointestinal tract is divided into several major anatomical regions, each with its own unique physiological functions and structure. The various regions share a basic structure. The inside has a mucosal lining beneath which is a thin muscular layer known as the muscularis mucosae. The mucosa serves many of the digestive and absorptive functions of the gastrointestinal tract. Beneath the mus-cularis mucosae is the submucosa. The next layer is the muscularis propria, which is responsible...

Inherent Mutability of Methylated Cytosine

The methylation of CpG dinucleotides creates mutagenic susceptibility targets that can subsequently undergo endogenous deamination to form TpG (CpA on the opposite strand) dinucleotide pairs (Figure 4). In contrast to cytosine deamination that results in DNA containing uracil, 5-methylcytosine deamination creates a C to T base substitution that is not as readily recognized by DNA repair proteins as being misplaced in the DNA strand. This contributes to inefficient repair of these lesions, and...

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...

Microscopic Features

Adenomas are typed as tubular, tubulovillous and villous according to the predominant architectural pattern (Figure 3) (Jass and Sobin, 1989). Tubules are lined by columnar epithelium and embedded within lamina propria where they proliferate by branching. Villi (in reality leaves) comprise a covering of columnar epithelium and a core of lamina propria. By forming complex, brain-like folds of epithelium, the surface area of a villous adenoma may be considerable and lead to significant loss of...