Table Of ContentMEDICAL 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
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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,
