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...

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...

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...

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...

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...

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...

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...

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...

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...

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...

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...

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...

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....

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...

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...

Introduction

Investigators in the field of cancer research have always regarded cell proliferation, a fortiori, as of paramount importance. The reasons for this are not difficult to identify. It is generally accepted that tumours arise as a result of a series of mutations occurring in a cell, often said to be a stem cell. In the colorectal epithelium, for example, several of the mutations required for malignant transformation have been identified such a series of mutations accumulate in a single cell and...

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...

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...

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...

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...

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...

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...

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...

Wilms Tumour

Wilms' tumour, like retinoblastoma, has also been known for some time to have a hereditary element. However, the genetic basis is far more complex and the familial element much smaller. The first step to identifying a gene came with the discovery of a cytogenetically visible deletion in chromosome 11 in families with autosomal dominant aniridia who appeared to be predisposed to Wilms' tumour (Riccardi et al., 1978). Deletions in this area (11p13) also lead to genital and renal anomalies and...

Adjuvant Therapy for Colon Cancer

Approximately 50 of subjects with stage III or Dukes C colon cancer will relapse with distant metastases and die within 5 years of surgery. This is explained by the presence of occult hepatic metastases at the time of surgical treatment. The aim of an adjuvant approach is to destroy these metastases at a time when they are of microscopic dimensions and therefore more amenable to cytotoxic therapy. Randomized controlled trials have to date demonstrated significant improvements in survival with...

At the Cell Surface The Reception of Wnt Signals

For many years the identity of Wnt receptors remained elusive, leaving a large gap in our understanding of Wnt signalling. This hole has now been filled with the finding that members of the Frizzled gene family can function as Wnt receptors (Figures 1 and 3 Bhanot et al, 1996 Yang-Snyder et al., 1996). Frizzled genes encode seven-transmembrane proteins with an N-terminal cysteine-rich domain that binds Wnts with high affinity. Like the Wnt gene family, members of the Frizzled gene family have...

Inhibitor Of Apoptosis Iap Family Proteins Function As Caspase Inhibitors

All protease networks studied to date include inhibitors which control flux through proteolytic cascades and which establish thresholds for protease activation which must be surpassed to trigger biological processes. The inhibitors of apoptosis proteins (IAPs) represent a family of anti-apoptotic proteins conserved throughout metazoan evolution that appear to serve this role. IAPs were first identified in the genomes of baculoviruses, where they suppress apoptosis induced by viral infection of...

In the Nucleus Regulation of Gene Expression by Catenin and TCFLEF

As we have seen, cells have evolved a very elaborate and complex mechanism for regulating intracellular levels of 3-catenin. Wnt signalling frees -catenin from the destruction complex and it now accumulates in the cell. What happens next It is now dogma that upon Wnt stimulation 3-catenin accumulates and enters the nucleus, where it regulates gene expression. However, when first proposed the idea that the nucleus was the primary location of catenin function in Wnt signalling seemed hard to...

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...

Figure 1 IFN7 signal pathway

Intracellular membrane-proximity domains of IFNGRs are then activated through auto- and transphosphorylation. The activation of the JAKs occurs in sequence, such that JAK2 activates first and is required for JAK1 activation. Once activated, the JAKs phosphorylate a tyrosine-containing sequence near the C-terminus of IFNGR1, where paired ligand-induced docking sites for STAT1 are formed. Two inactive, monomeric STAT1 proteins then bind to these sites through their SH2 domain and are...

Diffuse Idiopathic Neuroendocrine Hyperplasia Dipnech

DIPNECH is a proliferation of neuroendocrine cells limited to the bronchiolar epithelium (Figure 18 see colour plate section). There are increased numbers of scattered single cells, small nodules (neuroendocrine bodies) or linear proliferations of neuroendocrine cells within the bronchiolar epithelium. It is typically associated with obliterative bronchiolar fibrosis and co-existing interstitial or airway fibrosis or inflammation should be absent. This is because, especially with inflammation,...

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...

Malfunctions of Control

The first stages of cancer formation are associated with malfunctions in the control mechanisms described above, in such a way that the critical balance between cell proliferation and cell loss by differentiation or apoptosis is disturbed or deregulated. If this balance is shifted in favour of proliferation, the tissue will expand in a progressive and eventually uncontrolled manner, distorting the tissue structure and function. The balance may only need to be shifted slightly in favour of...

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...

Prognostic Factors

The most common forms of skin cancer, namely squamous cell and basal cell carcinoma, are slowly growing, locally invasive, and tend not to exhibit metastatic behaviour. As mentioned earlier, some squamous cell carcinomas, particularly those that involve facial skin, may metastasize to local lymph nodes. Basal cell carcinomas rarely metasta-size, but when they do, large tumour size tends to be a constant feature. Locally aggressive basal cell carcinomas often will show a sclerosing or diffusely...

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...

Figure 1 Schematic structures for receptor and nonreceptor protein tyrosine kinases showing variations in the two

Two of the most important are illustrated in Figure 3b, Ras-MAP kinase and JAK-STAT. The receptor-Ras-MAP kinase pathway consists of four main elements (Figure 3a and b Table 3) the receptor which receives and transmits the signal through the membrane an adaptor system (Grb2-SOS) which couples the receptor to a membrane switch (Ras) the Ras switch, which is activated by that coupling mechanism, then activates downstream kinases and the MAP kinase cascade...

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...

Mitochondrial Pathways For Caspase Activation

In addition to receptor-mediated mechanisms for coupling caspase activation to ligation of specific cell-surface receptors, a pathway has been elucidated which links mitochondrial damage to a mechanism for triggering caspase activation. This mitochondrial pathway for cas-pase activation is engaged in response to growth factor deprivation, genotoxic injury, hypoxia and many other insults, and is commonly referred to as the 'intrinsic' pathway, in contrast to the receptor-mediated caspase...

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....

Invasion

Invasion is the active translocation of neoplastic cells across tissue boundaries and through host cellular and extracellular matrix barriers. Invasion is dependent on the coordinated activity of a series of interacting proteins extending from the inside of the cell to the cell surface and the adjacent host cellular and extracellular microenvironment (Figure 3). Cellular adhesion, local proteolysis and motility are the triad of necessary functions that mediate invasion. While invasion is not...

Bax bcl2 and p53 in Neuroendocrine Tumours

The bax gene is one of the main effectors of apoptosis and can be considered a tumour suppressor gene. Bcl-2 is an oncogene and can block both p53-mediated and p53-independent apoptosis. There is an inverse correlation between the scores of Bax and bcl-2 expression in NE tumours. A predominant Bax expression is seen in low-grade NE tumours (TC or AC) and mainly bcl-2 expression in small-cell and large-cell lung cancers. The p16-retino-blastoma pathway is normal in typical carcinoids but...

Musings

The chemokine-induced cellular signal is complex and still poorly characterized. The activation of G-protein subunit-mediated signals is clear, but other non-G-protein-mediated signals still require clarification. Receptor de-sensitization and resensitization are a great mystery, with few well-characterized components, other than serine--threonine phosphorylation of the GPCR carboxyl tail. Several groups have shown tyrosine kinase activation in response to chemokines however, because the cell...

Janus Kinases

The Janus kinases (JAKs) are cytoplasmic tyrosine kinases which mediate signalling from a number of cell surface receptors which lack intrinsic tyrosine kinase activity. Four mammalian members of the JAK family are known, JAKs 1-3, and TYK2 (Ihle, 1995). Whereas JAK1, JAK2 and TYK2 are expressed ubiquitously, expression of JAK3 is confined to haematopoietic and lymphoid cells. Characteristic of the structure of JAKs is the presence of two JAK homology (JH) domains, of which the C-terminal (JH1)...

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...