bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of peroxisome proliferator-activated receptor activation on gonadotropin transcription and cell mitosis induced by bone morphogenetic proteins in mouse gonadotrope LβT2 cells
Authors: Takeda Masaya , Otsuka Fumio , Otani Hiroyuki , Inagaki Kenichi , Miyoshi Tomoko , Suzuki Jiro , Mimura Yukari , Ogura Toshio , Makino Hirofumi
Published: October 2007

Involvement of peroxisome proliferator-activated receptor-γ (PPAR-γ ) activation and bone morphogenetic protein (BMP) signaling in regulating cell proliferation and hormonal production of pituitary tumors has been reported, although the underlying mechanism remains poorly understood. Here, we investigated regulatory roles of PPARα and PPARγ in gonadotropin transcription and cell mitosis modulated by pituitary activin/BMP systems using a mouse gonadotropinoma cell line Lβ T2, which expresses activin/BMP receptors, transcription factor Smads, PPARα , and PPARγ . In Lβ T2 cells, BMP signaling shown by Smad1/5/8 phosphorylation and Id-1 transcription was readily activated by BMPs. A PPARγ agonist, pioglitazone significantly reduced BMP-induced DNA synthesis by Lβ T2; whereas the PPARα agonist, fenofibric acid, did not. In accordance with the effects on cell mitosis, pioglitazone but not fenofibric acid significantly decreased BMP-induced Id-1-Luc activation. Neither fenofibric acid nor pioglitazone affected activin signaling detected by (CAGA)9-Luc activity. Both PPARα and PPARγ ligands directly suppressed transcriptional activities of FSHβ , LHβ , and GnRHR. Activation of PPARα and PPARγ increased mRNA levels of follistatin, but did not affect the expression of follistatin-related gene. Thus, PPAR agonists not only directly suppress gonadotropin transcription and BMP signaling, but also inhibit the biological actions of activins which facilitate gonadotropin transcription through upregulating follistatin expression. In addition, pioglitazone increased BMP ligands mRNA, but decreased activin-β B mRNA in Lβ T2 cells. Collectively, PPAR activation differentially regulates gonadotrope cell proliferation and gonadotropin transcription in a ligand-dependent manner.
Effect of age and moderate food restriction on insulin sensitivity in Wistar rats: role of adiposity
Authors: Escrivá Fernando , Gavete M Lucía , Fermín Yasmín , Pérez Coralia , Gallardo Nilda , Alvarez Carmen , Andrés Antonio , Ros Manuel , Carrascosa José M
Published: October 2007

Insulin resistance develops with ageing in humans and rodents. Here, we have studied the evolution of insulin sensitivity with ageing trying to discriminate the role of adiposity from that of ageing in this process. We performed oral glucose tolerance tests and determined overall and tissue-specific glucose utilization under euglycemic-hyper-insulinemic conditions in 3-, 8-, and 24-month-old rats fed ad libitum, and in 8- and 24-month-old rats after 3 months of calorie restriction. Body composition and adipocyte-derived cytokines such as leptin, resistin, and adiponectin were analyzed. Overall insulin sensitivity decreases with ageing. Calorie restriction improves global insulin sensitivity in 8- but not in 24-month-old rats. Insulin-stimulated glucose utilization in adipose tissues decreases in 8 months, while in oxidative muscles it reaches significance only in older rats. Calorie restriction restores adipose tissue insulin sensitivity only in 8-month-old rats and no changes are observed in muscles of 24-month-old rats. Resistin and leptin increase with ageing. Food restriction lowers resistin and increases adiponectin in 8-month-old rats and decreases leptin in both ages. Visceral and total fat increase with ageing and decrease after calorie restriction. We conclude that accretion of visceral fat plays a key role in the development of insulin resistance after sexual maturity, which is reversible by calorie restriction. With aging, accumulation of retroperitoneal and total body fat leads to impaired muscle glucose uptake and to a state of insulin resistance that is difficult to reverse.
Reflections on the Health Social Sciences—Then and Now
Authors: Elling Ray
Published: October 2007

After its beginnings in the United States, medical sociology started to take hold in Germany in 1958 with a conference that resulted in the first book on medical sociology published in Germany. From uneasy marginality, the field has grown to include disciplines other than sociology—anthropology, economics, and political economy. Today, the field might best be called the “health social sciences.” The main body of work employs the consensual perspective, but work done using a class conflict perspective is increasingly significant.
Genetic Susceptibility to Cancer
Authors: Spain Sarah , Tomlinson Ian P. M.
Published: October 2007

Many cancers and benign tumours probably result, at least in part, from inherited factors. In addition, the presenting features of cancers, response to treatment, and outcome may depend on genetic influences. For most patients, these genetic factors are likely to take the form of alleles with small effects on risk or tumour behaviour, and most of the genes involved have not yet been characterized. The Mendelian (single gene) predisposition disorders that are associated with a high lifetime risk of cancer and/or benign tumours have been better characterized. Although there is considerable heterogeneity in these conditions in terms of the genes involved, tumour site, multiplicity of tumours, molecular pathways involved, and underlying mechanisms of tumourigenesis, most Mendelian tumour susceptibility genes are dominantly inherited tumour suppressors that normally restrain cell proliferation in some way, or recessively inherited alleles involved in DNA repair or the maintenance of genome integrity. Many of the genes involved in the Mendelian syndromes are mutated or otherwise altered somatically in sporadic cancers. Genetic testing for the Mendelian conditions is now largely routine, but should large numbers of low‐risk alleles be identified, the potential financial burden of population‐level genetic testing will be great. It will, therefore, be important to make sure that this testing is used selectively for cancers for which prevention is possible and is most effectively targeted at those with increased genetic risk.
HumanDNATumour Viruses
Authors: Talukdar Sabrina , Herrington C. Simon
Published: October 2007

The four human deoxyribonucleic acid (DNA) tumour viruses recognised by the World Health Organisation to be carcinogenic cause tumours by virtue of their reliance on host cell machinery for replication. The viruses modify host cells in such a way that they are susceptible to the synergistic effects of other carcinogens, resulting in cumulative mutations that push the infected cell along the multi‐step pathway to neoplasia. Tumour formation is a rare complication of these common viral infections and is determined by a combination of host, viral, and environmental factors. Viruses have crystallised current concepts in cancer biology and their involvement in human tumours has led to the development of vaccination strategies that aim to reduce the worldwide cancer burden attributed to these viruses.
Telomerase
Authors: Wright Woodring E. , Shay Jerry W.
Published: October 2007

Telomeres progressively shorten in almost all normal human tissues with increased age. In pre‐neoplasia, telomeres are exceptionally short. Almost all human malignant tumours express telomerase to maintain these short telomeres. This activity is absent or is at lower levels in normal tissues. This has led to approaches for inhibiting telomerase as a target for cancer therapeutics. Cancer stem cells have been shown to be both telomerase expressing and containing short telomeres. This suggests that telomerase inhibitors are likely to target both the bulk of the more differentiated tumour cells as well as the stem cells that provide the unlimited growth of most advanced cancers.
Signalling by Steroid Receptors
Authors: Speirs Valerie
Published: October 2007

Steroid hormones such as oestrogens control a wide variety of functions important for cell homeostasis, proliferation, differentiation, and apoptosis. Their action is mediated by specific hormone receptors, oestrogen receptor (ER)‐α and ERβ, which belong to a large superfamily of nuclear receptors. Typically, ERs function as ligand‐activated transcription factors, binding to specific oestrogen response elements (EREs) within target gene promoters and initiating a downstream response. Ligand‐independent gene transcription can also occur via tethered interactions with activating protein 1 (AP‐1) and stimulating protein 1 (SP1) proteins. A third pathway has been identified, involving membrane‐initiated signalling. These pathways are not mutually exclusive with evidence of considerable crosstalk between them. This chapter focuses on recent developments related to our understanding of these ER‐signalling mechanisms.
Signalling by Cytokines
Authors: Kawasaki Brian T. , Howard O. M. Zack , Gamero Ana M. , Farrar William L.
Published: October 2007

Cytokines are small, soluble proteins with a variety of biological effects. Many cell types, not limited to the immune system, secrete these proteins. Cytokines can be grouped into four major families based on structure: haematopoietins, interferons (IFN), tumour necrosis factor (TNF) and chemokines. Within the haematopoietin family, groups can be subdivided based on binding to their “common” cognate receptor. For the purposes of brevity, the γ‐common (γc) chain will be discussed as a model system for the haematopoietins. There are three classes of IFNs (types I, II, and III) and they constitute one of the largest and most divergent subfamily of cytokines. Membrane‐bound as well as secreted proteins make up the members of the TNF family of cytokines, which trimerize upon activation. Lastly, the chemokines form a class of cytokines that bind to a large family of seven transmembrane spanning G‐protein‐coupled receptors (GPCRs).
Signalling by Tyrosine Kinases
Authors: Carraway Kermit L. , Carraway Coralie A. Carothers
Published: October 2007

The first recognized oncogene was a protein‐tyrosine kinase, an enzyme which transfers phosphate from adenosine triphosphate (ATP) to proteins. Two classes of these enzymes have been described, receptor and non‐receptor, both of which have been implicated in numerous types of cancers. Phosphate groups on these enzymes or their substrates act as docking sites for specific domains on proteins, which initiate signalling pathways involved not only in oncogenesis, but also in mammalian cell differentiation, cell death, and angiogenesis. Activation of the kinases is critical to their actions and often involves extracellular ligands acting directly (receptor) or indirectly (non‐receptor) on the kinase. Kinases can also be regulated by dephosphorylation by phosphatases or proteolytic degradation. Downstream signalling pathways of the tyrosine kinases are often complex, diverse, versatile, and interactive, regulating multiple cellular functions, including transcription, translation, cell motility, cell polarity, and the cell cycle.
Invasion and Metastasis
Authors: Pierobon Mariaelena , Geho David , Belluco Claudio , Liotta Lance A.
Published: October 2007

Cancer is usually diagnosed and treated when it is too late for local therapeutic strategies and most patients already harbour occult or overt metastasis. Metastatic dissemination can occur via lymphatic and vascular systems and represents the final stage of a disease process that can evolve over 5–20 years. Unrestrained growth by itself does not cause metastasis; additional genetic mutations over and above those that cause uncontrolled proliferation are needed. Less than 0.05% of circulating tumour cells are successful in initiation and development of a metastatic process. Metastatic distribution varies widely with histological type and anatomical location of the primary tumour. The organ preference for metastatic colonization is strongly influenced by communications between the circulating tumour cells and the target host tissue through a variety of molecular mechanisms. Moreover the presence of the new malignant cells within the invaded host tissue is associated with a local reorganization of the stroma, blood vessels, lymphatics, and epithelial morphology. Host cells contribute to enzymes and cytokines that promote tumour cell survival and invasion. Significant progress has been made in our understanding of the molecular cross‐talk between tumour cells and host cells at the invasion front. Several molecules including cytokines, growth and motility factors, matrix components, and degradative enzymes are thought to be required for the invasion process. Based on the cellular and extracellular context of the microenvironment, cytokines, stromal elements, and immune factors may promote or retard cancer pathogenesis. 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. Cellular adhesion, local proteolysis at the cell surface and of the extracellular matrix, and motility are the triad of necessary functions that mediate invasion. Normal tissue morphology and organ architecture are tightly regulated by a communication reciprocity between the tissue cells and the extracellular matrix and/or basement membrane. Instead of being autonomous, malignant cells communicate extensively with other cells and the extracellular matrix. Moreover, the transition from normal epithelium to invasive carcinoma is sturdily associated with activation of local host vascular elements, stromal fibroblasts, and matrix turnover. Locally activated vascular channels at the invasive edge of the tumour are highly permeable and offer a reduced barrier for intravasation. The transformation of epithelial cells into mesenchymal elements plays an important role in the promotion of the invasive phenotype. Tumour cells that successfully invade and metastasize are selected out because somatic genetic progression has resulted in an altered communication circuit that continues to call up and support invasion and survival.
Mechanisms of Chemical Carcinogenesis
Authors: Gooderham Nigel J. , Carmichael Paul L.
Published: October 2007

It is generally accepted that exposure to noxious chemicals is the single most important contributor to the incidence of human cancer. Invariably, exposure to such chemicals is through complex mixtures where it is often masked by the myriad of other materials present. In the majority of instances, exposure is frequently repeated, often over a lifetime. The consequence of this exposure is an interaction of the chemical with key biological macromolecules, usually DNA, resulting in biochemical changes that are, for the most part, unnoticed. Yet, such exposure, especially when cumulative, ultimately leads to a profound change in the behaviour of cells via a series of subtle and insidious events. At the point at which these chemical/environment‐mediated events give rise to cellular changes that can be detected (often the appearance of a lump), the damage has been done and the cancer is established. Defining how exposure to chemicals can lead to these complex biological events and ultimately to the development of neoplasia has been extremely important in our understanding of the aetiology of human cancer. This knowledge has aided and guided our approach to assessing the risk to such chemicals and has offered insights into how cancer can be avoided and treated.
Stem Cells and Tumourigenesis
Authors: Alison Malcolm R. , Burkert Julia , Wright Nicholas A. , Leedham Simon
Published: October 2007

The origin and propagation of neoplastic growth appear to be from stem cells, initially affecting normal stem cells and then involving neoplastic stem cells whose identity will be paramount for successful chemotherapeutic targeting. Many, if not all cancers contain a minority population of self‐renewing stem cells, thecancer stem cells(CSCs) that are entirely responsible for sustaining the tumour as well as giving rise to proliferating but progressively differentiating cells that contribute to the cellular heterogeneity typical of many solid tumours. Thus, the bulk of the tumour is often not the clinical problem; the identification of CSCs and the factors that regulate their behaviour are likely to have an enormous bearing on the way we treat neoplastic disease in the future. This chapter summarizes our knowledge of the origins of some cancers from normal stem cells, the evidence for the existence of cancer stem cells and illustrates some of the stem cell renewal pathways that are frequently aberrant in cancer.
Signalling by Ras and Rho
GTPases
Authors: Wallace Sean W. , Jaffe Aron B.
Published: October 2007

RAS and RHO proteins constitute two branches of the RAS superfamily of small guanosine triphosphatases (GTPases) (Figure 1). Like all GTPases, these proteins cycle between an active, guanosine triphosphate (GTP)‐bound form, and an inactive, guanosine diphosphate (GDP)‐bound form. Two families of proteins, guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs), activate and inactivate the GTPases, respectively, and the activity of GEFs and GAPs are controlled by a large number of cellular cues. Active GTPases interact with a diverse group of proteins, termed
effectors
, which transduce the signal from the GTPase, resulting in a range of cellular responses. RAS GTPases and components of the signalling pathways controlled by them are frequently mutated in human cancers. RHO GTPases are key regulators of many normal cellular processes which go awry during tumour progression.
Physical Causes of Cancer
Authors: Schwartz Jeffrey L.
Published: October 2007

Physical carcinogens act by imparting energy into the biological material. This chapter summarizes what is known about different physical carcinogens. This chapter focuses primarily on the carcinogenic effects of ionizing radiation, such as γ rays and X rays, and on non‐ionizing radiation, such as ultraviolet light and microwave radiation. The chapter also contains information on the evidence for and against electric and magnetic field (EMF) and ultrasound exposure leading to cancer. All these physical agents are ubiquitous in our environment. Understanding the risks associated with exposure aids in developing appropriate protection standards and approaches to reducing risks.
p53 Family Pathway in Cancer
Authors: Bourdon Jean‐Christophe , Lane David P.
Published: October 2007

P63, P73, and P53 are members of a transcription factor family involved in cell responses to stress and differentiation.P53is the most frequently mutated gene in human cancer (50%) and P53 activity is considered to be ubiquitously lost in cancers.P63,P73, andP53genes have a dual gene structure. They encode for multiple P63, P73, or P53 proteins containing different protein domains (isoforms) owing to multiple splicing, alternative promoter, and alternative initiation of translation. In this review, we describe the different P63/P73/P53 isoforms and their roles in cancer. The interactions between P53, P63, and P73 isoforms are likely to be fundamental to our understanding in the transition between normal cell cycling and the onset of tumour formation.

Our clinical data suggest that failure of appropriate expression of P53 isoforms have a role in carcinogenesis since attenuation of the WT P53 response would render the cells more susceptible to further genetic damage and therefore to neoplastic transformation and tumour progression. Tumours with abnormal P53 isoform expression would have a predicted phenotype of WT P53 by sequence but compromised P53 activity. Moreover, P53 immunostaining on tumour sections should be carefully interpreted as commonly available P53 antibodies do not detect every P53 isoform. We recommend the use of polyclonal anti‐p53CM1 antibody as it recognizes all P53 isoforms which can be localized in the nucleus and in the cytoplasm. Therefore, as P53 staining could be different from one tumour to another, we recommend the use of the secondary HRP‐conjugated anti‐rabbit IgG antibody alone as a negative control and the assessment of CM1 reactivity on positive controls. Such controls are forgotten in many immunohistochemistry studies.
Micro‐
RNAs
as Oncogenes and Tumour Suppressors
Authors: Thomson J. Michael , Hammond Scott M.
Published: October 2007

Sequencing and annotation efforts have compiled a list of protein‐coding genes in the human genome. Largely overlooked, however, is the presence of non‐coding RNA genes. Micro‐RNAs comprise one such group of non‐coding RNAs. Due to the widespread effects they have on gene expression, micro‐RNAs are receiving a tremendous amount of scientific interest. This has reached a peak with the identification of specific micro‐RNA genes that function as human oncogenes and tumour suppressors. This chapter will present an overview of this amazing class of RNAs, and discuss their connection with human cancer.
Non‐Genotoxic Causes of Cancer
Authors: Roberts Ruth A.
Published: October 2007

Cancer is a multi‐stage process by which a normal cell progresses through increasing abnormality to malignancy. Genotoxic carcinogens cause cancer by inducing DNA damage that can lead to altered cellular behaviour via changes in gene expression and/or functionality of the expressed mutated proteins. In contrast, non‐genotoxic carcinogens cause cancer without directly altering the DNA sequence; in general, they act by altering cell‐growth regulation via mechanisms other than mutation. The concept of non‐genotoxic causes of cancer is best understood within the multi‐stage model of carcinogenesis. In this model, spontaneous DNA damage is fixed into the genome during DNA synthesis; this “initiated” cell can then be promoted by further rounds of cell replication to form a tumour provided it is protected from apoptosis. Thus, any chemical or physical stimulus that induces cell proliferation and/or suppresses apoptosis may cause cancer. This chapter will discuss examples and mechanisms of non‐genotoxic carcinogenesis, human relevance, and issues around detection and risk assessment.
Short‐Term Testing for Genotoxicity
Authors: Gatehouse David
Published: October 2007

Exposure to particular chemicals or complex mixtures can lead to cancer in later life, and it is now believed that many cancers can arise from damage to DNA and the resulting mutations. As a consequence of this, it has become necessary to determine whether widely used chemicals or potentially useful new chemicals possess the ability to damage DNA. Data concerning the genotoxicity of a new chemical have become part of the basic toxicological information package.

In this chapter, the individual test systems that are required for genotoxicity screening are described together with a discussion on how the results obtained should be interpreted. The test systems described are the bacterial mutation assay (commonly termed the
Ames test
),
in vitro
mammalian cell assays for the detection of chromosome damage and gene mutations, and
in vivo
rodent assays for the detection of micronuclei and unscheduled DNA repair synthesis. As well as these primary test systems, there is also a description of the supplementary assays that may be required when investigating positive effects, including the comet assay and gene mutation assays using transgenic animals. Detailed guidance on the performance of any of these tests is not given, but this information is referenced at the end of the chapter. The chapter concludes with a brief overview of some of the recent developments in the field, specifically the use of modified assays for high‐throughput screening, the application of expert computer systems for predicting genotoxicity, and the possible impact of toxicogenomics on genotoxicity screening in the future.
Molecular Epidemiology of Cancer and the Use of Biomarkers
Authors: Vineis Paolo
Published: October 2007

Molecular epidemiology was introduced in the study of cancer in the early 1980s, with the expectation that it would help overcome some of the limitations of other forms of epidemiology. The expectation was that improvements in exposure assessment, the measurements of early and common changes preluding the disease, and the identification of subgroups in the population with higher (genetic) susceptibility to cancer might increase the ability of epidemiological studies to identify the causes of cancer and to investigate mechanisms. Research in molecular epidemiology in the last 20 years has, in fact, followed this general model and many key research findings are supportive. For example, as originally proposed for genotoxic carcinogens, a continuum between exposure and disease has been described, which involves metabolism (activation or deactivation of the carcinogen), adduction to proteins or deoxyribonucleic acid (DNA) (i.e., formation of links by the active metabolite), structural DNA alterations like mutations or chromosome damage, and finally cancer onset. Genetic, nutritional, and clinical susceptibility are viewed as potentially important effect modifiers. The chapter discusses the main methodological problems encountered in investigations of molecular epidemiology.
Occupational Causes of Cancer
Authors: Weiderpass Elisabete , Boffetta Paolo , Vainio Harri
Published: October 2007

In this chapter, we summarize the evidence about known and suspected occupational carcinogens and cancer risk in humans. We list the agents of mixture for which, according to the definitions from the International Agency for Research on Cancer (IARC), there is sufficient evidence for carcinogenicity in humans (Group 1), and the agents (mixture) that are probably carcinogenic to humans (Group 2 A). We also summarize the estimates of the burden of cancer attributable to occupation for mesothelioma, lung, bladder, sinonasal, and laryngeal cancers. Finally, we comment on possible preventive strategies to avoid cancers caused by occupational exposures.
Multidisciplinary Team Management of Colorectal Cancer
Authors: Wasan Harpreet S.
Published: October 2007

The treatment of colorectal cancer should only be managed within the context of a multidisciplinary team to improve patient outcomes. Complex clinical decisions, combined with increasing options for management compel us to ensure that the patient is at the centre from the outset in mapping a treatment pathway and strategy. Traditional combined modality approaches between general surgeons, radiologists, general medical oncologists, and radiotherapists are shifting rapidly into superspecialist arenas. Specialist imaging and interventional radiologists, surgeons expert in total mesorectal excisions, expert pathologists, liver and lung surgeons, and gastrointestinal oncologists with expertise and access to the latest biologically targeted agents (including trial compounds) are increasingly expected to be part of the decision‐making process at some stage of the patient's cancer journey. The synergies and potential toxicities of different sequential multidisciplinary approaches can only be decided with dynamic regard to the expanding evidence base and experience of each team.

Even the small percentage of patients with early cancers such as Dukes' A cancers need assurance that the local surgical and pathology standards are such that the probability of understaging is negligible within minimum audit standards, as defined and reviewed regularly by the specialist multidisciplinary team. These are, however, the only groups of patients who may not need oncological input. Thus the vast majority of colorectal cancer patients (greater than 90%) will need complex discussions on risk‐benefit of different management strategies.

The expanding evidence base for surgical quality, adjuvant chemotherapy, neoadjuvant, adjuvant rectal chemoradiotherapy, and resection of limited metastatic disease implies that an increasing number of patients are surviving for 5 years. This rising percentage is a true reflection of the successful working of modern multidisciplinary teams.
Rational Drug Design of Small Molecule Anticancer Agents: Early Clinical Development
Authors: Molife Rhoda , Collins Ian , Workman Paul , Kaye Stan B.
Published: October 2007

There has been a significant increase in the understanding of the molecular changes leading to malignant transformation, and cancer scientists and physicians are now at the dawn of another era in cancer therapeutics. The identification of new drug targets and potential biomarkers, and the development of molecular targeted therapies for use in oncology are moving rapidly forward. It is imperative that appropriate and speedy advances in clinical trial design accommodate these developments, as the traditional design of early phase trials for ‘standard’ anti‐cancer therapies may not necessarily be appropriate for these new agents. In this chapter, we discuss some of the challenges posed in early clinical development of novel targeted therapies. These include the redefining of trial endpoints such as maximum tolerated dose, dose limiting toxicity and radiological response and applying new concepts such as novel clinical trial design, maximum biological dose, use of surrogate tissue as a biomarker for drug effect, and prolonged disease stasis as a measure of clinical benefit. We review clinical studies of several classes of small molecule anticancer therapies to illustrate attempts to maximise the benefits of these non traditional methodologies and minimise the limitations in driving the field of molecular cancer therapeutics further forward.
Intervention and Chemoprevention of Cancer – Treatment of Carcinogenesis
Authors: Doody Linda A. , Sigman Caroline C. , Kelloff Gary J.
Published: October 2007

This chapter provides an overview of strategies for chemoprevention. An exploration of molecular target‐based chemopreventive drug discovery and early development lays the groundwork for a sequential drug development programme, which is translational in nature and builds on a rational mechanism‐based and empirical agent discovery approach, and leads to Food and Drug Administration (FDA) approvals for chemopreventive uses. An important aspect of this programme is identification of precancers such as intraepithelial neoplasia (IEN) as well as early biomarkers of neoplastic progression, which can serve as surrogate end points for cancer incidence in chemoprevention studies.
Oral Cavity and Major and Minor Salivary Glands
Authors: Tilakaratne Wanninayake M.
Published: October 2007

Cancer of the oral cavity is almost synonymous with squamous cell carcinoma as 90% of cancers in the oral mucosa appear to be of this type. The sixth most common oral malignancy is the different types of adenocarcinoma arising from salivary glands. A small proportion of cancers in the oral cavity are composed of melanoma, lymphoma, and various types of sarcomas. Oral squamous cell carcinoma is the sixth common malignancy and is a major cause of cancer morbidity and mortality worldwide. Although the aetiology is thought to be multifactorial, tobacco use in many different forms appears to play a major role. It is clear that various other factors such as genetic susceptibility, alcohol, nutritional deficiencies, viruses, fungi, and ultraviolet light have either a synergistic role or direct effect on oral carcinogenesis. A significant number of cases occur in a background of either a precancerous lesion or a precancerous condition. Molecular markers which have been investigated for determining different aspects of oral cancer can be classified into DNA content (ploidy), loss of heterozygosity, expression of oncogenes and onco‐suppressor genes, proliferation markers, and differentiation markers. However, prediction of malignant transformation of precancers and prognosis of oral cancers with the help of molecular markers need further research. Despite the advancement in treatment involving surgery, chemotherapy, and radiotherapy, the long‐term survival has been less than 50% with no significant improvement in prognosis over the last four decades. Salivary neoplasms account for up to 2% of all neoplasms in the head and neck. Although the exact aetiology of salivary gland tumours is far from clear, various aetiological factors such as radiation, viruses, occupational, hormonal, nutritional, and smoking have been suggested. Unlike most cancers, salivary tumours do not show any evidence of familial predisposition. Surprisingly, only a few studies have been carried out on salivary tumours in order to investigate molecular aspects. Prognosis of salivary tumours mostly depends on microscopical grade and tumour type. Surgery is the treatment of choice for a large majority of both benign and malignant salivary tumours. Chemotherapy and radiotherapy are used mostly as palliative measures.
Respiratory System
Authors: Hasleton Phillip S. , Sloan Philip
Published: October 2007

The respiratory tract is a common site for cancer. Exposure to inhaled industrial and environmental particles, particularly those associated with smoking, is a major cause. Viruses also play a part, particularly the Epstein‐Barr virus (EBV) in nasopharyngeal carcinoma and human papillomavirus in squamous carcinomas of oropharynx, larynx, and bronchus. We focus on the more common and important cancers of the respiratory tract and give differential diagnoses where relevant. The World Health Organization has recently produced revised classifications of tumours of the respiratory tract (2004) and head and neck (2005). Sarcomatoid carcinoma has been added to the previously recognized squamous cell carcinoma, small cell carcinoma, adenocarcinoma, and large cell undifferentiated carcinoma of the lung in the new classification. Sinonasal undifferentiated carcinoma is also included as a recognized entity. It is increasingly recognized that precursor and early lesions are the best targets for interventions. Detection, biology, and current practice regarding assessment of precursor lesions are covered. It is increasingly recognized that many respiratory cancers arise in a field and second primaries with similar molecular features to the original tumour are being described.
Upper Gastrointestinal Tract
Authors: Stemmermann Grant N. , Noffsinger Amy E. , Fenoglio‐Preiser Cecilia M.
Published: October 2007

Backgrounds of different types of oesophageal and gastric cancers are well known. Each of these cancers associates with known environmental exposures and carries a poor prognosis if sufficiently advanced to cause symptoms. A diet that provides fresh vegetables and fruit on a year‐round basis to all members of the society, the correction of tobacco and alcohol abuse, and the prevention ofHelicobacter pylorigastritis should prevent all but the small number of these cancers that arise from inherited germ‐line mutations. Knowing the clinical and anatomic precursors of these cancers enables us to find them at an early, treatable stage.
Lower Gastrointestinal Tract
Authors: Jass Jeremy R.
Published: October 2007

This chapter provides an overview of benign and malignant neoplasms affecting the lower intestinal tract, but the main focus in on the commonest epithelial malignancy, namely, colorectal cancer. The multifactorial causation of colorectal cancer including both genetic and environmental factors is emphasized. Classical pathology is now supplemented by the application of molecular markers that allow colorectal cancers to be subclassified into new groups with their own clinical, pathological, and molecular features. Additionally, prognostic and predictive markers are becoming better established in clinical management, though their ultimate potential is yet to be fully realized. Surgical management remains the main therapeutic option, but adjuvant and neoadjuvant therapy are showing increasing clinical benefit with respect to both local recurrence and survival.
Models for Liver Cancer
Authors: Feo Francesco , Pascale Rosa M. , Calvisi Diego F.
Published: October 2007

Primary liver tumours include hepatocellular carcinomas (HCCs), cholangiocarcinomas, and hepatoblastomas. HCC is the most frequent liver tumour, whose development is preceded, both in humans and rodents, by the appearance in the liver of foci of altered hepatocytes (FAHs) and dysplastic nodules. Bipotential hepatic progenitor cells (HPCs), which may differentiate into hepatocytes or cholangiocytes, are liver tumour precursors. Several rodent models have been developed to study the aetiology, evolution, and pathogenesis of preneoplastic and neoplastic liver lesions. They include the woodchuck hepatitis model, chemical models in which hepatocyte initiation by a carcinogen is followed by a growth stimulus inducing clonal expansion of initiated cells, diet‐linked models based on induction of methyl donor deficiency, and transgenic/knockout models, particularly useful to study
in vivo
role(s) of genes favouring or suppressing neoplastic cell growth. Furthermore,
in vitro
growing liver tumour cell lines have been used to study the role of single genes or signal transduction pathways, the effect of inhibitor compounds and genome engineering on tumour growth, and gene expression profiles. Transplants of
in vitro
growing cells are currently used for chemopreventive and therapeutic approaches to hepatocarcinogenesis. Animal models of liver cancer allowed investigation of the molecular alterations involved in early stages and in the progression phase of hepatocarcinogenesis, thus evidencing the interspecies commonalties of the basic mechanisms of hepatocarcinogenesis, and strongly contributing to understanding the molecular bases of the disease. Finally, animal models allowed investigation of genetic predisposition to liver cancer and contributed to map predisposition genes, understanding the genetic model, and some effector mechanisms of cancer modifier genes.
Models for Skin Cancer
Authors: Philpott Michael P. , Bergamaschi Daniele , Storey Alan
Published: October 2007

Malignant melanoma, basal cell carcinoma (BCC), and squamous cell carcinoma (SCC) are the three most common types of skin cancer. Malignant melanoma commonly arises from melanocytes in the epidermis and is the most lethal of skin cancers. BCC arises from keratinocytes and is the commonest cancer. There is considerable debate as to whether BCC arises from hair follicle keratinocytes and also because of the association of BCC with mutations that activate the sonic hedgehog (SHH) pathway, whether BCC may reflect failed organogenesis. SCC also arises from keratinocytes and is a more aggressive tumour than BCC and can form lethal metastases, whereas BCC rarely metastasize. All three skin cancers lend themselves to bothin vivoandin vitromodels and these are discussed in this chapter.
Liver, Gallbladder, and Extrahepatic Bile Ducts
Authors: Kanel Gary C.
Published: October 2007

Both benign and malignant hepatic neoplasms and tumourlike lesions provide interesting clues in tumour pathogenesis. This chapter discusses these tumours, with special emphasis on the two most common primary neoplasms, hepatocellular carcinoma and cholangiocarcinoma. The epidemiology, the various aetiologic factors, pathophysiologic concepts, and pathology are presented with brief mention on clinical presentations and treatment options and outcomes. Additionally, a brief discussion of tumours of the gallbladder and extrahepatic biliary system is also included.
Breast
Authors: Gudi M. , Stamp G. W. H.
Published: October 2007

This chapter gives an overview of the pathological changes in the breast and the current approaches to treatment and diagnosis. The micro‐anatomical structure of the breast is described in relation to pathogenesis of common benign diseases of the breast which may simulate cancer clinically. The generation of epithelial hyperplasias and definition of atypical hyperplasias (ADH and ALH) is addressed with updated classification. Emphasis is placed on the evolution of lobular and ductal
in situ
neoplasia and their relationships to invasive carcinoma in the main types of breast cancers are described together with the parameters used for pathological assessment. The molecular genetic and biological alterations in breast cancers are listed, and the relationship of these factors to potential diagnostic and therapeutic approaches to breast cancer are outlined.
Female Reproductive System
Authors: Aguilera‐Barrantes Irene , Euscher Beth , Morisson Carl , Nuovo Gerard J.
Published: October 2007

The study of the female reproductive system is an excellent example of the importance of molecular pathology to diagnosis and treatment. The classic example is infection of the uterine cervix by human papillomavirus (HPV). The recent FDA approval of vaccines against HPVs 6, 11, 16, and 18 mark the culmination of years of work where HPV detection has increased the accuracy of the Pap smear. These vaccines, which have little to no side effects, most likely are the harbingers of less toxic and effective therapies against cervical cancer that invariably contains HPV. Similarly, molecular testing for targets such as p16 is becoming more useful in the diagnosis and more accurate characterization of endometrial cancers and may also herald changes in the treatment of these cancers. Ovarian tumours represent another fertile area for molecular clinical‐pathology correlation. This is because of the very well characterized ovarian cystadenomas of low malignant potential where histologic markers are usually a poor indicator of clinical behaviour. It is very likely that additional research will identify protein and/or RNA targets that differentiate the aggressive from benign acting tumours in this group and lead to more effective treatment. This chapter will combine the classic histopathology of the female reproductive system with clinical correlates and add to this important mixture newer insights provided by molecular diagnostics.
Heart
Authors: Virmani Renu , Burke Allen
Published: October 2007

Cardiac tumours are rare. In children, the most common are rhabdomyoma and cardiac fibroma, non‐neoplastic growths that are associated with extracardiac malformations. True neoplasms occur primarily in adults. Most are benign (cardiac myxoma), but malignant heart tumours (cardiac sarcomas) may also occur, and clinically mimic myxoma. Any cardiac tumour, whether biologically malignant or truly neoplastic may cause morbidity or mortality by obstructing blood flow or compressing vital structures.
Advantages and Limitations of Models for Cancer and Malignant Cell Progression
Authors: Haier Jörg , Nicolson Garth L.
Published: October 2007

Modelling of cancer is one of the most difficult tasks in cancer research. The establishment and choice of appropriate models for certain topics, aspects, and questions in cancer development and progression requires a knowledge of the advantages and limitations, possible results, and impossible interpretations of the available models. The initial section of this chapter provides general remarks about models in cancer research. This section focuses on the description of model characteristics, based on overviews of the biological background of many aspects of cancer. In the first part, general techniques that are frequently used in cancer research are explained. The second part of this section describes options for the investigation of certain cancer characteristics, whereas the last part summarizes the available models for different tumour entities.
Models for Angiogenesis
Authors: Kassis Jareer N. , Cohen Joshua G. , Rasool Nabila , Kohn Elise C.
Published: October 2007

The study of angiogenesis has produced a plethora of creative assays through which various aspects of vascular formation and growth are observed, measured, evaluated, and inhibited. A basic theme of angiogenesis investigation is that multiple models are needed to prove a hypothesis. Thus, different aspects are tested in separate models in order to circumscribe those selected effects on the vasculature. Traditional models of the study of angiogenesis have generally been categorized into eitherin vitroorin vivoassays.In vitromodels allow for more strict control over the local microenvironment, sometimes at the expense of authenticity to thein vivoevent, whereas in vivo models enable more accurate observations in a simulated live environment at the expense of optimizing certain variables. A balance of various techniques involving bothin vitroandin vivomodels has led to a better understanding of the overall process of angiogenesis, and thus enabled the development of more effective targeting and therapeutic agents.
Models for Tumour Cell Adhesion and Invasion
Authors: Fisch Katja M. , Haier Jörg
Published: October 2007

The localization of tumour metastasis in distant organs is not determined solely by anatomical considerations. Adhesion of metastatic cells to and migration through the microvascular vessel walls of host organs require specific interactions between the tumour cells and endothelial cells, (EC) the extracellular matrix, or surrounding cells. This chapter describesin vitroandin vivomethods to investigate these specific interactions, their principles, applications, and biological and technical limitations. The cell detachment assay, microtitre plate–based adhesion assay, flow or dynamic cell adhesion assay, spreading assay, migration, invasion, and motility assays (Boyden chamber and microscopy–based techniques), as well as intravital microscopy are explained in detail. These methods are increasingly being used for a detailed study on the involvement of complex interactions of signalling cascades in the metastatic behaviour.
Models for Tumour Cell—Stromal Cell Interactions
Authors: Eble Johannes A.
Published: October 2007

Stromal cells in the vicinity of tumour cells are not an inert component of an organ. Cancer cells induce the fibroblasts of the surrounding connective tissue to develop into carcinoma‐associated fibroblasts (CAFs), also termedreactive stroma cells, which have biosynthetic capacities similar to fibrotic cells or fibroblasts in granulation tissue during wound healing. By producing growth factors, extracellular matrix (ECM) proteins, and proteinases, the CAFs generate an environment that supports tumour proliferation and progression. Understanding these communication pathways between reactive stroma cells and the cancer cell is the basis for intervening in the tumour‐stroma relationship and preventing stromal cells from promoting cancer cells.
Models for Sarcomas
Authors: Hotfilder Marc , le Viseur Christoph , Vormoor Josef
Published: October 2007

Sarcomas are rare tumours in patients under the age of 20. Because of their characteristic chromosomal translocations Ewing's sarcomas have been a paradigm for understanding the biology of sarcomas. Since the survival rates in Ewing's sarcoma patients with metastasis and relapse are still unsatisfactory, new therapeutic options have to be developed. Model systems based on fibroblast cell lines have helped in understanding the biology of the transforming protein EWS/FLI1. Cell lines established from primary Ewing's sarcoma are now in use to test new therapeutic options. Since these models only poorly reflect the conditions within the patients, xenograft mouse models have recently been developed to study the biology of Ewing's sarcoma in a more relevantin vivoenvironment. These new model systems will help define novel therapeutic targets and support the preclinical evaluation of new treatments.