Table Of ContentNEW TRENDS IN CANCER
FOR THE 21st CENTURY
ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY
Editorial Board:
NATHAN BACK, State University of New York at Buffalo
IRUN R. COHEN, The Weizmann Institute of Science
DAVID KRITCHEVSKY, Wistar Institute
ABEL LAJTHA, N. S. Kline Institute for Psychiatric Research
RODOLFO PAOLETTI, University of Milan
Recent Volumes in this Series
Volume 524
DIPEPTIDYL AMINOPEPTIDASES IN HEALTH AND DISEASE
Edited by Martin Hildebrandt, Burghard F. Klapp, Torsten Hoffmann,
and Hans-Ulrich Demuth
Volume 525
ADVANCES IN PROSTAGLANDIN, LEUKOTRIENE, AND OTHER BIO ACTIVE
LIPID RESEARCH: Basic Science and Clinical Applications
Edited by Zeliha Yazici, Giancarlo Folco, Jeffrey M. Drazen, Santosh Nigam,
and Takao Shimizu
Volume 526
TAURINE 5: Beginning the 21st Century
Edited by John B. Lombardini, Stephen W. Schaffer, and Junichi Azuma
Volume 527
DEVELOPMENTS IN TRYPTOPHAN AND SEROTONIN METABOLISM
Edited by Graziella Allegri, Carlo V. L. Costa, Eugenio Ragazzi, Hans Steinhart,
and Luigi Varesio
Volume 528
ADAMANTIADES-BEHCET'S DISEASE
Edited by Christos C. Zouboulis
Volume 529
THE GENUS YERSINIA: Entering the Functional Genomic Era
Edited by Mikael Skurnik, Jose Antonio Bengoechea, and Kaisa Granfors
Volume 530
OXYGEN TRANSPORT TO TISSUE XXIV
Edited by Jeffrey F. Dunn and Harold M. Swartz
Volume 531
TROPICAL DISEASES: From Molecule to Bedside
Edited by Sangkot Marzuki, Jan Verhoef, and Harm Snippe
Volume 532
NEW TRENDS IN CANCER FOR THE 21st CENTURY
Edited by Antonio Llombart-Bosch and Vicente Felipo
A Continuation Order Plan is available for this series. A continuation order will bring delivery of each new volume
immediately upon publication. Volumes are billed only upon actual shipment. For further information please contact
the publisher.
NEW TRENDS IN CANCER
FOR THE 21st CENTURY
Edited by
Antonio Llombart-Bosch
University of Valencia
Valencia, Spain
and
Vicente Felipo
Valencian Foundation for Biomedical Research
Valencia, Spain
Springer Science+Business Media, LLC
Library of Congress Cataloging-in-Publication Data
International Symposium on Cancer "New Trends in Cancer for the 21st Century" (2002:
Valencia, Spain)
New trends in cancer for the 21st century/edited by Antonio Llombart-Bosch and
Vicente Felipo.
p. ; cm. — (Advances in experimental medicine and biology; v. 532)
Includes bibliographical references and index.
ISBN 978-1-4613-4914-3 ISBN 978-1-4615-0081-0 (eBook)
DOI 10.1007/978-1-4615-0081-0
1. Cancer—Treatment—Congresses. 2. Cancer—Molecular aspects—Congresses. I.
Llombart Bosch, Antonio. II. Felipo, Vicente. III. Title. IV. Series.
[DNLM: 1. Neoplasms—immunology—Congresses. 2. Neoplasms—therapy—Congresses.
3. Angiogenesis Factor—therapeutic use—Congresses. 4. Antineoplastic
Agents—therapeutic use—Congresses. QZ 266 1609n 2003]
RC270.8.I5286 2003
616.99'406—dc21
2003047451
Proceedings of the International Symposium on Cancer: New Trends in Cancer for the 21st Century, held
November 10-13, 2002, in Valencia, Spain
ISBN 978-1-4613-4914-3
©2003 Springer Science+Business Media New York
Originally published by Kluwer Academic/Plenum Publishers, New York in 2003
Softcover reprint of the hardcover 1st edition 2003
http://www.wkap.nl/
10 9 8 7 6 5 4 3 21
A C.I.P. record for this book is available from the Library of Congress
All rights reserved
No part of this book may be reproduced, stored in a retrieval system, or transmitted in any form or by
any means, electronic, mechanical, photocopying, microfilming, recording, or otherwise, without written
permission from the Publisher, with the exception of any material supplied specifically for the purpose of
being entered and executed on a computer system, for exclusive use by the purchaser of the work.
Permissions for books published in Europe: [email protected]
Permissions for books published in the United States of America: [email protected]
In Memoriam ofMs. Ana Vines Rubert
PREFACE
ThisvolumecontainsthemajorityoftheconferencespresentedattheInternational Symposium
onCancer"NewTrendsinCancerforthe21stCentury",held inValencia, Spain,November 10-13,
2002. This Simposium was one of the activities of the Clitedra Santiago Grisolia and of the
FundacionMuseudelesCiencies"PincipeFelipe"ofValencia.
It is estimated thatevery yearnearly 3million Europeans develop cancer, leading to 750.000
deaths per year. This represents a tremendous burden that cannot be ignored by politicians and
citizens, taking into account that these deaths occur not only in an ageing population but also in
children and in adults in the most active period oftheir lives. The probability ofcure for cancer
patients, considering all types ofcancer, within the different states ofthe European Union (EU),
ranges from between one fourth and one half, and the survival rates in different European
populations varies widely being low in western Europe. Everybody is conscious that cancer in
Europeiswithoutdoubtamajorhealthproblem.Thereforegreatereffortisneededtoachievebetter
resultsindecreasingboththeincidenceandthemortality.
In this sense, the European Parliament under the auspices of the European Commission
Research Directorate-General has expressed the need for a more active policyin orderto develop
newstrategiesinprevention,cancercareandresearch. Thefollowingneedshavebeenidentified: a)
developingevidence-basedguidelinesforearlydetection,diagnosis,treatmentandafter-careforthe
most common types of cancer; b) cancer research should be oriented towards a more
interdisciplinaryapproachand shouldreceive more financial support; c) more research on courses
oftreatment,introducingindependentclinicalassaysonahighernumberofpatients;d)comparative
research on the cost-effectiveness ofvarious detection and treatment methods in order to increase
efficiency and reduce costs in the health care system; e) development ofEuropean modules for
continuedtraining inresearch and ofclinical specialists in the various fields; and f) to ensurethat
the existingnetworkscancontinuetheirsuccessfulactivityin the future and thatnew oneswill be
created.
ThemainobjectiveoftheSymposium "NewTrends inCancerforthe21stCentury"wastojoin
outstandingscientistsfromovertheworldwhodeveloptheiractivitiesindifferentareasofthe fight
a~ainstcancer,givingthemtheopportunitytoimprovetheirknowledgeinotherareasandexchange
ideasandinformation.
Thecausesofcancerandthemanyfactorswhichinfluenceitsemergenceareverycomplexand
heterogeneous.Themalignanttransformedcellcontainssignalsthatstimulateorinhibitthedisease
and arise from the stepwise accumulation of genetic changes that confer the mutated cell the
propertiesofunlimitedgrowthandresistancetohomeostaticregulatorymechanisms.
Oneofthemaintargetsincanceristhecellcyclemachinerywhichiscontrolledbyanumberof
extrinsic signals and tumour suppressor proteins that decide whether the cell should remain
quiescent or enterinto active growthand division. This decision is mainly taken at the restriction
point at the middle of the G1 phase, but there are certain checkpoints that ensure the correct
transitionofeachphasethroughthecellcycle.Severalanimalmodelshavebeendevelopedwiththe
aim of understanding the role played by the different elements integrating these cell cycle
vii
viii Preface
checkpoints. These animal models may be a valuable tool to design and validate new therapeutic
strategiesagainsttumordevelopment.
From the pathological point of view, the diagnosis and clinical classification oftumours is
based mainly upon the recognition of the microscopical tumoral pattern with the support of
immunophenotypingandsomeotheremergingmoleculartechniquesthathelptodistinguishseveral
tumor subtypes and grades and correlate them with the clinical stage and response to treatment.
However, the molecular heterogeneity of cancer cells and of their supporting stroma and
vascularization, produces numerous biological variations, within morphologically similar
malignancies,thatcurrentlyescapethecurrentpossibilitiesofdiagnosisandprognosisandtherefore
toarationaltherapeuticapproach.Thedevelopmentofanovelandsophisticatedtechnologyforthe
study of tumour profiling, both at the genetic level (genetics and epigenetics) and at protein
expression profiles (proteomics), is opening doors to what is considered the new molecular
pathology. This represents an exceptional opportunity for histopathology sincewith the expansion
ofalarge numberofassayable markers, it isnow possible to gather abettermolecularportrait of
tumors.
Most tumors acquire the capacity of invasion and metastasis and escape the barriers ofthe
host's immune system. One of the main focuses of attention in this sense is the study of the
phenomenon of angiogenesis: structural bases and main molecular players, as well as the
therapeuticpossibilitiesthatexisttoabrogatethisprocessintumors. Ontheotherhand, stimulation
ofthehostimmunesystemby meansofnewlydevelopedanti-tumoral vaccines has openedone of
themostexcitingfieldsinthefightagainstcancer.
Thesearchfor anddevelopmentofnewtherapeuticdrugsdirectedagainstspecifictargetssuch
as inhibitors of tyrosin kinase receptors or monoclonal antibodies which down-regulate the
hyperactive function of some oncogenes, has considerably improved the outcome for several
patients(PhaseIIandIIIstudies)whichonthecontrarywouldhaveapproachedtotheoutcome.
Specialmentioninthefightagainstcancerhastobemadeoforganizationssuchasthe EORTC
(European Organization for Research and Treatment of Cancer), the OECI (Organization of
European Cancer Institutes) and the comprehensive cancer centers that promote and co-ordinate
high-qualitylaboratoryresearchandclinicaltrialsand also providecentral facilities with scientific
expertiseandadministrativesupportforthisnetworkofscientistsandclinicalinvestigators.
Thisbookprovides,therefore,an updateonthe knowledge oncertaincrucial aspectsregarding
the latest aspects on research in the field of cancer, such as basic diagnostic and therapeutic
research.
Wewouldliketoexpressourgratitudetoall theparticipantsfortheirwrittencontributionsand
fortheirenlightenedandfruitfuldiscussion.
We also acknowledge withdeep gratitudethe Gomez Mata family who take the initiative and
provided financial support to organize this Symposium to honour the memory ofMs Ana Vines
Rubertwho diedofcancer. This represents an exceptional exampleofthe society's feelings about
thisdisease.
We also thank the Department of Pathology of the University of Valencia, the Fundacion
Instituto Valenciano de Oncologia, the Oficina de Ciencia y Tecnologia de la Generalitat
Valenciana,theCatedraSantiagoGrisoliaandtheMuseoPrincipeFelipeoftheCiudaddelasArtes
y las Ciencias ofValencia, which provided the personnel and the facilities to organize both the
Symposiumandthesessions.
AntonioLlombart-Bosch
VicenteFelipo
CONTENTS
DrivingtheCellCycletoCancer 1
MarcosMalumbres,SarahL. Hunt,RocioSotillo,JavierMartin,JunOdajima,
AlbertoMartin,PierreDubus,SagrarioOrtega,andMarianoBarbacid
Proliferation: TheCellCycle 13
ManuelSerrano
MolecularAnalysisofGeneExpressioninTumorPathology..'" ,.., 19
HeinzHofler,KatjaSpecht, andKarl-FriedrichBecker
EwingTumorBiology: PerspectivesforInnovativeTreatmentApproaches 27
HeinrichKovar
CancerEpigenetics: DNAMethylationandChromatinAlterationsinHumanCancer .... 39
ManelEsteller
MolecularAnalysisofCancerUsingDNAandProteinMicroarrays 51
JuanMadoz-GurpideandSamM. Hanash
ProteomicApproachestotheDiagnosis,Treatment,andMonitoringofCancer 59
JuliaD. Wulfkuhle, CloudP.Paweletz,PatriciaS. Steeg,EmanuelF.PetricoinIII,
and LanceLiotta
StructuralBasisofTumoralAngiogenesis '" , 69
AntonioLlombart-Bosch,JoseA. Lopez-Guerrero,CarmenCardaBatalla,Amparo
RuizSaun,andAmandoPeydro-Olaya
MatrixMetalloproteinasesandTumorProgression 91
JoseM.P. Freije, MilagrosBalbin, AlbertoM. Pendas, LuisM. Sanchez,
XoseS.Puente,and CarlosLopez-Otin
AngiogenesisInhibitorsand TheirTherapeuticPotentials 109
Yihai Cao
ix
x Contents
MutatedTyrosineKinases asTherapeuticTargetsinMyeloidLeukemias 121
MartinSattler,BlancaScheijen,EllenWeisberg, andJamesD. Griffin
TargetingPDGFReceptorsinCancer- RationalesandProofofConceptClinical
Trials 141
DanielGeorge
Immune-PromotedTumorCellInvasionandMetastasis. Newconsiderations
incancertherapy 153
EmilioBarberaGuillem andJames W. Sampsel
ImprovementsofSurvivalinNinePhaseIIClinicalStudiesWithDifferentTypesof
CancerUponAnti-TumorVaccinationwithanAutologousTumorCellVaccine
ModifiedbyVirus InfectiontoIntroduceDangerSignals 175
VolkerSchirrmacher
CausationandPreventionofSolelyEstrogen-InducedOncogenesis: Similarities
toHumanDuctalBreastCancer 195
JonathanJ. Liand SaraAntoniaLi
Cyclooxygenase-2InhibitorsinCancerPreventionandTreatment 209
JaimeL.Masferrer
ExosomesforImmunotherapyofCancer 215
NathalieChaput,NECSchartz,FabriceAndre, and LaurenceZitvogel
BreastCancerGeneExpressionAnalysis- TheCaseforDynamicProfiling 223
MatthewJ. Ellis
DevelopmentoftheEpidermalGrowthFactorReceptorInhibitor
TARCEVATM (OSI-774) 235
ViktorGIiinwaldandManuelHidalgo
Gefitinib(IRESSA,ZD 1839)forNon-SmallCellLungCancer(NSCLC):
RecentsResultsandFurtherStrategies 247
ChristianManegold
MechanismofActionofAnti-HER2Monoclonal Antibodies: ScientificUpdateon
Trastuzumaband2C4 253
JoanAlbanell,JordiCodony, AnaRovira, BegofiaMellado,andPereGascon
EORTCResearchandDevelopment:AchievementsandFuturePerspectives 269
DenisLacombe,RalphCrott,andFranyoiseMeunier
Contributors 277
Index 283
