bluuebunny/crossref_metadata_2025 huggingface dataset:
The Biology of Tumour Stroma
Authors: Guyot Christelle , Lepreux Sébastien , Darby Ian A. , Desmoulière Alexis
Published: October 2007

The cooperation between epithelial and mesenchymal cells is essential for embryonic development and certainly plays an important role in pathological phenomena such as wound healing and tumour progression. Many epithelial tumours are characterised by the local accumulation of connective tissue cells and extracellular material; this phenomenon has been calledstroma reaction, which shows many similarities in its organisation and evolution with the granulation tissue that develops during tissue repair. One of the cellular components of stroma reaction is the myofibroblast, a modified fibroblast that has become capable of expression of α‐smooth muscle actin, the actin isoform typical of vascular smooth muscle cells, and also capable of synthesis of significant amounts of collagen and other extracellular matrix components. The myofibroblast is a key cell for connective tissue remodelling that takes place during wound healing and fibrosis development. Myofibroblasts are also capable of interaction with epithelial cells and other connective tissue cells and may thus control such phenomena as tumour invasion and angiogenesis. In this chapter, we discuss the mechanisms of myofibroblast evolution during normal and malignant conditions, and the interaction of myofibroblasts with other cells in order to control tumour progression. On this basis, we suggest that the myofibroblast may represent a new and important target for anti‐tumour therapy.
Angiogenesis
Authors: Billioux Alexander C. , Modlich Ute , Bicknell Roy
Published: October 2007

Angiogenesis is the process in which new blood vessels are produced by extending the existing vasculature. This process is a part of embryonic development, following directly after vasculogenesis, or the development of blood vessels
de novo
. Angiogenesis after embryogenesis is rare in the adult, occurring largely only during menstruation and wound healing. Nevertheless, many disorders result in the stimulation of angiogenesis, with this aberrant vascular development often playing a key role in the disorder's pathology. This phenomenon is especially relevant in cancer.

Most solid tumours are dependant on angiogenic vascular development for invasive growth and metastasis. Non‐vascularized tumours remain small, rarely growing beyond a few millimetres in diameter. However, after the stimulation of local vascular development – termed the “
angiogenic switch
” – the cancer is able to grow substantially in size and make use of the vascular and lymphatic systems for the systemic dispersal of cells.

Tumour angiogenesis, though stimulated by aberrant growth patterns and modulated growth factor expression, takes place in much the same manner as physiological angiogenesis during development. Thus, understanding the normal process and function of angiogenesis has proved valuable to understanding the ways in which tumours exploit this phenomenon and how this exploitation may be therapeutically abrogated. In this chapter, the physiological process of angiogenesis – stimulation of the quiescent vasculature, breakdown of the extracellular matrix, migration, proliferation, and vascular maturation – is presented, followed by a description of aspects of tumour angiogenesis peculiar to this phenomenon. Finally, a discussion of the role of angiogenic markers in cancer diagnostics is provided.
Epidemiology in the Identification of Cancer Causes
Authors: Lagiou Pagona , Trichopoulos Dimitrios , Adami Hans‐Olov
Published: October 2007

Primary prevention represents the most promising strategy for effective cancer control and requires identification of carcinogenic agents and of the conditions that favour the exposure of susceptible individuals to these agents. An agent is judged to be “conclusively” carcinogenic in humans when there is sufficient evidence of carcinogenicity derived from epidemiological studies; only rarely does evidence from non‐human systems suffice. This chapter addresses conceptual and practical issues in assessing cancer aetiology, outlines the descriptive epidemiology of cancer, gives an overview of the available analytic epidemiologic study designs, examines the role of chance, confounding, and bias, and introduces principles of causal inference in cancer epidemiology.
The Formation of
DNA
Adducts
Authors: Phillips David H.
Published: October 2007

Genotoxic carcinogens initiate the carcinogenic process in mammalian cells by damaging DNA. Where the damage results in attachment of the carcinogen, or its activated metabolite(s) to DNA, the resulting DNA adducts can lead to errors in replication and a permanent alteration in the genetic code. Mutations in critical genes can result in malignant transformation. Several techniques are available with sufficient sensitivity to detect DNA adducts formed as a consequence of occupational or environmental exposure to carcinogens. Detection and identification of DNA adducts in human DNA can provide important clues to the aetiology of cancer. Strategies that inhibit the formation of DNA adducts may have utility in chemoprevention of cancer, and monitoring of DNA adduct formation and removal offers an intermediate biomarker for the assessment of carcinogen exposure and risk of cancer.
The Links between Inflammation and Cancer
Authors: Balkwill Frances , Charles Kellie A. , Mantovani Alberto
Published: October 2007

Inflammation is a crucial function of the innate immune system that protects against pathogens and initiates specific immunity. Acute inflammation is a tightly controlled process that normally resolves via active repair processes, but this does not always happen. Many of the diseases of middle and old age may be driven, at least in part, by chronic, “smouldering”, unresolved and often subclinical inflammation. In the past 5 years or so there has been great interest in the role of chronic inflammatory processes in malignant disease. It appears that neoplastic tissue selects for the type and extent of inflammation most favourable to tumour growth and progression. There is accumulating evidence that the cells and the chemical mediators of chronic inflammation are found in cancers; general or cell‐specific gene inactivation of key inflammatory mediators influences neoplastic progression, and population‐based studies link inflammatory disease or non‐steroidal anti‐inflammatory drug (NSAID) use with risk of some cancers. If genetic damage isthe match that lights the fireof cancer, inflammation can be considered as afuel that feeds the flame.
Regulation of Translation in Malignant Transformation
Authors: Clemens Michael J.
Published: October 2007

Gene expression is regulated at the level of translation by a number of mechanisms that are susceptible to aberrant control in malignant cells. In particular, polypeptide chain initiation factor eIF4E is often overexpressed in tumours. The availability and/or activity of eIF4E and other initiation factors can be regulated by signal transduction pathways that modulate the state of phosphorylation of these factors (or of proteins that interact with them). The key rate‐limiting steps in such pathways may thus constitute targets for therapeutic intervention. A promising example is the use of rapamycin and its derivatives to inhibit the activity of the protein kinase mammalian target of rapamycin (mTOR), an enzyme that directly influences the ability of the 4E binding proteins to sequester eIF4E and thus control translation. The effects of initiation factor overexpression can be mRNA selective, because such effects are influenced by the structures of the untranslated regions (UTRs) of mRNA molecules. Increased understanding of the regulatory mechanisms involved in the control of translation of specific mRNAs is likely to lead to the development of novel strategies for cancer treatment.
The Retinoblastoma Tumour Suppressor
Authors: Dirlam Alexandra , Macleod Kay F.
Published: October 2007

The retinoblastoma tumour suppressor (pRB) is functionally inactivated in most human cancers. pRB regulates cell cycle checkpoints, cell death, cellular senescence, and terminal differentiation through interactions with members of the E2F family of transcription factors, chromatin‐remodelling factors and with tissue‐restricted transcription factors. The RB‐related “pocket proteins”, p107 and p130 also interact with E2Fs to regulate cell cycle, although neither p107 nor p130 are known tumour suppressors in human cancer, despite data from mouse models indicating their ability to compensate for Rb loss under certain circumstances. This chapter discusses the latest findings on the role of pRB in development and tumourigenesis to help determine which functions of pRB contribute most to its tumour‐suppressor activity, why certain tumours select against RB but others do not, and what kind of additional mutations are likely to cooperate with RB loss in cancer as a function of tissue type.
Development and Cancer: TheHOXGene Connection
Authors: James Jacqueline A. , Grier David G. , Thompson Alexander , Lappin Terry R. J.
Published: October 2007

Homeobox genes nave been identified in the genomes of all animals mapped so far. The Human Class 1 homeobox (HOX) genes are clustered on four different chromosomes, 7p15, 17q21, 12q123 and 2q31. The proteins encoded by these genes act as master regulators of transcription. During embryogenesis they define axial patterning and developmental cues. The discovery that genes initially expressed in embryogenesis are often re‐expressed in neoplasia has led to the concept that ‘Oncology recapitulates Ontogeny’. IndividualHOXgenes have been identified in specific developmetal processes,e.g.downregulation ofHOXB5appears necessary for normal lung development. In other processes such as haematopoiesis sub‐sets ofHOXgenes are associated with lineage commitment and differentiation. Generally higherHOXgene expression is associated with a more primitive phenotype. The oncogenic potential of HOX proteins has been linked with leukaemia and solid tumours. Chromosomal translocations involving severalHOXgenes indicate they play a direct role in leukaemogenesis. Known regulators ofHOXexpression such as MLL are also directly involved in the onset and maintenance of leukaemia. Current investigations ofHOXgene expression in various cancers indicate their potential for disease classification and prediction of clinical outcome. Model systems of dysregulated HOX expression suggest a functional role for these master regulators in cancer, often associated with a more aggressive phenotype, such as high metastatic potential. Future work to test the concept that ‘Oncology recapitulates Ontogeny’ will involve elucidation of the upstream regulators and downstream targets within the HOX‐axis.
Infectious Agents and Cancer
Authors: Duensing Stefan , Moore Patrick S. , Parsonnet Julie
Published: October 2007

Infection is second only to smoking as a cause of human cancer. Microbial agents implicated in carcinogenesis run the gamut from simple viruses to complex parasites. Mechanisms of carcinogenesis imputed to these agents are as diverse as the agents themselves. These mechanisms provide important insights into cancer more generally, including the role of proto‐oncogenes in tumour development and the effects of inflammation on host cells. Because infections can often be prevented through vaccines or public health measures, or can be treated with anti‐microbial agents, they provide a promising arena for cancer control.
Cancer Bioassays
Authors: Maronpot Robert R.
Published: October 2007

Rodent cancer bioassays have a long history of identifying carcinogenic potential of synthetic and natural chemicals, chemical mixtures, and a variety of commercial products including drugs. The rodent cancer bioassay is a reliable approach to hazard identification with a primary goal of identifying potential human carcinogens. The emphasis here is on the word potential. Human exposure scenarios are highly variable; typically involve simultaneous exposure to multiple dietary, occupational, and environmental agents; and any subsequent disease burden is influenced by age at exposure, lifestyle, and socioeconomic situations. Further, the rodent physiology, metabolism, and detoxification processes and exactly how they handle specific chemicals will frequently have important similarities and differences from those processes in humans. Consequently, the long‐term rodent cancer bioassay will never be completely accurate in identifying agents that cause human cancer. Amongin vivoanimal carcinogenicity testing strategies, the long‐term rodent cancer bioassay remains the standard against which alternative approaches are compared.
Unknown Primary
Authors: Oien Karin A. , Stewart Ian , Evans T. R. Jeffry
Published: October 2007

Ten percent to 15% of all cancer patients present with metastatic disease, of initially unknown origin. In one‐third, a primary site cannot be identified, which is called
metastatic cancer of unknown primary
(
CUP
). CUPs may present in solid organs, for example, liver, or in lymph nodes or serous cavities. CUP generally has a poor prognosis but there are so‐called “favourable” subsets of patients whose tumours are sensitive to therapy. To predict the patient's outcome and provide optimal treatment, it is therefore important to identify the type and subtype of the metastatic cancer, and, depending on the cancer type, to identify or predict its most likely site of origin. This can be achieved through clinical assessment, because different cancers tend to metastasize in characteristic patterns, and through investigations including radiology, serum tumour markers, and pathology. For the latter, microscopic examination of a biopsy of the metastasis itself enables tumour typing through morphology and immunohistochemistry. Lymphoma, melanoma, and sarcoma are first considered and excluded, because the diagnosis of CUP is usually limited to carcinomas; 90% of CUPs are adenocarcinomas, from lung, pancreas, stomach, colon, ovary, breast, prostate, and so on. Adenocarcinomas from different primary sites are sensitive to different chemotherapeutic agents and so it is important to identify or predict the site of origin and this can now be achieved through immunohistochemical profiling. The diagnostic and therapeutic nihilism of the past in CUP patients is thus disappearing; continued improvement in their outcome depends ultimately on the development of novel therapies.
Dietary Genotoxins and Cancer
Authors: Sugimura Takashi , Wakabayashi Keiji , Nagao Minako
Published: October 2007

Tobacco smoking, diet, and infections/inflammation are three major factors for cancer causation in humans. There are many types of genotoxic compounds, such as mycotoxins, pyrrolidine alkaloids, mushroom hydrazines, nitrosamines, polycyclic aromatic hydrocarbons (PAHs), and heterocyclic amines (HCAs), in diet. They are derived from fungus metabolites, edible plant components, and produced during cooking, storage, and fermentation of food. Some are food additives, mainly of the preservative type. In addition to genotoxic agents present as microcomponents, macrocomponents, including fatty acids, salts, and fibres, are indicated to be associated with human cancer. At the same time, many anticarcinogenic compounds are also included in the diet. The significance of dietary factors for human cancer development is described.
RNAInterference
Authors: Moss Charlotte , Lemoine Nick
Published: October 2007

Ribonucleic acid interference (RNAi), a recently discovered novel mechanism of post‐transcriptional gene silencing (PTGS) has quickly found multiple applications in genetic research and is now established as the method of choice for achieving gene knockdown in functional genetic studies. The potential of this technique for therapeutic use has generated much excitement. This chapter aims to describe the mechanism underlying RNAi, to discuss some of the challenges anticipated in translating this powerful research tool into a clinical setting and how these are currently being addressed.
Collaborative Approach to Multidisciplinary Breast Cancer Care
Authors: Alvarado Michael D. , Ewing Cheryl , Esserman Laura J.
Published: October 2007

Care for the breast cancer patient is changing rapidly and a comprehensive breast care centre, utilizing a multidisciplinary approach, is becoming the standard of care. The mutidisciplinary approach brings together a highly coordinated setting composed of specialists from all the disciplines involved in breast cancer care. By designing systems that focus on the needs of the patient, a service delivery model can concentrate on the coordination of care, while improving the experience for the patient through innovation and translational research.
Multidisciplinary Management of Genitourinary Malignancies
Authors: Rathkopf Dana , Scher Howard I.
Published: October 2007

The outcomes for patients with genitourinary malignancies range from highly curable to palliative depending on both disease extent and site of origin. Overall results across the spectrum of these tumours are optimized by a planned integrated multimodality approach.
Management of Haematological Malignancies
Authors: Gribben John G.
Published: October 2007

The successful treatment of haematological remission resulting in the increased improvement in survival and cure of the patients represents one of the great successes in oncology. Subsequent improvements in outcome have followed advances in understanding of the molecular pathogenesis of these diseases and institution of therapy targeting the pathways specifically perturbed in these diseases.
Mechanisms and Management of Cancer Pain
Authors: Anand Uma
Published: October 2007

Chronic intractable pain is experienced by an overwhelming majority of cancer patients, compromising their quality of life. The pain can be due to several causes: infiltration by tumours, bone metastases, or a consequence of therapy. The mainstay of analgesia has been opioid treatment of various formulations, but this is limited in efficacy and is not without considerable side effects. Recent advances in understanding the underlying pathophysiological and molecular mechanisms of cancer pain have been derived from animal models and related histopathological findings from chronic pain patients. The identification of novel drug targets, and their imminent clinical trials, provides the prospect of new treatments for alleviating cancer pain in the near future.
Head and Neck Cancer
Authors: Seiwert Tanguy Y. , Vokes Everett E.
Published: October 2007

Head and neck cancer (HNC) is the fifth most common cancer worldwide and, in particular, locoregionally (LR) advanced disease continues to be a challenge.

HNC treatment has improved dramatically during the past decade owing to advances in radiation and chemotherapy (namely concurrent chemoradiotherapy (CRT)) and improvements in surgical technique. Multiple differing treatment approaches exist. We therefore attempt to give an overview of the field and make recommendations on the basis of available data.

In the future the integration of epidermal growth factor receptor (EGFR) inhibitors will further increase efficacy and limit toxicities. In addition, the integration of induction chemotherapy is currently being investigated as a measure to decrease distant metastatic spread.

HNC – using an integrated multidisciplinary treatment approach involving chemotherapy and radiation, as well as surgery and novel therapeutics – is a highly curable disease.
Gene Knockouts in Cancer Research
Authors: Merghoub Taha , Pandolfi Pier Paolo
Published: October 2007

Understanding genetic pathways is a prerequisite for the development of molecular and pharmacological therapies in order to treat and prevent cancer effectively. Transgenic approaches and mouse modelling have been developed as standard techniques for gene targeting that enables the dissection of cancer‐related cellular mechanisms. The possibility of manipulating and culturing pluripotent mouse embryonic stem cells has allowed for the generation of mice with a specific alteration in a chosen target gene. Transgenic mice harbouring activated forms of proto‐oncogenes or dominant negative forms of tumour‐suppressor genes have been generated in order to test the causal relationship between their expression and tumour development. In order to circumvent certain limitations of unspecific genetic alterations, conditional targeting strategies and tissue‐specific expression methods have been created, making it possible to introduce more subtle gene alterations and identify tumour modifiers and cancer‐related signaling networks. This chapter describes basic techniques for the generation of gene alterations in mice, their usefullness, and their limitations.
Introduction to the Diagnosis of Cancer
Authors: Wilczynski Sharon Poltis
Published: October 2007

The diagnosis is a name that is given to a disease process that summarizes its probable natural history, and possible aetiology and is the foundation for all potential treatment. Making a diagnosis of cancer in an individual patient is a complex process that requires the integration of clinical, molecular, and morphologic findings. In this chapter we discuss how cancer is detected in a population by screening as well as the methods that are used to classify tumours including histopathology, immunohistochemistry, and molecular studies. Features of tumours that are important for treatment such as grade, stage, and predictive and prognostic factors as well as the monitoring of response to therapy are also covered.
Models for Genitourinary Cancer – Hereditary Renal Carcinogenesis
Authors: Hino Okio
Published: October 2007

The Eker (Tsc2gene mutant) rat model of hereditary renal carcinoma (RC) is an example of Mendelian dominantly inherited predisposition to a specific cancer in an experimental animal. Recently, we discovered a new hereditary RC in the Japanese rat, which was named the “Nihon” rat. The predisposing (Bhd) gene could be a novel renal tumour‐suppressor gene.

We present these unique models for the study of problems in renal carcinogenesis.
Mouse Models for Gastrointestinal Cancer
Authors: Goodlad Robert A.
Published: October 2007

Intestinal cancer is a complex multi‐stage process, which involves interactions between various tissue systems. Animal models are thus essential for its study and the investigator is offered a large range of mouse models. The rationale behind the choice of models will be explained and the advantages and limitations discussed.
Models for Human Leukaemias
Authors: Koschmieder Steffen , Serve Hubert L.
Published: October 2007

Animal models for human leukaemias have provided important insight into their molecular pathogenesis. As a consequence, molecularly targeted therapy for several human leukaemias has entered clinical practice, which greatly improves efficacy and lowers toxicity of anti‐leukaemic treatment. Several organisms are being utilized to study the process of leukaemic transformation, including not only
Drosophila
,
Caenorhabditis elegans
, or
Xenopus
but also zebrafish. Most frequently though, spontaneous or induced leukaemias in the mouse are used. Using xenotransplant models of human leukaemic cell lines and leukaemic cells from patients into immunodeficient mouse strains, we have learnt important lessons about the composition of the leukaemic cell population in human disease. In fact, these experiments led to the description of leukaemia‐initiating cells, the first described cancer stem cell. However, animal models have also led to the definition of oncogenes required for leukaemic transformation and are also being used for the evaluation of molecular therapeutic targets. Two strategies for the evaluation of genes in the pathogenesis of human leukaemias are frequently used: (i) transplantation strategies, where genetically modified cell lines or primary bone marrow is injected into recipient animals. (ii) Analyses of genetically modified animals. Both model systems have led to important insights into the role of human oncogenes in leukaemic transformation. Most recently, these model systems are combined to yield sophisticated information about the cooperation of oncogenes, to identify genes that are important for abnormal stem cell functions, and to evaluate the oncogene products as therapeutic targets.
The Role of Epigenetic Alterations in Cancer
Authors: Ballestar Esteban , Esteller Manel
Published: October 2007

Epigenetics has burst into the cancer field. DNA methylation changes, implicated in both silencing of tumour‐suppressor genes and chromosomal instability, were among the first recognized epigenetic alterations. More recently, disruption of the histone modification profile has just started to be unravelled. The impact of epigenetic alterations covers many different aspects of cancer: it provides a context to explain chromosomal rearrangements, inactivation of tumour‐suppressor genes and, in general, aberrant expression of many genes involved in cell differentiation, proliferation, apoptosis, and so on. Moreover, the recognition of epigenetic alterations in all types of cancers has multiple implications: first, it sheds light on the mechanistic insights by which genetic alterations are complemented in the development and progression of cancer; second, epigenetic alterations exhibit a prominent role in the initiation of cancer. In addition, because epigenetic changes are reversible, enzymes involved in their maintenance stand as targets for a variety of compounds used for therapy.
Pancreas
Authors: Hruban Ralph H. , Wilentz Robb E. , Fukushima Noriyoshi , Goggins Michael
Published: October 2007

Cancer of the pancreas is fundamentally a genetic disease; a disease caused by inherital and acquired alderations in cancer associated genes.
Urinary Tract
Authors: Tamboli Pheroze , Gomez José A. , Jiménez Rafael E.
Published: October 2007

This chapter covers the most common tumours that affect the urinary tract, including tumours arising from the kidney, renal pelvis, ureter, urinary bladder, and urethra. The tumours discussed in this text include Wilms' tumour, renal cell carcinoma, urothelial carcinoma, squamous carcinoma, and adenocarcinoma.
Lymph Nodes
Authors: Müller‐Hermelink Hans Konrad , Ott German , Haralambieva Eugenia
Published: October 2007

The current chapter provides comprehensive data on the tumours derived from the lymphoid tissues that are most commonly affecting the lymph nodes. We discuss the principles of the current classification of lymphoid neoplasia, its clinical relevance, and the possible use of different prognostic factors. For every disease entity, up‐to‐date information on the specific clinical presentation and site of involvement, morphology, including different morphological variants, immunophenotype and genetics is offered. Basically, the lymphoid tumours consist of Hodgkin's disease and non‐ Hodgkin's lymphomas and the latter are subclassified into B‐ and T‐cell lymphomas, according to their putative cell of origin. On the basis of the literature and our own experience we review the relevance of specific lymphoma features for the diagnosis and clinical outcome of lymphoma patients.
Bones
Authors: Klein Michael J.
Published: October 2007

Bone tumours represent some of the least common malignant and benign human neoplasms. They are classified not only by their cellular contents but also by the extracellular connective tissue matrix they produce. Their accurate diagnosis rests not simply upon the histology but in the correlation of their clinical, radiographic, and pathologic features. This constellation of features is usually fairly reproducible for any given bone tumour. While many of the tumours have no known predispositions, a modest number are associated with genetic predispositions. In addition, some non‐neoplastic diseases and iatrogenic causes may also predispose to the development of certain bone tumours. While untreated malignant bone tumours are highly lethal, the advent of chemotherapy in addition to surgery has made overall survival more favourable.
Neuromuscular System
Authors: Fung Kar‐Ming , Trojanowski John Q.
Published: October 2007

The discussion focuses on tumours of the central and peripheral nervous systems. It starts with a brief discussion on the normal development of the nervous system, followed by a discussion on the epidemiology, aetiology, detection, and prevention of brain tumours. Details of the more commonly encountered tumours of the central and peripheral nervous systems are discussed. The molecular genetics section focuses on hereditary cancer syndromes related to the nervous system and also the pathogenesis and progression of brain tumours. Prognostic factors and clinical management of brain tumours are also briefly discussed.
Eye and Ocular Adnexa
Authors: Burnier Miguel N. , Odashiro Alexandre Nakao , Gregoire François J.
Published: October 2007

Ocular pathology is a subspecialty of both pathology and ophthalmology with few specialists around the world. Like many other pathology specialties, the clinical–pathological correlation is essential for a correct diagnosis. Most of the diseases and tumours affecting the eye and ocular adnexae can be seen in other sites of the body. However, there are some specific tumours that are characteristic of the eye and are rarely found or do not exist anywhere else, like sebaceous carcinoma of the eyelid, conjunctival melanosis, retinoblastoma, and uveal melanoma. Also, the eye can be a source of systemic diseases and disseminated tumours. In this chapter we review the most important tumours in ophthalmic pathology emphasizing the clinical features, pathological diagnosis, and differential diagnosis.
Ear
Authors: Wenig Bruce M.
Published: October 2007

The ear and temporal bone represent a complex anatomic region that includes the organs of hearing and balance. Neoplasms of the ear and temporal bone are uncommon. This chapter details the clinical and pathologic features of the more common neoplasms occurring in the ear and temporal bone. Despite their relative rarity, recognition of the specific clinical and pathologic features should allow for their recognition and differentiation from similar appearing lesions/neoplasms. Treatment is often predicated on the specific tumour type, although the primary mode of the treatment for the more common neoplasms of this anatomic region is surgical resection. Several middle ear/temporal bone neoplasms may be indicators of associated diseases, including acoustic neuromas and meningiomas with neurofibromatosis, and endolymphatic sac papillary tumours with von Hippel‐Lindau syndrome. Knowledge of these unique associations may prompt evaluation and diagnosis of the associated disease and/or syndrome.
Transgenic Technology in the Study of Oncogenes and Tumour‐Suppressor Genes
Authors: Wynshaw‐Boris Anthony
Published: October 2007

Genetic manipulation of the mouse via transgenic or knockout techniques has revolutionized the study of genes that cause cancer. The development of this technology has allowed investigators to examine the biological activity of genes that are important for the formation of cancer. In this chapter, the basic experimental design for the use of genetic manipulation of the mouse for the study of oncogenes and tumour‐suppressor genes will be discussed. Chromosome engineering techniques will be described. More recent strategies that allow investigators to have exquisite control over gene activation and inactivation have refined the use of mouse models to more accurately reflect and model human cancer. However, limitations to the use of mouse models still exist and will be discussed.
Genetic Models: A Powerful Technology for the Study of Cancer
Authors: Wang Ping , Li Suling
Published: October 2007

Transgenics has been proved to be an irreplaceable tool for cancer research. Not only have transgenic models provided the mechanisms of cancer‐related genes, but also models for development of therapeutic strategies. Since cancer is a consequence of genetic events that occur in a permissive epigenetic state influenced by environmental factors, the naturally occurring tumourigenesis in humans is far more complicated than cancer models generated by conventional transgenic technologies. Such a limitation promotes unlimited modification of transgenic technologies for the generation of murine cancer models with latent, conditional, and inducible alleles to better mimic the
in vivo
setting in which sporadic human cancers occur. In these mice, somatic mutations can be induced in a tissue‐specific and time‐controlled fashion, which more faithfully mimics sporadic tumour formation. These conditional models provide opportunities to gain insight into the role of genes in the initiation, progression, and treatment of cancer, and mimic human cancers better than ever before.
Models for Tumour Growth and Differentiation
Authors: Riedel Heimo
Published: October 2007

Human tumour growth can typically be studied only during the last quarter of its development after the tumour has been detected and in the presence of therapeutic interference. The progress of a large tumour does not correlate well with its early, but undetected, stages of cell proliferation. Tumour proliferation is described by (i) the rate of individual cell division, (ii) the growth fraction of the cell population, and (iii) the rate of cell loss from the growing population such as through differentiation or cell death. Cell proliferation and differentiation are largely seen as opposed concepts such that a terminally differentiated cell can no longer proliferate or undergo malignant transformation or such that tumours typically represent a reduced level of cell differentiation. The concept of (proto)oncogenes and the opposed tumour‐suppressor genes, both typically involved in cell proliferation control has been instrumental in defining the series of sequential genetic alterations that result in tumourigenesis. This has been complemented by cell culture, including three‐dimensional models based on primary and immortalized lines. With the available tools of modern molecular biology, primary human cells have been transformed to a malignant phenotype through the sequential introduction of at least four genetic alterations. This phenotype is scored by tumourigenicity in an immunocompromised mouse model and significantly depends on the stromal microenvironment. Aided byin vitromodels a limited number of genetic alterations have now been defined, of which some are found in virtually all human cancers. These can now be specifically targeted by rational drug design with increased selectivity and reduced cytotoxicity. Drugs to exploit the residual capacity of tumour cells to undergo differentiation are under investigation and promise loss of tumourigenesis with minimal impact on normal cell proliferation.
Models for Tumour Metastasis
Authors: Hill Richard
Published: October 2007

Metastasis is a process by which tumour cells establish new growths at sites in the body distinct from the primary tumour. It is complex, involving a number of stages including escape of tumour cells from the primary tumour and arrest, intravasation, and development of a new growth in a distant organ or lymph node. Although some of the individual stages can be modelled
in vitro
, an assessment of the ability of individual tumour cells to complete all stages requires the use of
in vivo
metastasis models. Many different models have been used for studying the multiple aspects of metastasis, but identifying appropriate models that mimic all the characteristics of specific human cancers remains a problem. Metastasis is a very inefficient process with very few tumour cells demonstrating the capacity to grow to form macrometastases, even though they may have initiated the growth of micrometastases. Many specific genetic changes have been identified in tumour cells (and host normal tissue) that can enhance or inhibit metastasis formation but the efficacy of such genetic changes appears to be highly tumour‐cell specific. Recent work developing genetically engineered mouse (GEM) models and models involving human normal tissues transplanted into immune‐deficient mice (SCID‐hu models) is opening up new ways to address some of the many questions remaining about the molecular mechanisms underlying the metastatic process.
Models for Tumour Cell—Endothelial Cell Interactions
Authors: Gassmann Peter , Nicolson Garth L. , Haier Jörg
Published: October 2007

The endothelium is composed of a continuous, semipermeable, and metabolically highly active lining of endothelial cells (ECs) and an underlining basement membrane composed of various extracellular matrix components. The endothelium serves multiple physiologic functions in health and is fundamentally involved in many pathophysiologic conditions like inflammation; wound healing; and cancer, beside others. Endothelial cells mediate the nutritional supply of growing cancerous lesions, are involved in the body's immunologic response to cancer, and mediate initial interactions between circulating tumour cells and metastasis target organs. Endothelial cells and the basement membrane are not uniform throughout the body, but display distinct morphologic and functional characteristics depending on the vascular province they are derived from. Primary derived EC are usually not transformed and lose their endothelial differentiation during
in vitro
culture. Therefore, easily accessible macrovascular ECs like “human umbilical vein endothelial cells” (HUVEC) have been widely used in cancer research. These models are easily reproducible and standardized throughout the literature. Nevertheless, tumour cell–EC interactions are highly dependent on the ECs' origin and microvascular endothelial cells (MECs) show significant differences compared to macrovasular ECs in their morphologic and functional characteristics while interacting with other cell types like tumour cells. Therefore, while analysing tumour cell–EC interactions the ECs' source needs to be carefully selected according to the study's intention and has significant impact on experimental results obtained.
Models for Drug Development and Drug Resistance
Authors: Chou Joseph H. , Chang Tai‐Tsung , Chou Ting‐Chao
Published: October 2007

This chapter describes the drug development process and models in the historical and future perspectives. The features of different models are given and the advantages and disadvantages are elaborated. The focus is at preclinical levels with special emphasis on the evaluation of efficacy and toxicity of candidate antitumour compounds. Methods of overcoming drug resistance are described with special emphasis on drug combinations and computerized, automated data analysis for the quantitation of synergism or antagonism. The theoretical basis of the concept of combination index, dose‐reduction index, isobologram, and polygonogram (i.e., the Chou‐Talalay method) is also given. A specific example for preclinical pharmacological, toxicological, and therapeutic evaluation of a microtubule stabilization antitumour agent—fludelone—that leads tode factotherapeutic cure against human tumour xenografts is provided. Specific examples for the reversal of multidrug resistance by ardeemin or ningalin are illustrated.
Models for Immunotherapy and Cancer Vaccines
Authors: Meisel Roland , Tröger Anja , Moritz Thomas , Dilloo Dagmar
Published: October 2007

Immunotherapy of cancer has emerged as a promising new strategy to complement standard anticancer therapies such as chemotherapy, surgery, and radiotherapy. While the currently available data from clinical trials of cancer vaccines provide evidence for the therapeutic benefit of this approach, it is currently confined to a minority of patients. In this chapter, we give an overview on current concepts and experimental models of cancer immunotherapy with a particular focus on cancer cell‐ and dendritic cell–based vaccines. We then proceed to discuss the emerging new data on immune evasion strategies of cancer such as the secretion of paracrine immunoinhibitory factors and the role of regulatory T cells. Exploration of immune escape mechanisms are critical for identification of novel immunotherapy targets to allow for further optimization of cancer immunotherapy. Such strategies hold considerable promise when incorporated into multimodal approaches as exemplified by the combination of chemotherapeutic cytoreduction with tumour vaccination or adoptive transfer of immune effector cells as described in the final part of this chapter. The rapid preclinical evaluation of these novel approaches is today greatly facilitated by the widespread availability of “fully humanized” mouse xenograft models. In addition, good manufacturing practice (GMP)‐grade reagents for immune cell purification support a swift transfer of new experimental insights from bench to bedside. Also targeting patients with low tumour burden instead of bulky or metastasized disease will further the success of clinical immunotherapy.
Models for Gene Therapy
Authors: Sweeney Colin L. , Lin Yuan , Gerson Stanton L.
Published: October 2007

There have been a number of approaches for gene therapy of cancer, directed either at the tumour or at normal host cells. Cancer‐directed strategies include tumour‐suppressor gene transfer, gene knockdown, suicide gene transfer, and oncolytic viruses. Host‐directed strategies include anti‐angiogenic, immunomodulatory, and drug‐resistance gene therapy. In this chapter, preclinical models are discussed for each of these approaches.
Models for Breast Cancers
Authors: Eccles Suzanne A. , Paon Lenaic
Published: October 2007

Breast cancer afflicts a high proportion of women and its underlying causes are not fully understood. There are many risk factors that contribute to breast cancer, and a small proportion of cases have been attributed to inherited predisposition genes. Recently, there have been attempts to improve the classification of breast cancers, notably by gene expression microarray techniques, with the aim of providing more sophisticated prognostic information, to identify new targets for therapy and even to determine women most likely to need (and/or benefit from) additional interventions. With much more still to be learned about the basic biology of breast cancers, and a great deal to be gained by studying possible means of preventing progression or controlling disseminated disease, laboratory models are still essential. This section attempts to give an overview ofin vitroandin vivosystems that may be useful to further our knowledge in these areas.
Models for Lymphoma
Authors: Enns Andreas , Haier Jörg
Published: October 2007

Lymphomas belong to the most complex and heterogeneous set of malignant tumours known to oncology. During the last few decades a high number of experimental approaches were introduced to unravel the pathophysiology of lymphomas and to help in developing new therapeutic strategies. This chapter begins with a description of the main known pathophysiological mechanisms, which contribute to the development of lymphomas, such as aberrant chromosomal translocations taking place during the maturation of B lymphocytes, the role of tumour‐suppressor genes and oncogenes during the lymphomagenesis, and the involvement of some viruses is also discussed. This compact overview is followed by presentation of the lymphoma cell lines pointing out the specific features and problems, which have to be considered for use as
in vitro
models for lymphoma research. Finally, xenogeneic and genetically engineered mouse models employed in lymphoma research are discussed.
Conventional Chemotherapeutics
Authors: Barrett Sophie V. , Cassidy Jim
Published: October 2007

Chemotherapeutic agents are a vital component in the treatment of virtually all cancers. This chapter aims to give an overview of the different classes of chemotherapy drugs in use today, including their mechanisms of action, pharmacokinetics and pharmacodynamics, activity, and toxicity. The groups discussed include the antifolates, antimetabolites, alkylating agents, platinum agents, topoisomerase inhibitors, antitumour antibiotics, and antimicrotubule agents.
Modern Approaches to Radiation Therapy
Authors: Tsien Christina I. , Lawrence Theodore
Published: October 2007

Recent advances in technology have led to dramatic improvements in radiation treatment planning, and delivery. These technical advances have allowed us to deliver higher radiation doses to the tumour while limiting dose to the normal surrounding tissues. Parallel advances in imaging and molecular biology have improved our ability precisely to define target volumes at risk, enhance radiation sensitivity, as well as to evaluate response to therapy. In this chapter, we will focus on the clinical improvements that have been achieved from both technological advances in radiotherapy (RT) planning and treatment delivery in combination with radiation response modifiers such as altered fractionation, chemotherapy, and molecularly targeted therapy.
Cancer Vaccines
Authors: Laheru Dan , Jaffee Elizabeth M.
Published: October 2007

The identification of key signalling pathways involved in immune‐system regulation, along with the development of early pancreatic tumours in mouse models, has provided new opportunities for pancreatic cancer treatment and prevention. Immunotherapy for pancreatic cancer is one approach that is at a crucial crossroads, as therapeutics that are designed to target pancreatic‐cancer‐associated antigens and regulatory signalling molecules are entering clinical trials.
Antihormonal Therapy for Breast and Prostate Cancer
Authors: Cordera Fernando , Jordan V. Craig
Published: October 2007

Breast and prostate cancers are the most common malignancies in developed countries. Unlike other forms of cancer, these tumours express specific steroid receptors that regulate their behaviour and can predict response to treatment. Antihormonal therapy simply involves denying access of the natural ligand to the relevant steroid hormone receptor. Antihormonal therapy achieves this by decreasing the synthesis of the natural ligands, blocking the specific receptors, binding specific receptors and modulating the receptor‐mediated gene transcription, or by destruction of the receptor. This form of targeted therapy has conclusively been shown to benefit patients with breast and prostate cancer and has an important role in chemoprevention.
Anti‐angiogenic and Anti‐stromal Therapy
Authors: Bhattacharyya Madhumita
Published: October 2007

Anti‐angiogenic and anti‐stromal therapies are being developed for the treatment of cancer. Elucidation of the factors involved in tumour angiogenesis, in particular, the VEGF‐VEGFR pathway, has enabled new targeted therapies to be developed. Bevacizumab and the multi‐targeted receptor tyrosine kinase inhibitors have shown clinical efficacy when given in combination with conventional cytotoxic therapy. Other agents include endogenous inhibitors of apoptosis, matrix metalloproteinase inhibitors, and integrin antagonists, which are in the early phases of clinical development. Angiogenic inhibitors may synergize with conventional cytotoxic therapy and radiotherapy in decreasing tumour growth.
Mesh Generation and Mesh Adaptivity: Theory and Techniques
Authors: George P. L. , Borouchaki H. , Frey P. J. , Laug P. , Saltel E.
Published: October 2007

In this chapter we are concerned with mesh generation methods and mesh adaptivity issues. Many techniques are nowadays available to complete meshes of arbitrary domains for computational purposes. Planar, surface and volume meshing have been automated to a large extent. Over the last few years, meshing activities have been focused on adaptive schemes where the features of a solution field must be accurately captured. To this end, meshing techniques must be revisited in order to be capable of completing high quality meshes conforming to these features. Error estimates are therefore used to analyze the solution field at a given stage and, on the basis of the results the information they yield, adapted meshes are created before computing the next stage of the solution field. A number of novel meshing issues must be addressed including how to construct a mesh adapted to what the error estimate prescribes, how to handle large size meshes, how to consider moving boundary problems, etc.