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...

Familial Adenomatous Polyposis FAP

FAP is the model condition by which researchers have hoped to transpose knowledge of a rare genetic disease to a commonly occurring cancer. FAP is an autosomal dominant condition characterized by the development of hundreds to thousands of adenomatous polyps in the colon and rectum, usually by 30 years of age (Figure 3 see colour Table 1 Examples of autosomal dominant syndromes predisposing to cancer and their chromosomal location Table 1 Examples of autosomal dominant syndromes predisposing to...

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...

Larynx

Squamous papillomas may arise from the true cords, at other sites in the larynx, the oropharynx and the trachea. They may be part of juvenile laryngeal papillomatosis, which may be single or multiple. 'Juvenile' is arbitrarily classified as presenting before the age of 20 years. Multiple is usually defined as more than three lesions. Most laryngeal papillomas are probably caused by HPV, types 6 and 11 (Travis et al., 1999). These tumours are glistening, nodular, exophytic masses and, depending...

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,...

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...

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)....

DNA Repair

In addition to polymorphisms in carcinogen metabolism, a potentially important source of variability is also DNA repair capability, including the genetic instability syndromes. These are rare, recessive traits that include ataxia-telangiectasia, Fanconi anaemia and Bloom syndrome, all characterized by both chromosome instability and high risk of cancer, and xeroderma pigmentosum, characterized by extreme susceptibility to UV radiation-induced skin cancer (Friedberg et a ., 1995). In addition to...

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...

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...

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...

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...

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,...

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...

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...

NAcetyltransferases NAT1 NAT2 and Cytochrome P450 CYP Enzymes

The weak effects of diet upon cancer risk might be increased by genetic factors. For example, at least three enzymes (NAT1, NAT2 and CYP1A2) influence the metabolism of heterocyclic amines produced in the course of cooking meat at high temperatures and hydrocarbons contained in tobacco smoke. Particular genetic polymorphisms affect the activities of these enzyme systems, but consistent correlations between genotypes, lifestyle factors and risk have not been demonstrated to date (Potter, 1999).

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...

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...

Chance Confounding And Bias

Three issues need to be resolved before an epidemiological association could be considered true and therefore deserve interpretation in causal terms chance, confounding and bias. Probabilistic processes always have a built-in uncertainty, but we can reduce the chance-related uncertainty by using progressively larger numbers in a study, and we can assess its possible influence by utilizing statistical procedures that generate what has become known as the P value. This value indicates how likely...

Precursors of Skin Cancer Dysplastic Moles and Actinic Solar Keratoses

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...

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...

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...

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...

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...

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...

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...

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,...

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...

Pathology Tumours Of The Liver

The term 'hepatoma' is often used loosely to describe any primary tumour in the liver but it has no precise meaning. Many different types arise which are designated by their cell of origin (Anthony, 1994). The commonest is liver cell or hepatocellular carcinoma, followed by bile duct or cholangiocarcinoma and various sarcomas, of which angio-sarcoma is the most important. Benign tumours are uncommon. Table 1 shows a detailed classification of liver tumours but only those that are common and or...

The Protein Defective in Werner Syndrome WRN

Werner syndrome (WS) is a homozygous recessive disease characterized by early onset of normal ageing including wrinkling of skin, greying of hair, cataracts, diabetes and osteoporosis. Neoplasms, particularly sarcomas, are observed at higher prevalence in WS patients than in normal individuals of the same age. The symptoms of WS begin to appear near puberty, and most patients die before reaching age 50. Because the clinical features of WS are similar to symptoms of ageing in normal individuals...

Viral Replication

The term RNA tumour viruses generally represents retro-viruses that contain reverse transcriptase (RT), which transcribes genomic RNA into DNA upon infection. Cores of the viral particles contain two copies of a single-stranded, positive RNA, Gag protein and reverse transcriptase. The core is enveloped with membrane similar to the plasma membrane of host cells, on which the viral Env (envelope) glycoprotein is exposed. The interaction of the Env protein with a receptor on a target cell membrane...

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)...

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...

Epidermis

The outermost layer of the skin, the epidermis, is another example of a self-renewing tissue. The epidermis is predominantly made up of keratinocytes (about 80 of the total). Other epidermal cell types exist with specific functions melanocytes give the skin its pigmentation and afford some protection against ultraviolet light, Merkel cells sense fine mechanical events and Langerhans cells form part of the body's immune system. The outer surface of the epidermis is called the stratum corneum and...

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...

Molecular Mechanism of Pathogenesis

The aetiological role of HTLV-1 in ATL has been demonstrated by sero-epidemiology and molecular biology of HTLV-1 and ATL. The bases of this are as follows (1) ATL and HTLV-1 geographically overlap (population level) (2) most ATL patients are infected with HTLV-1 (individual level) (3) leukaemic cells from ATL patients are infected with HTLV-1 (cell level) (4) more importantly, the leukaemic cells show monoclonal integration of proviral DNA (molecular level) and (5) HTLV-1 has the capacity to...

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...

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...

Vessel Formation And Maturation

In the final stage of angiogenesis, vessel assembly and maturation result in a vessel that is a stable conduit for blood flow. This is achieved by two processes, namely anastomosis of the developing sprouts and recruitment of pericytes. Subsequent to the degradation of the basement membrane and outgrowth of vessel sprouts, the sprouts develop into hollow tubes and two sprouts may then join to form a tube through which blood flows. Once formed, the endothelial tubes recruit a layer of pericytes...

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...

Sinonasal TNK Cell Lymphoma

Virtually no B cells are seen in normal nasal epithelium but there are T cells. T helper cells outnumber the T cytotoxic suppressor cells. T NK cell lymphoma used to be termed midline malignant reticulosis, lethal midline granuloma and midfacial destructive lesion, amongst others. These terms are now no longer used. T NK lymphoma is an angio-centric, immunoproliferative lesion. It is commoner in Asians. The disease can occur at any age with a median of 47 years with a male predominance (Aozasa...

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...

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...

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)....

Exogenous Antigenotoxins

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...

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...

Consequences of Disrupted Tissue Organisation

Based on the above, it is clear that 3D tissue-type morphology and the related intracellular organisation imposed by the ECM determine whether cells will differentiate, proliferate or undergo apoptosis. With respect to differentiation, it is clear that in addition to cellular rounding, establishing polarity and forming junctional complexes are equally critical for maintaining this state. It might be predicted Figure 2 Intracellular organisation of polarized, quiescent epithelial cells in...

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...

Restoring a Cells Balance of Surface Receptors and Interaction with the BM Can Reverse Tumorigenesis

Although attempting to restore a normal dialogue with the ECM might at first seem somewhat naive to apply to genetically destabilized tumour cells, in fact re-establishing a functional BM and 3D organisation, or restoring a tumour cell's ability to recognize and respond to BM, can in fact induce growth arrest in tumorigenic cells. Trans-fection of the tumorigenic breast epithelial cell line MDA-435 with the NM-23 tumour suppressor resulted in the ability of the cells to resynthesize and deposit...

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...

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...

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...

Figure 3 Organisation of a PV consensus genome in kilobase pairs The open boxes represent ORFs labelled E1E6 or LI and

The total protein mass) with the capsid proteins, but this does not occur in lesions caused by other PVs (Arrand, 1994). The E5 proteins are small (44-90 amino acids) and extremely hydrophobic polypeptides, which are present within intracellular membrane compartments, including the Golgi apparatus. In bovine (B)PVs, E5 is the major transforming protein and appears to stimulate mitogenesis by interfering with growth factor receptor signal transduction pathways (Stoppler et al., 1994). The E6...

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...

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...

Introduction

The concept that chemicals can cause cancer chemical carcinogenesis has been accepted for some time. As long ago as 1775, the English physician Sir Percival Pott noted the incidence of scrotal cancer in chimney sweeps and perceptively suggested that the disease was related to their occupation. He further suggested that it was soot that was the cause of their disease. Since this observation, the number of chemicals strongly associated with the development of cancer has substantially increased....

Microscopic Features Histological Patterns and Cytological Variants Ultrastructure and Special Techniques

Canalicular Expression Cea Poly

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...