bluuebunny/crossref_metadata_2025_split huggingface dataset:
Telomerase
Authors: Wright Woodring E. , Shay Jerry W. 
Published: October 2007

AbstractTelomeres 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

AbstractSteroid 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

AbstractCytokines 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

AbstractThe 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

AbstractCancer 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

AbstractIt 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

AbstractThe 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

Abstract

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

Abstract
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

AbstractP63, 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

Abstract
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

AbstractCancer 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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

AbstractThere 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

AbstractThis 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.