Cancerremainstobeoneofthemostdevastatingdiseasesworldwidesincelong ago. Thepoorprognosisofcancerislargelyduetometastasis. Metastasisisoften depictedasamultistageprocessinwhichmalignantcellsspreadfromtheprimary locustodistantorgansviacirculation. Whereasgeneticalterationsweresuggested tobeessentialfortransformationofprimarytumorcellsintometastaticphenotype, epigeneticeventsareequallyimportant,whichmaybetriggeredbymetastaticf- torswhereverintheprimarytumorlocus,bloodcirculationandthesecondaryloci. Signaltransductionsinitiatedbythemetastaticfactorsareresponsibleformediating themolecularandcellularprocessesleadingtometastasis. Blockadeoftherelevant molecularpathwaysisoneofthemosteffectivestrategiesforpreventionoftumor metastasis. Clinicaltrialsareunderwaywithpromisingoutcome. Inthisbook, wetakecomprehensive review inregard withthisexciting eld ofcancerresearch. Chapter1takesabriefoverviewofrecentlyidenti edsignal mechanismsforeachstepoftumormetastasisincludingtheinitiationstage,intra- sation,anti-anoikisinbloodcirculation,homing,extravasationand nalsurvivalin themetastaticsite. Chapter2makesacompletedreviewforthemolecularandcel- lareventsinvolvedininitiationofmetastasis. Especially,thesignalingmechanisms formediatingtumorprogressioninducedbysomeimportantmetastaticfactorsare described. InChapters3and4,thecentralrolesofMAPKanditsdownstreameff- torsMAPKAPKplayineachstepoftumormetastasisarewelldelineated. Chapter5 furtherdescribesdetailedlyabouthowGrb2andotheradaptorproteins,upstreamof MAPK cascade, contribute tometastasis. InChapter 6, therole ofreactive o- genspecies(ROS)intumorprogressionarehighlighted. Moreover,thepotential contribution of ROS to cross talk between major signaling cascades that lead to sustainedMAPKactivationareproposedinChapter7. Chapter8takesaninsight intothesignalingmechanismsfordynamictraf ckingandturnoveroffocalad- sionproteinsinregulationoftractionandretractionforces,whichareneededfor celllocomotionandinvasion. Chapter9describestheinvolvementofNotchsign- ingpathwaywhichisnotonlyessentialforembryonicdevelopmentbutalsoplays importantroleintumorprogression. Chapter10reviewedtherecentlyidenti ed cancer- and metastasis-initiating cells involved in tumor progression. Especially, signal pathways that are frequently deregulated in cancer stem/progenitor cells v vi Preface duringcancerprogressionarehighlighted. Chapter11describestheroleoflipid rafts, a special component within membrane lipid domain, in signal transd- tion triggered by growth factor receptors leading to tumor metastasis. Finally, Chapters12,Chapters13,andChapters14presentthesignalingpathwaysresp- sibleformetastaticprogressionofspeci ctumorsincludingovariancancer,uveal melanomaandhepatoma,respectively. WethankallthecontributorsofeveryChapterinthebookincludingJia-RuWu, Chi-TanHu,LaureVoisin,StephanieDuhamel,SylvainMeloche,AlexeyShiryaev, MarijkeVanGhelue,UgoMoens,AlessioGiubellino,PraveenR. Arany,Moulay A. Alaoui-Jamali, Krikor Bijian, Panagiota Toliopoulos, Pingyu Zhang, Patrick A. Zweidler-McKay,MurielleMimeault,SurinderK. Batra,SamirKumarPatra, LydiaW. T. Cheung,CarmanK. M. Ip,AliceS. T. Wong,CecileLaurent,Jerome Couturier,XavierSastre-Garau,LaurenceDesjardins,EmmanuelBarillot,Sophie Piperno-Neumann,SimonSauleandRajagopalN. Aravalli. Wehopethisbookmightstimulatemorecancerbiologiststoemphasizethis eld whichbene tsdevisingmoreeffectivemoleculartargetingstrategiesforprevention ofcancermetastasis. Hualien,Taiwan Wen-ShengWu Chi-TanHu Contents 1 Overview of Signal Transduction in Tumor Metastasis...1 Wen-ShengWuandJia-RuWu 2 Microenvironment Triggers EMT, Migration and Invasion of Primary Tumor via Multiple Signal Pathways ...9 Wen-ShengWuandChi-TanHu 3 The ERK1/2 MAP Kinase Signaling Pathway in Tumor Progression and Metastasis ...25 LaureVoisin,StephanieDuhamel,andSylvainMeloche 4 Mitogen-Activated Protein Kinase-Activated Protein Kinases and Metastasis...41 AlexeyShiryaev,MarijkeVanGhelue,andUgoMoens 5 Grb2 and Other Adaptor Proteins in Tumor Metastasis ...77 AlessioGiubellinoandPraveenR. Arany 6 The Role of ROS Signaling in Tumor Progression...103 Wen-ShengWuandJia-RuWu 7 Signal Cross Talks for Sustained MAPK Activation and Cell Migration Mediated by Reactive Oxygen Species: The Involvement in Tumor Progression...

This monograph, written by well renowned breast cancer expect, Dr. Jose Russo, provides new insight on the pathobiology of breast cancer from the most current advances in the field, translational research, initiation and progression of the disease, the mechanism of invasion and metastasis and the concept of stem cells in treatment and drug resistance. The role of personalized medicine and genomic testing are also explored, which will provide a window to the future progress of cancer care.

In addition to its metabolic and endocrinologic effects, obesity and adipose tissue have now been shown to be associated with low grade inflammation resulting in cellular and humoral inflammatory factors of which the latter may act by endocrine, paracrine and autocrine mechanisms. These inflammatory mediators have increasingly been suggested as contributing to the obesity link to carcinogenesis and cancer promotion.

This volume of Energy Balance and Cancer will focus on recent developments and cutting edge research pointing to inflammation and inflammatory factors as key mediators of this linkage. The volume first provides information on inflammation as an important link between obesity and insulin resistance, which is in itself linked to promotion of cancer through hyperinsulinemia. The volume then covers some of the most important mechanisms by which obesity leads to inflammation, including the novel inflammasome concept, alterations in chromatin structure, circulating inflammatory factors, unique cellular interactions between adipocytes and macrophages and the direct link of dietary fat to inflammation and cancer.

Overall, this volume will provide important insight to help understand how inflammation may help modulate the linkage between obesity and cancer and serve as a platform for developing future research in this area.

A comprehensive, down-to-earth guide for anyone diagnosed with breast cancer. Being diagnosed with breast cancer can be scary and confusing. There are medical terms to learn, options to consider, and important decisions to make, all while trying to carry on with work, family, and life. The Breast Cancer Book can't reverse a diagnosis or make breast cancer disappear, but every page can inform and empower you or your loved ones, no matter where you are in the breast cancer experience. Written by three trusted experts-an oncologist, a breast surgeon, and a two-time breast cancer survivor-this multidisciplinary book walks you through everything you need to know about breast cancer so that you can make the best decisions about diagnosis, treatment, and follow-up care. In plain, easy-to-understand language that illuminates all the facets of this disease, the authors draw on their professional experience and the most current scientific knowledge to * describe the risk factors for breast cancer; * explain the various tests used to detect cancer; * clarify the full range of treatment options, from surgery, chemotherapy, and radiation to newer combination therapies; * provide insight from experts in genetics, radiation oncology, and breast reconstruction; * present inspirational true stories of breast cancer survivors; and * simplify complex concepts with detailed graphics, tables, illustrations, and photographs. A crash course on breast cancer that will help get you or anyone you love through the physical and emotional challenges of the disease, The Breast Cancer Book will also help readers communicate with their cancer team. Packed with information, this compassionate guide is the most up-to-date book available.

Identification of cancer risk factors and potential prevention strategies have been some of the most important medical and research contributions to the improvement of public health in the past half-century (Steele 2003). Und- standing the role of lifestyle, exposure to endogenous factors and exogenous environmental factors, and individual genetic and epigenetic variability have contributed significantly to this effort. Cancer prevention strategies have been developed based on results of epidemiologic, preclinical, and clinical studies that have generated clues for identifying risk factors that may be modulated by changes in lifestyle, such as smoking cessation or dietary modification (Greenwald 2002a). In addition, significant progress in medical interventions involving chemoprevention-a pharmacological approach to intervention that aims to prevent, arrest, or reverse either the initiation phase of carcinogenesis or the progression of premalignant cells-is beg- ning to pay dividends in reducing risks associated with cancer. Emerging technologies, identification of biomarkers of risk, and advances in genetics research also are finding applications in chemoprevention research that p- mise to speed the acquisition of knowledge on the molecular and cellular - fects of chemopreventive agents. 2 Lifestyle Approaches Population studies from the 1950s through the early 1980s provided c- pelling evidence that modifiable lifestyle choices can either increase or - crease cancer risk. For example, several landmark epidemiologic studies in the 1950s showed a clear association between smoking and lung cancer (Wynder and Graham 1950; Levin et al. 1950). In 1964, the U. S.

Leading clinicians and investigators review in a comprehensible and user-friendly style all the latest information about the molecular biology of cell cycle control and demonstrate its clinical relevance to understanding neoplastic diseases. Topics range from Cdk inhibitors and cell cycle regulators to the prognostic value of p27 and tumor suppressor genes as diagnostic tools. Actual case studies show how the new molecular understanding has produced such drugs as Flavopiridol and Sulindac. The book brings all the recent critical research findings to bear on clinical practice, and clearly shows their powerful impact on the diagnostics, prognostics, and therapeutics of cancer, AIDS, and cardiovascular disease.

Expert laboratory and clinical researchers from around the world review how to design and evaluate studies of tumor markers and examine their use in breast cancer patients. The authors cover both the major advances in sophisticated molecular methods and the state-of-the-art in conventional prognostic and predictive indicators. Among the topics discussed are the relevance of rigorous study design and guidelines for the validation studies of new biomarkers, gene expression profiling by tissue microarrays, adjuvant systemic therapy, and the use of estrogen, progesterone, and epidermal growth factor receptors as both prognostic and predictive indicators. Highlights include the evaluation of HER2 and EGFR family members, of p53, and of UPA/PAI-1; the detection of rare cells in blood and marrow; and the detection and analysis of soluble, circulating markers.

This important reference book presents the experience of Japanese surgeons in the operative treatment of bone and soft-tissue tumors arising in and around the pelvis. Drawing on more than three decades of work in the field, the authors chart the progress they have witnessed and helped to bring about in the diagnosis and treatment of pelvic tumors. Among those developments are improvements in imaging and other diagnostic methodologies, as well as advancements in microsurgery, methods of irradiation, and adjuvant chemotherapy. Major sections of the book include surgical anatomy, histological classification, biopsy, preparation, surgical approach, reconstructive surgery, and complications and sequelae. Seventeen illustrative cases present the outcomes of a broad spectrum of operative treatments, creating a valuable resource and reference for orthopedic surgeons, oncologists, and all who are involved in the diagnosis and treatment of pelvic tumors.

In anticipation of the opening of the H. Lee Moffitt Cancer Center and Research lnstitut on the campus of the University of South Florida, an international symposium, "The First Annual H. Lee Moffitt Symposium on Cancer Biology and Therapeutics" was held in Tampa, Florida on January 20-22, 1986. In this first symposium we decided to present a broad-based series of topics dealing with the major issues in the field of cancer. These topics ranged from the biochemistry of the cancer cell to the design of antineoplastic agents, through tumor cell heterogeneity, treatment of ltuman neoplasms to immunological aspects of cancer biology and tr atment. The speakers chosen represented individuals of international acclaim who are very active in the area of cancer research and treatment. The symposium brought together scien tists/physicians from six nations including Austria, Canada, France, Hungary, West Germany, and of course, the United States. The congeniality of the participants promoted the friendly exchange of knowledge which, it is hoped, will greatly hasten the time when successful management of human cancer will become routine. Future symposia in this series will be highly focused and will deal with a single facet of this vast field of cancer research and treatment. Joseph G. Cory, Editor Andor Szentivanyi, Editor University of South Florida, 1986 V ACKNOWLEDGMENTS This volume presents the Proceedings of the H. Lee Moffitt International Syn osium on Cancer Biology and Therapeutics which was held in Tampa, Florida on January 20, 21, and 22, 1986."

Leading researchers are specially invited to provide a complete understanding of a key topic within the multidisciplinary fields of physiology, biochemistry and pharmacology. In a form immediately useful to scientists, this periodical aims to filter, highlight and review the latest developments in these rapidly advancing fields.

Over the last decade, cytokine research has emerged as one of the most exciting and critical fields for providing fundamental knowledge of normal and abnormal human development. Today, it is apparent that cytokines orchestrate growth from the early embryonic stage to maturity and are responsible for the normal function of virtually every organ system. Furthermore, virtually all disease states have been associated, at least in part, with cytokine aberrations. In this volume, the editors have brought together internationally known experts in the field of interleukin research to provide a comprehensive review of the biology of the interleukins and their role in both health and illness, while maintaining a balance between the basic science and clinical aspects. Cytokines: Interleukins and their Receptors should be of interest to a wide variety of researchers including clinical hematologists, oncologists, immunologists, in addition to medical and PhD students and researchers with an interest in cytokines.

The growth in chemotherapy has led to a great need for all those involved to be familiar with safe procedures based on best evidence-based practice. Practical Chemotherapy: a multidisciplinary guide is a comprehensive and straightforward guide describing over 70 widely used chemotherapy regimens, helping to make their prescription and administration safer and less problematic. Checklists throughout the book are specifically tailored for the needs of each professional group involved in treatment, and are intended to help prevent potentially serious mistakes that can occur. This book is unique in its practical emphasis and will be invaluable for doctors, pharmacists and nurses working in oncology and haematology.

This unique volume traces the critically important pathway by which a "molecule" becomes an "anticancer agent. " The recognition following World War I that the administration of toxic chemicals such as nitrogen mustards in a controlled manner could shrink malignant tumor masses for relatively substantial periods of time gave great impetus to the search for molecules that would be lethal to specific cancer cells. Weare still actively engaged in that search today. The question is how to discover these "anticancer" molecules. Anticancer Drug Development Guide: Preclinical Screening, Clinical Trials, and Approval, Second Edition describes the evolution to the present of preclinical screening methods. The National Cancer Institute's high-throughput, in vitro disease-specific screen with 60 or more human tumor cell lines is used to search for molecules with novel mechanisms of action or activity against specific phenotypes. The Human Tumor Colony-Forming Assay (HTCA) uses fresh tumor biopsies as sources of cells that more nearly resemble the human disease. There is no doubt that the greatest successes of traditional chemotherapy have been in the leukemias and lymphomas. Since the earliest widely used in vivo drug screening models were the murine L 1210 and P388 leukemias, the community came to assume that these murine tumor models were appropriate to the discovery of "antileukemia" agents, but that other tumor models would be needed to discover drugs active against solid tumors.

The rapidly evolving field of Palliative Care focuses on the management of phenomena that produce discomfort and that undermine the quality of life of patients with incurable medical disorders. The interdisciplinary clinical purview includes those factors - physical, psychological, social, and spiritual - that contribute to suffering, undermine the quality of life, and prevent a death with comfort and dignity. Palliative Care is a fundamental part of clinical practice, the "parallel universe" to therapies directed at cure or prolongation of life. All clinicians who treat patients with chronic life threatening diseases are engaged in palliative care, continually attempting to manage complex symptomatology and functional disturbances. The scientific foundation of palliative care is advancing, and similarly, methods are needed to highlight, for practioners at the bedside, the findings of empirical research. Topics in Palliative Care Series is divided into sections that address a range of issues. Addressing aspects of sumptom control, psyshocsoical functioning, spiritual or existential concerns, ethics, and other topics, the chapters in each section review the given area and focus on a small number of salient issues for analysis. The authors present and evaluate existing data, provide a context drawn from clinical and research settings, and integrate knowledge in a manner that is both practical and readable. The specific topics covered in Volume 5 are Cultural issues in Palliative Care, Palliative Care in Geriatrics, Communication Issues in Palliative Care, Outcomes Research in Palliative Care, Opiod Tolerance; Reality of Myth?, and Pain and other symptoms: Treatment Challenges.

Written by experts in psycho-oncology, this book synthesizes the findings of the latest research on women's cancers to empower women to make informed choices about treatment options. Each year, hundreds of thousands of women are diagnosed with cancer in the United States alone. The total number affected is larger still, comprising siblings, parents, partners, and children of these women. In this single-volume work, an international team of experts address the physical, medical, and psychological matters that are triggered by a diagnosis of having a form of "women's cancer"-breast, cervical, endometrial, gestational, ovarian, uterine, vaginal, and vulvar being some of the more common. The handbook examines and explains each type of women's cancer, covering the specifics of incidence, diagnosis, treatment options, and more, providing an up-to-date guide for women and their families to assist in making informed choices about their treatment options. The book includes personal accounts from women who survived cancers and beat their emotional challenges, addresses myths versus realities regarding women's cancers, and covers relevant, related topics such as race, sexual orientation, religion, and cancer coping. Special attention is given to the impact of women's cancers on relationships, intimacy, and body image, as well as psychological factors such as anxiety, depression, and fear. Presents up-to-date research on women's cancers and current information about diagnoses and treatment options Considers women's cancers from a family systems perspective that recognizes the impact of women's cancers on loved ones and offers strategies for these related challenges, such as how to address the topic of cancer with children Provides readers with information on how to prevent and deal with cancer discrimination in the workplace as well as guidance for employers Includes an appendix with information about organizations focused on women's cancers and healing

Where do you begin to look for a recent, authoritative article on the diagnosis or management of a particular malignancy? The few general oncology textbooks are generally out of date. Single papers in specialized journals are informative, but seldom comprehensive; these are more often preliminary reports on a very limited number of patients. Certain general journals frequently publish good in-depth reviews of cancer topics, and published symposium lectures are often the best overviews available. Unfor tunately, these reviews and supplements appear sporadically, and the reader can never be sure when a topic of special interest will be covered. Cancer Treatment and Research is a series of authoritative volumes that aim to meet this need. It is an attempt to establish a critical mass of oncology literature covering virtually all oncology topics, which is revised frequently to keep the coverage up to date, and which is easily available on a single library shelf or by a single personal subscription. We have approached the problem in the following fashion: first, by dividing the oncology literature into specific subdivisions, such as lung can cer, genitourinary cancer, pediatric oncology, etc.; and second, by asking eminent authorities in each of these areas to edit a volume on the specific topic on an annual or biannual basis. Each topic and tumor type is covered in a volume appearing frequently and predictably, discussing current diag nosis, staging, markers, all forms of treatment modalities, basic biology, and more."

The Ninth Annual Pezcoller Symposium entitled "The Biology of Tumors" was held in Rovereto, Italy, June 4-7, 1997. It focused on the genetic mechanisms underlying het erogeneity of tumor cell populations and tumor cell differentiation, on interactions be tween tumor cells and cells of host defenses, and the mechanisms of angiogenesis. With presentations at the cutting edge of progress and stimulating discussions, this symposium addressed issues related to phenomena concerned with cell regulation and cell interactions as determined by activated genes through the appropriate and timely media tion of gene products. Important methodologies that would allow scientists to measure dif ferentially genes and gene products and thus validate many of the mechanisms of control currently proposed were considered, as were the molecular basis of tumor recognition by the immune system, interactions between cells and molecular mechanisms of cell regula tion as they are affected by or implemented through these interactions. The molecular and cellular mechanisms of tumor vascularization were also discussed. It was recognized that angiogenesis provides a potential site of therapeutic intervention and this makes it even more important to understand the mechanisms underlying it. We wish to thank the participants in the symposium for their substantial contribu tions and their participation in the spirited discussions that followed. We would also like to thank Drs."

A wide range of research methods for the study of vascular development, from basic laboratory protocols to advanced technologies used in clinical practice, are covered in this work. A range of methodologies such as molecular imaging platforms and signalling analysis, along with tumour models are collated here. Four sections explore in vitro techniques, in vivo and ex vivo manipulations, imaging and histological analysis and other novel techniques in vascular biology. Readers will discover basic methodologies used for analysis of endothelial cell growth in vitro, including co-culture models of vessel formation. Authors also explore isolation and purification of cells and methods for analysis of data and visualization of localized vasculature with modern imaging platforms. Both animal models and human disease are covered in this work. Each chapter contains helpful sections on trouble shooting, additional notes and links, supporting the reader to carry out protocols. This book will appeal to students, researchers and medical professionals working in all vascular-linked fields such as cardio- and cerebrovascular, cancer and dementia.

Over the last 50 years, drug development and clinical trials have resulted in successful complete responses in diseases such as childhood leukemia, testicular cancer and Hodgkin's disease. We are still, however, confronted with over 500,000 cancer-related deaths per year. Clearly, the phenomenon of drug resistance is largely responsible for these failures and continues to be an area of active investigation. Since the last volume in this series, we have learned that the energy-dependent drug efflux protein, p-glycoprotein, encoded by the MDR 1 gene, is a member of a family of structurally related transport polypeptides, thus allowing us to explore the relationship between structure and function. In addition to ongoing well designed clinical trials aimed at reversing MDR mediated drug resistance, the first gene therapy studies with the MDR 1 gene retrovirally transduced into human bone marrow cells are about to be initiated. Although MDR is currently the most understood mechanism of drug resistance, we are uncovering increasing knowledge of alternative molecular and biochemical mechanisms of drug resistance to antimetabolites, cisplatin and alkylating agents and developing new strategies for circumventing such resistance. It is clear that drug resistance is complex, and many mechanisms exist by which cancer cells may overcome the cytotoxicity of our known chemotherapeutic agents. As our understanding of each of these mechanisms expands, well designed models will be necessary to test laboratory hypotheses and determine their relationship to drug resistance in humans. It is this integration of basic science and clinical investigation that will both advance our scientific knowledge and result in the improvement of cancer therapy.

Interest in angiogenesis research remains strong in recent years and exciting new discoveries, about modulators of angiogenesis, their receptors, the transduction mechanisms and the angiogenic genes involved, have contributed to our present day understanding of this complex process. This knowledge has provided the basis and broadened the scope of angiogenesis - based therapy in oncology and many other clinical conditions. This monograph contains the contributions to the NATO Advanced Study Institute on "Angiogenesis: Models, Modulators and Clinical Applications," which was held in Rhodes, Greece, from June 20-30, 1997. This was the fourth of a series of NATO supported international meetings on Angiogenesis aiming to bring together basic scientists with clinicians to exchange ideas, disseminate new knowledge and discuss the present status and potential new directions in this fast moving area of biomedical research. The International Organising Committee that included Drs. E. Dejana, C Haudenschild, M. Hackel, H. Kleinman, P. Lelkes, M. Presta, P. Polverini, D. Thompson, has provided invaluable help with their insightful suggestions in the formulation of the scientific program for which I am grateful. I wish to thank all the participants for their enthusiastic participation and their complimentary comments on the success of the conference.

Clinical trials remain the most important vehicle for improving the care of cancer patients. This text presents the fundamental components and challenges involving clinical investigations. Leading experts discuss the critical issues covering the spectrum of important topics from planning to application. The book has a foreword by Samuel A. Wells, Jr., MD, Professor of Surgery, Duke University Medical Center, Durham, NC, former Director of the American College of Surgeons and Founder of the American College of Surgeons Oncology Group.