Chemokine Receptors in Cancer

181 Pages·2009·4.651 MB·English

by  Chareeporn Akekawatchai, Marina Kochetkova, Jane Holland (auth.), Amy M. Fulton (eds.)

CANCER DRUG DISCOVERY AND DEVELOPMENT
Chemokine
Receptors
in Cancer
Edited by
Amy M. Fulton
Cancer Drug Discovery and Development
Series Editor: Beverly A. Teicher
Forothertitlespublishedinthisseries,goto
http://www.springer.com/series/7625
Amy M. Fulton
Editor
Chemokine Receptors
in Cancer
Editor
AmyM.Fulton
DepartmentofPathology
SchoolofMedicine
MarleneandStewart
GreenebaumCancerCenter
UniversityofMaryland
BaltimoreMD21201
USA
[email protected]
ISBN978-1-60327-266-7 e-ISBN978-1-60327-267-4
DOI10.1007/978-1-60327-267-4
LibraryofCongressControlNumber:2009921125
#HumanaPress,apartofSpringerScienceþBusinessMedia,LLC2009
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Preface
The chemokine receptors are a diverse family of seven-transmembrane
G-protein-coupled receptors binding a large family of ligands. Chemokine
receptorswerefirstidentifiedonleukocytesandmediatedirectedmigrationof
manyhostcellstositesofligandexpression.Itisnowwellestablishedthatmost
malignantcellsalsoexpressoneormorechemokinereceptor.Thisvolumewill
summarize the growing body of evidence that several chemokine receptors
contributetotumorbehavior.
ThereisabundantevidencethatCXCR4,whichiswidelyexpressedinmany
malignancies,contributestotheabilityoftumorcellstometastasizetositesof
ligandexpression.EvidenceforregulationofCXCR4byhypoxiaisdescribed.
LikeCXCR4,bothCCR7andCXCR3functiontopromotetumorcellhoming
and metastasis of melanoma, breast and colon cancers. Several chemokine
receptors also function to support the survival and proliferation of tumor
cells either directly or through transactivation by tyrosine kinase-coupled
growthfactorreceptors.
While chemokine receptors expressed on tumor cells generally support
tumor growth and dissemination, expression of these receptors on host cells
has both pro-tumor and anti-tumor functions. Both angiostatic and
angiogeneic functions of CXC chemokines acting on endothelial cells have
been described. The CXCR3 receptor expressed on malignant cells promotes
metastasisbutCXCR3+Th1cellsandNKcellsplayaprotectiveroleinseveral
tumor models. Data demonstrating the potential therapeutic potential of
CXCR3 ligand overexpression acting on host immune and endothelial cells
are also summarized. The CCR5/CCL5 axis has a complex role in tumor
behavior with induction of an early protective T-cell response that is
ultimatelyoverriddenbyatumorgrowth-promotingroleofCCL5.
There are also several chemokine receptors that act as decoy receptors,
binding ligands with high affinity. Although these receptors do not transduce
signalsthat mediateintracellular responses,ligandbindingdoescontribute to
tumorbehavior.Forexample,theD6receptormayactasabiologicalsinkto
reducethebioavailabilityofpro-angiogenicchemokines.Differencesindecoy
receptor expression in different populations may contribute to disparities in
cancerincidenceandoutcome.
v
vi Preface
Thetherapeuticpotentialandchallengesoftargetingchemokinereceptorsin
cancer is also discussed. Based on promising preclinical data, antagonists of
CXCR4 are currently being evaluated in clinical trials. Initial studies have
indicated that inhibition of several other chemokine receptors, expressed on
themalignantcell,showspromise;however,thisapproachiscomplicatedbythe
factthatmanyprotectivehostcellsexpressthesamereceptors.Insummary,the
study of chemokine receptors in cancer has rapidly expanded since the initial
description,in2001,ofCXCR4andCCR7incancercells.Manystudiesattest
totheimportanceofchemokinereceptorsasdeterminantsoftumorbehavior.
The current challenge is to understand the mechanisms underlying these
functionsandtomoreeffectivelytargetthesereceptorstherapeutically.
AmyM.Fulton
Baltimore,MD,USA
Contents
ChemokinesandChemokineReceptorsinCancerProgression ......... 1
ChareepornAkekawatchai,MarinaKochetkova,
JaneHolland,andShaunR.McColl
CXCR4andCancer.......................................... 31
BungoFurusatoandJohngS.Rhim
HIF-1RegulationofChemokineReceptorExpression ............... 47
ElizabethW.NewcombandDavidZagzag
ChemokineReceptorsInvolvedinColonCancerProgression,
andLymphNodeMetastasis................................... 63
MakotoMarkTaketoandKenjiKawada
TheCXCR3/CXCL3AxisinCancer............................. 79
YanchunLiandAmyM.Fulton
RolesforCCR7inCancerBiology .............................. 93
LeiFangandSamT.Hwang
TheCCL5/CCR5AxisinCancer ............................... 109
GaliSoriaandAditBen-Baruch
CXCChemokinesinCancerAngiogenesis......................... 131
B.MehradandR.M.Strieter
TheRolesofChemokinesandChemokineReceptors
inProstateCancer........................................... 153
ThorstenEismann,NadineHuber,andAlexB.Lentsch
Index..................................................... 171
vii
Contributors
ChareepornAkekawatchai ChemokineBiologyLaboratory,TheSchoolof
MolecularandBiomedicalScience,TheUniversityofAdelaide,Adelaide,SA
5005,Australia
AditBen-Baruch DepartmentofCellResearchandImmunology,GeorgeS.
WiseFacultyofLifeSciences,TelAvivUniversity,TelAviv69978,Israel
ThorstenEismann DepartmentofSurgery,UniversityofCincinnatiCollegeof
Medicine,Cincinnati,OH45267-0558,USA
LeiFang DermatologyBranch,NationalCancerInstitute,CenterforCancer
Research,Bethesda,MD20892,USA
AmyM.Fulton MarleneandStewartGreenebaumCancerCenterand
Department of Pathology, University of Maryland School of Medicine,
655WestBaltimoreStreet,BaltimoreMD21201,USA
BungoFurusato CenterforProstateDiseaseResearch,DepartmentofSurgery,
Uniformed Service University of the Health Science, Bethesda, MD 20814;
Department of Genitourinary Pathology, Armed Forces Institute of
PathologyWashington,DC20307,USA
JaneHolland ChemokineBiologyLaboratory,TheSchoolofMolecularand
Biomedical Science, North Terrace Campus, Level 5, The University of
Adelaide,Adelaide,SA5005,Australia
NadineHuber DepartmentofSurgery,UniversityofCincinnatiCollegeof
Medicine,Cincinnati,OH45267-0558,USA
SamT.Hwang DepartmentofDermatology,MedicalCollegeofWisconsin,
Milwaukee,WI53226,USA
KenjiKawada DepartmentofSurgery,GraduateSchoolofMedicine,Kyoto
University,Sakyo,Kyoto606-8501,Japan
ix
x Contributors
MarinaKochetkova ChemokineBiologyLaboratory,TheSchoolofMolecular
and Biomedical Science, The University of Adelaide, Adelaide, SA 5005,
Australia
AlexB.Lentsch DepartmentofSurgery,UniversityofCincinnatiCollegeof
Medicine,Cincinnati,OH45267-0558,USA
YanchunLi MarleneandStewartGreenebaumCancerCenter,Universityof
MarylandSchoolofMedicine,Baltimore,MD21201,USA
ShaunR.McColl ChemokineBiologyLaboratory,TheSchoolofMolecular
andBiomedicalScience,TheUniversityofAdelaide,SouthAustralia,5005
BornaMehrad DivisionofPulmonaryandCriticalCareMedicine,
Department of Medicine, University of Virginia, Charlottesville, VA 22908,
USA
ElizabethW.Newcomb DepartmentofPathology,NewYorkUniversity
Cancer Institute, New York University School of Medicine, New York, NY
10016,USA
JohngS.Rhim DepartmentofSurgery,CenterforProstateDiseaseResearch,
Uniformed Service University of the Health Science, Bethesda, MD 20814,
USA
GaliSoria DepartmentCellResearchandImmunology,GeorgeS.Wise
FacultyofLifeSciences,TelAvivUniversity,TelAviv69978,Israel
RobertM.Strieter DivisionofPulmonaryandCriticalCareMedicine,
Department of Medicine, University of Virginia, Charlottesville, VA 22908,
USA
MakotoMarkTaketo DepartmentofPharmacology,GraduateSchool
ofMedicine,KyotoUniversity,Sakyo,Kyoto606-8501,Japan
DavidZagzag DepartmentofPathologyandDivisionofNeuropathologyand
Department of Neurosurgery, New York University Cancer Institute, New
YorkUniversitySchoolofMedicine,NewYork,NY10016,USA
Chemokines and Chemokine Receptors in Cancer
Progression
ChareepornAkekawatchai,MarinaKochetkova,JaneHolland,
andShaunR.McColl
Abstract Directed cell migration is a fundamental component of numerous
biologicalsystemsandiscriticaltothepathologyofmanydiseases.Although
theimportanceofchemokinesinprovidingnavigationalcuestomigratingcells
bearingspecificreceptorsiswell-established,howchemokinefunctionisregu-
latedisnotsowellunderstoodandmaybeofkeyimportancetothedesignof
newtherapeuticsfornumeroushumandiseases,particularlyforthecontrolof
cancergrowthandmetastasis,diseasesinwhichchemokineshaverecentlybeen
implicated. In this review, we discuss the general views on the role of specific
chemokinesinthesepathologicalprocesses.Inaddition,wediscusstwonovel
aspects of chemokine cancer biology; cross-talk between chemokine and
growthfactorreceptors,andrefractorychemokinereceptors.
Introduction
Cancer comprises a large group ofdiseases which share an important charac-
teristic of uncontrolled growth. In most tissues and organs, homeostasis is
maintainedbyabalancebetweencellproliferationandcelldeath.Occasionally,
cellslosetheabilitytorespondtothenormalgrowthcontrolmechanismsand
clonesofcellsarisewhichcanexpandtoaconsiderablesizeproducingtumours
orneoplasms.Atumourthatremainsinitsoriginallocation,isnotabletogrow
indefinitelyanddoesnotinvadesurroundingtissueistermedbenign,whereasa
tumourwhichgrowsextensivelyandbecomesinvasiveisknownasamalignant
tumourorcancer.Inaddition,mostmalignanttumoursareabletometastasize,
aprocessofnewtumourformationandgrowthindistantorgans,whichisthe
causeof90%ofhumandeathsfromcancer[115].
Studies on the molecular biology of tumour progression have emphasized
the importance of the interaction between the tumour and host homeostatic
C.Akekawatchai(*)
ChemokineBiologyLaboratory,TheSchoolofMolecularandBiomedicalScience,
TheUniversityofAdelaide,Adelaide,SA5005,Australia
A.M.Fulton(ed.),ChemokineReceptorsinCancer,CancerDrugDiscovery 1
andDevelopment,DOI10.1007/978-1-60327-267-4_1,
(cid:2)HumanaPress,apartofSpringerScienceþBusinessMedia,LLC2009