The impact of tumor biology on cancer treatment and multidisciplinary strategies PDF
Preview The impact of tumor biology on cancer treatment and multidisciplinary strategies
MEDICAL RADIOLOGY Radiation Oncology Editors: L. W. Brady, Philadelphia H.-P. Heilmann, Hamburg M. Molls, Munich C. Nieder, Bodø M. Molls ∙ P. Vaupel ∙ C. Nieder M. S. Anscher (Eds.) The Impact of Tumor Biology on Cancer Treatment and Multidisciplinary Strategies With Contributions by M. S. Anscher · S. T. Astner · M. J. Atkinson · M. Baumann · C. Belka · N. Cordes J. Dahm-Daphi · P. Dent · E. Dikomey · J. Drevs · I. Eke · S. Grant · P. R. Graves A.-L. Grosu · S. Hehlgans · M. Hiraoka · G. Iliakis · S. Itasaka · I. L. Jackson A. M. Kaindl · C. A. Klein · T. Klonisch · M. Krause · M. Los · M. P. Mehta · M. Gužvić M. Molls · G. Multhoff · U. Nestle · C. Nieder · J. Norum · K. Oexle · S. Panigrahi A. Pawinski · I. Rashedi · H. C. Rischke · V. Schneider · K. Schulze-Osthoff · S. Song S. Tapio · K. Valerie · P. Vaupel · Z. Vujaskovic · W. A. Weber · D. Zips Foreword by L. W. Brady, H.-P. Heilmann, M. Molls, and C. Nieder 123 Michael Molls, MD Carsten Nieder, MD Professor, Direktor, Klinik und Poliklinik für Professor Strahlentherapie und Radiologische Onkologie Department of Internal Medicine – Oncology Klinikum rechts der Isar der Technischen Nordlandssykehuset HF Hospital Universität München 8092 Bodø Ismaninger Straße 22 Norway 81675 München Germany Mitchell S. Anscher, MD, FACR, FACRO Florence and Hyman Meyers Professor and Chair Peter Vaupel, Dr. med., MA/Univ. Harvard Department of Radiation Oncology Professor of Physiology and Pathophysiology Virginia Commonwealth University School Institute of Physiology and Pathophysiology of Medicine University Medical Center 401 College Street Duesbergweg 6 P. O. Box 980058 55099 Mainz Richmond, VA 23298-0058 Germany USA MEDICAL RADIOLOGY ∙ Diagnostic Imaging and Radiation Oncology Series Editors: A.L. Baert ∙ L.W. Brady ∙ H.-P. Heilmann ∙ M. Knauth ∙ M. Molls ∙ C. Nieder Continuation of Handbuch der medizinischen Radiologie Encyclopedia of Medical Radiology ISBN 978- 3-540-74385-9 e-ISBN 978-3-540-74386-6 DOI 10.1007/978-3-540-74386-6 Library of Congress Control Number: 2008928298 © 2009 Springer-Verlag Berlin Heidelberg This work is subject to copyright. All rights are reserved, wether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broad-casting, reproduction on microfilm or any other way, and storage in data banks. Duplication of this publication or parts thereof is permitted only under the provisions of the German Copyright Law of September 9, 1965, in it current version, and permission for use must always be obtained from Springer. Violations are liable to prosecution under the German Copyright Law. 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Cover design: Verlagsservice Teichmann, Mauer, Germany Production, reproduction and typesetting: le-tex publishing services oHG, Leipzig, Germany Printed on acid-free paper 9 8 7 6 5 4 3 2 1 springer.com Foreword The rapidly changing concepts in radiation oncology with the development of more precise in- strumentation for delivery of radiation therapy and a greater emphasis on hypofractionation technologies require a very intimate knowledge of tumor biology and the influence of various biologic factors on dose distribution within the tumor in terms of homogeneity as well as preven- tion of any late effects on normal tissue surrounding the tumor itself. Not only are these major factors in clinical practice but also the known factors of inhomogeneity of cancer cells, the impact of microenvironment in terms of radiation effect, and host factors make it mandatory to design therapeutic strategies to improve the outcome and to diminish any potential short-term or long- term risks from the radiation therapy. The authors have developed an outstanding text that deals with these strategies and how they would impact on established and emerging new technologies and treatment. The context of the presentations within a multidisciplinary combined modality therapy program is incredibly im- portant. In this volume, various topics are reviewed including tumor genesis, cell proliferation, an- giogenesis, the physiologic characteristics of malignant tissues, invasion and adhesion, the route and role pursued in the development of metastasis, and the role of the human immune system in cancer prevention and development. Important chapters focus on cancer diagnosis and treatment along the basic principles of che- motherapy, radiotherapy, and molecularly targeted therapy. The presented rational adaptations allow for the design of translational studies and become increasingly more important as a better understanding is gained of gene expression profiling, gene transfer and silencing, proteomics and molecular imaging and their impact on the development of treatment programs. The authors’ aim is to educate and inspire those who devote most of their work to research in cancer and its clinical treatment. It represents an outstanding presentation in these regards. Philadelphia Luther W. Brady Hamburg Hans-Peter Heilmann Munich Michael Molls Bodø Carsten Nieder Preface Numerous developments in molecular biology and information technology over the past decade have led to an explosive growth in cancer biology research. Much of the research has focused on the underlying mechanisms of carcinogenesis, tumor progression and metastasis. Knowledge gained from this research has led to the development of new classes of drugs that target specific pathways known to be involved in one or more of the processes that may be altered as part of the malignant phenotype. Radiation oncology as a specialty has benefited from this technological revolution, and it is now possible to target therapies much more precisely and safely than in the past. It is critically important, however, that the radiation oncologist becomes knowledgeable not only about new developments in radiation biology, but also about cancer biology in general. In fact, radiation bi- ology has embraced molecular biology to such a degree that there are now few classically trained radiobiologists remaining on the faculties of many radiation oncology departments. The purpose of this book is to provide the practicing radiation oncologist, as well as those in training, with a concise overview of the most important and up-to-date information pertain- ing to tumor biology as it impacts on cancer treatment. This information is not limited to that directly related to the interaction of radiation with cells and tissues, for it is important that the radiation oncologist have a broader understanding of tumor biology. It is the intent of the editors to provide chapters from experts in not only the basic sciences, but also in the translational application of key basic biological concepts. Thus, the book con- tains chapters on the fundamental basic principles of cancer biology, such as tumorigenesis, cell growth and proliferation, angiogenesis, tumor physiology, the biology of metastasis and the role of the immune system. More clinically related topics, such as molecular and biological imaging and molecular targeted therapies for both cancer treatment and normal tissue injury, are also included. In order to be able to read and understand the latest literature, it is important to have an understanding of the principles behind some of the latest tools employed by scientists to conduct their research. To that end, chapters describing techniques such as gene expression profiling, gene transfer and gene silencing are also included. We hope that the reader will find this book a useful guide to the molecular era of cancer biology and to the implications of increasing biology knowledge of personalized cancer therapy, particularly as it applies to the field of radiation oncology. Munich Michael Molls Mainz Peter Vaupel Bodø Carsten Nieder Richmond Mitchell S. Anscher Contents 1 Tumorigenesis ........................................................ 1 Michael J. Atkinson and Soile Tapio 2 Tumor Growth and Cell Proliferation ................................ 19 MAREK LOS, Iran Rashedi, Soumya Panigrahi, Thomas Klonisch, and Klaus Schulze-Osthoff 3 Tumor Angiogenesis .................................................. 39 Vesile Schneider, Hans Christian Rischke, and Joachim Drevs 4 Pathophysiology of Solid Tumors ..................................... 51 Peter Vaupel 5 Adhesion, Invasion, Integrins, and Beyond ........................... 93 Nils Cordes, Stephanie Hehlgans, and Iris Eke 6 The Biology of Cancer Metastasis .................................... 117 Miodrag Gužvić and Christoph A. Klein 7 Role of the Immune System in Cancer Development and Therapeutic Implications .......................................................... 129 Gabriele Multhoff and Sabrina T. Astner 8 Tumor Detection by Biological Markers .............................. 147 Carsten Nieder and Adam Pawinski 9 Tumor Imaging with Special Emphasis on the Role of Positron Emission Tomography in Radiation Treatment Planning ............. 153 Anca-Ligia Grosu, Wolfgang A. Weber, and Ursula Nestle 10 Quantitative Cell Kill of Radio- and Chemotherapy .................. 169 Michael Molls, Carsten Nieder, Claus Belka, and Jan Norum 11 The Impact of Molecularly Targeted Therapy in Multi-Modality Therapy ........................ 191 Shiyu Song, Paul Dent, and Steven Grant X Contents 12 Target-Based Interventions to Treat Radiation-Induced Lung Injury 221 Isabel L. Jackson, Mitchell S. Anscher, and Zeljko Vujaskovic 13 Mechanisms of Treatment Resistance: Molecular and Clinical Examples for Radio- and Chemotherapy .............................. 243 Carsten Nieder 14 DNA Repair and Cell Cycle Regulation After Ionizing Irradiation .... 251 George Iliakis, Jochen Dahm-Daphi, and Ekkehard Dikomey 15 Physiological Mechanisms of Treatment Resistance .................. 273 Peter Vaupel 16 Influence of Time Factor and Repopulation on Treatment Resistance 291 Daniel Zips 17 Molecular Tools, Expression Profiling ................................ 299 Angela M. Kaindl and Konrad Oexle 18 Strategies of Gene Transfer and Silencing, and Technical Considerations ....................................................... 313 Kristoffer Valerie and Paul R. Graves 19 Tumor Biology’s Impact on Clinical Cure Rates ...................... 323 Michael Baumann and Mechthild Krause 20 Dose-Escalated High-Precision Radiotherapy: a Method to Overcome Variations in Biology and Radiosensitivity Limiting the Success of Conventional Approaches? ......................................... 335 Carsten Nieder and Minesh P. Mehta 21 Treatment of the Primary Tumor in Metastatic Cancer: Influence on Outcome ................................................ 347 Satoshi Itasaka and Masahiro Hiraoka Subject Index .............................................................. 355 List of Contributors ....................................................... 359 1 Tumorigenesis Michael J. Atkinson and Soile Tapio Contents K E Y P O I n T S 1.1 Introduction 2 • Analysis of the DNA of tumor cells reveals that 1.2 early Mutational events a finite number of gene mutations are respon- in Carcinogenesis 3 sible for the transmission of the phenotypic 1.2.1 Alterations of the Genetic Code 3 1.2.2 Events Accompanying changes characteristic of the tumor. These mu- Progression 5 tations may have arisen sporadically through 1.2.3 Proliferation Modifying Genes 5 misrepair of endogenous DNA damage from 1.2.4 Acquisition of the Invasive/ oxidative stress and DNA replication errors, Metastatic Phenotype 6 or through mistakes in somatic recombination 1.3 Inherited susceptibility 6 events. Alternatively, they may be induced ex- 1.4 oncogenes 7 ogenously through the DNA-damaging action of environmental agents such as ionising radia- 1.5 tumor suppressor Genes 10 tion and UV light. 1.6 MicroRnAs in Human Cancer 11 • Failure of the damage control processes to cor- 1.7 Lifestyle, environmental rect the damage before it is incorporated per- and occupational Factors manently into the genome during replication is Causing Cancer 12 critical. • 1.8 Cancer stem Cell Hypothesis In addition to the intragenic mutations, there is and Microenvironment 14 a range of additional mechanisms whereby the 1.9 Radiation-Induced Cancers 14 genome may become perturbed during tumor development. Alterations in the copy number 1.10 Conclusions 15 of cellular genes are common in human tumors. References 15 Both allelic gains and losses are encountered. Amplification of genetic regions may take the form of intrachromosomal duplications, lead- ing to the in situ amplification of a gene with oncogenic properties at its normal chromo- somal location. Transcription of the amplified gene complex subsequently leads to overex- pression of the gene product. Alternatively, the amplification may occur extrachromosomally, leading to the formation of multiple copies of M. J. Atkinson, PhD chromosomal fragments (double minutes). Professor, Institute of Radiobiology, Helmholtz Centre • The spectrum of mutational events in tumor Munich, German Research Centre for Environmental Health, cells can also include chromosomal transloca- Ingolstädter Landstraße 1, 85764 Neuherberg, Germany tion and inversion events leading to the struc- S. Tapio, PhD tural rearrangement of parts of the genome. Institute of Radiobiology, Helmholtz Centre Munich, Ger- man Research Centre for Environmental Health, Ingolstädter This may result in a fusion of two unrelated gene Landstraße 1, 85764 Neuherberg, Germany 2 M. J. Atkinson and S. Tapio metastasise from their initial locations to proliferate in fragments, creating a chimeric gene instructing inappropriate tissue compartments. This chapter de- production of a protein with abnormal function. scribes the early stages of tumorigenesis, starting with Alternatively, the rearrangement may transpose genetic mutations and alterations in gene expression an endogenously active promoter with coding and biological signalling, and finally discusses inherited sequences from a gene that is normally either or environmental factors accelerating the initiative pro- tightly regulated or transcriptionally silent in cess to malignancy. the tissue. This form of mutation leads to the inappropriate expression of the protein. • Two non-mutational events are also implicated in the changes in gene expression during onco- 1.1 genesis. In the first situation, transcriptional si- Introduction lencing of an essential tumor suppressor gene is associated with non-mutational changes to the The scientific search for the cause of cancer can be structure of the gene promoter region. Changes traced back to Hippocrates. His suggestion that an in the methylation status of individual nucle- imbalance in the bodily fluids was the cause of cancer otides of the DNA as well as to the methylation predated both the cellular theory of Johannes Müller and acetylation status of the DNA-binding his- and Rudolf Virchow and the oncogenetics of Vogelstein tone core proteins are involved in regulating lo- and colleagues. The Hippocratic view remained the cal gene expression. A second non-mutational conventional wisdom for generations, but was rapidly event is gene silencing through endogenous discarded in favour of more evidence-based models RNA-binding microRNA molecules. (Fig. 1.1). Maybe, given the importance now ascribed to • Oncogenes are genes that, through the action the local tissue microenvironment in cancer, we should of the proteins they encode, cause cancer when give more credit to Hippocrates. transcribed. Oncogenes arise through the mu- After cancer was recognized as a cell-based disease, tation of normal cellular genes with regulatory scientific effort focussed on understanding the processes activities called proto-oncogenes. involved in the genesis and behaviour of the abnormal • Tumor suppressor genes encode proteins that cells. Whilst the origins of the cellular building blocks are responsible for control processes essential of tumors can be traced back to an apparently normal to limiting cell proliferation. They act upon parental tissue, cancer cells clearly evolve unique pheno- pathways involved in growth control, cell cycle typic characteristics. Insight into potential mechanisms regulation and the maintenance of cell integ- behind this process came from the early epidemiological rity (DNA repair and apoptosis). studies by Percival Pott, Bernardino Ramazzini and oth- • Carcinogens include a number of different ers, who demonstrated exogenous causes for some can- substances that are directly involved in the ini- cer through infection, wounding or noxious chemicals tiation or promotion of cancer in humans. The (McDermott et al. 2007; Aronson 2007; Breasted nature of carcinogens varies from radiation to 1922). The seminal study of Theodor Boveri, suggest- chemical substances, bacteria and viruses. ing that tumors arise through abnormal distribution • Evolving concepts of tumor stem cells, the reg- of chromosomes, focussed attention upon the genome ulation of coordinated expression programmes (Manchester 1995; Harris 2008). Although Peyton by non-translated microRNAs and the role of Rous almost simultaneously established that the malig- the tumor microenvironment are just three ar- nant phenotype could be transferred to normal cells in eas where new knowledge is opening up pos- tumor cell extracts (Vogt 1996), the discovery of the sibilities for the diagnosis and treatment of ma- central role of genetic material in the process had to lignant disease. await the explosion of interest in molecular biology that followed the clarification of the structure of DNA. This new era saw the identification of tumor-inducing genes Abstract within the genome of oncogenic viruses, the discovery that these viral genes were in fact mutated derivatives Tumor cells possess a range of inherited phenotypic of cellular genes and that endogenous mutation of these features that distinguish them from normal cells. They very same cellular genes could give rise to cancers. acquire the ability to undergo almost continual unregu- Although it was comforting to assume that a simple lated growth, resist cytotoxic chemicals and are able to gene mutation underlies the development of cancer,
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