Diverse effects of hypoxia on tumor progression

148 Pages·2010·2.118 MB·English

by  Alexander Pietras, A. Sofie Johnsson (auth.), M. Celeste Simon (eds.)

M. Celeste Simon
Editor
Diverse Effects of Hypoxia
on Tumor Progression
Editor
M.CelesteSimon,PhD
UniversityofPennsylvania
SchoolofMedicine
19104-6160Philadelphia
Pennsylvania
USA
[email protected]
ISSN0070-217X
ISBN:978-3-642-13328-2 e-ISBN:978-3-642-13329-9
DOI10.1007/978-3-642-13329-9
SpringerHeidelbergDordrechtLondonNewYork
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Preface
Solidtumorsfrequentlycontainareasofoxygendeprivation(hypoxia)duetorapid
cell proliferation and/or vascular insufficiency. The presence of hypoxic domains
typically correlates with poor patient prognosis, due to the relative resistance of
hypoxic cells to conventional cancer therapies and effects of O availability on
2
diseaseprogression.Theresponseofmalignantcellstohypoxiahasbeenthefocus
of intense research over the last decade. In this issue of Current Topics in Micro-
biologyandImmunology,wepresentchaptersdescribingtheimpactofhypoxiaon
components of the tumor microenvironment (such as endothelial cells, inflamma-
torycells,andtumor-associatedfibroblasts),theexpressionofuniquemicroRNAs,
tumorcelldifferentiationstatus,andmetastasis.Eachreviewchapterdescribesthe
stateofthefieldstudyingthesetopicsandposesimportantquestionsforthefuture.
Theoverallgoalistodepicttumorphenotypesandassociatedmolecularpathways
tobeexploitedinthedevelopmentofnoveltherapeuticstobeusedagainstabroad
spectrumofhumancancers.
Summer2010 CelesteSimon
v
.
Contents
TheHIF-2a-DrivenPseudo-HypoxicPhenotypeinTumor
Aggressiveness,Differentiation,andVascularization ....................... 1
AlexanderPietras,A.SofieJohnsson,andSvenPa˚hlman
HypoxiaandHypoxiaInducibleFactorsinCancerStem
CellMaintenance .............................................................. 21
ZhizhongLiandJeremyN.Rich
RoleofCarcinoma-AssociatedFibroblastsandHypoxiainTumor
Progression .................................................................... 31
AmatoJ.GiacciaandErnestinaSchipani
TheRoleofHypoxiaRegulatedmicroRNAsinCancer .................... 47
RobertMcCormick,FrancescaM.Buffa,JiannisRagoussis,
andAdrianL.Harris
OxygenSensing:ACommonCrossroadinCancer
andNeurodegeneration ....................................................... 71
AnneliesQuaegebeurandPeterCarmeliet
Hypoxia-InducibleFactorsasEssentialRegulatorsofInflammation .... 105
HongxiaZ.ImtiyazandM.CelesteSimon
HypoxiaandMetastasisinBreastCancer ................................. 121
HeleneRundqvistandRandallS.Johnson
Index .......................................................................... 141
vii
.
Contributors
Francesca M. Buffa Molecular Oncology Laboratories, Weatherall Institute
of Molecular Medicine, University of Oxford, John Radcliffe Hospital,
Oxford OX3 9DS, UK
PeterCarmeliet VesaliusResearchCenter(VRC),VIB,K.U.Leuven,Campus
Gasthuisberg, Herestraat 49, 3000 Leuven, Belgium, peter.carmeliet@
vib-kuleuven.be
Amato J. Giaccia Department of Radiation Oncology, Division of Cancer
and Radiation Biology, Stanford University School of Medicine, Stanford,
CA 94305-5152, USA, [email protected]
Adrian L. Harris Molecular Oncology Laboratories, Weatherall Institute of
Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford
OX3 9DS, UK, [email protected]
Hongxia Z. Imtiyaz Abramson Family Cancer Research Institute, Univer-
sity of Pennsylvania, 438 BRB II/III, 421 Curie Boulevard, Philadelphia, PA
19104-6160,USAandHowardHughesMedicalInstitute,Chevy Chase,MD,
USA, [email protected]
Randall S. Johnson Molecular Biology Section, Division of Biological
Sciences, University of California, San Diego, CA 92093, USA, rjohnson@
biomail.ucsd.edu
A. Sofie Johnsson Department of Laboratory Medicine, Center for
Molecular Pathology, Lund University, University Hospital MAS, Entrance
78, 205 02 Malmo, Sweden
Zhizhong Li Department of Radiation Oncology, Duke University Medical
Center, Durham, NC 27710, USA
ix
x Contributors
Robert McCormick Molecular Oncology Laboratories, Weatherall Institute
of Molecular Medicine, University of Oxford, John Radcliffe Hospital,
Oxford OX3 9DS, UK
Sven Pahlman Department of Laboratory Medicine, Center for Molecular
Pathology, Lund University, University Hospital MAS, Entrance 78, 205 02
Malmo, Sweden, [email protected]
Alexander Pietras Department of Laboratory Medicine, Center for Mole-
cular Pathology, Lund University, University Hospital MAS, Entrance 78,
205 02 Malmo, Sweden
Annelies Quaegebeur Vesalius Research Center (VRC), VIB, K.U. Leuven,
Campus Gasthuisberg, Herestraat 49, 3000 Leuven, Belgium
JiannisRagoussis MolecularOncologyLaboratories,WeatherallInstituteof
Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford
OX3 9DS, UK
Jeremy N. Rich Department of Stem Cell Biology and Regenerative Medi-
cine,LernerResearchInstitute,ClevelandClinic,Cleveland,OH44195,USA,
[email protected]
Helene Rundqvist Molecular Biology Section, Division of Biological
Sciences, University of California, San Diego, CA 92093, USA
Ernestina Schipani Endocrine Unit, Department of Medicine, MGH-
Harvard Medical School, Boston, MA 02114, USA
M. Celeste Simon Abramson Family Cancer Research Institute, University
of Pennsylvania, 438 BRB II/III, 421 Curie Boulevard, Philadelphia, PA
19104-6160,USAandHowardHughesMedicalInstitute,Chevy Chase,MD,
USA and Department of Cell and Developmental Biology, University of
Pennsylvania School of Medicine, Philadelphia, PA 19104, USA, celeste2@
mail.med.upenn.edu
a
The HIF-2 -Driven Pseudo-Hypoxic Phenotype
in Tumor Aggressiveness, Differentiation,
and Vascularization
AlexanderPietras,A.SofieJohnsson,andSvenPa˚hlman
Contents
1 Introduction.................................................................................. 2
2 PhenotypicEffectsofHIF-2aElimination.................................................. 3
3 HIF-2DuringNormalSympatheticNervousSystem(SNS)Development.................. 4
4 HypoxiainSolidTumorsandRelationtoTumorAggressiveness.......................... 5
5 DifferentialTumorHIFExpressioninRelationtoPatientOutcome........................ 6
5.1 Neuroblastoma......................................................................... 6
5.2 BreastCarcinoma...................................................................... 7
5.3 RenalCellCarcinoma................................................................. 8
5.4 NonsmallCellLungCarcinoma....................................................... 9
5.5 Glioblastoma ......................................................................... 10
6 HypoxiaandTumorCellDifferentiation...................................................10
7 HIF-2aandTumorInitiating/StemCells...................................................11
8 HIFsandVascularization...................................................................13
9 HIF-2aandthePseudo-HypoxicPhenotype:TargetsforTumorTreatment...............14
References.......................................................................................15
Abstract Cellular adaptation to diminished tissue oxygen tensions, hypoxia, is
largelygovernedbythehypoxiainducibletranscriptionfactors,HIF-1andHIF-2.
TumorhypoxiaandhighHIFproteinlevelsarefrequentlyassociatedwithaggres-
sive disease. In recent years, high tumor cell levels of HIF-2 and the oxygen
sensitive subunit HIF-2a have been associated with unfavorable disease and
shown to be highly expressed in tumor stem/initiating cells originating from
neuroblastoma and glioma, respectively. In these cells, HIF-2 is active under
nonhypoxic conditions as well, creating a pseudo-hypoxic phenotype with clear
influence on tumor behavior. Neuroblastoma tumor initiating cells are immature
with a neural crest-like phenotype and downregulation of HIF-2a in these cells
A.Pietras,A.S.Johnsson,andS.Pa˚hlman(*)
DepartmentofLaboratoryMedicine,CenterforMolecularPathology,LundUniversity,Univer-
sityHospitalMAS,Entrance78,20502Malmo¨,Sweden
e-mail:[email protected]
M.CelesteSimon(ed.),DiverseEffectsofHypoxiaonTumorProgression, 1
CurrentTopicsinMicrobiologyandImmunology345,DOI10.1007/82_2010_72
#Springer‐VerlagBerlinHeidelberg2010,publishedonline:2June2010
2 A.Pietrasetal.
resultsinneuronalsympatheticdifferentiationandthecellsbecomephenotypically
similartothebulkofneuroblastomacellsfoundinclinicalspecimens.Knockdown
ofHIF-2ainneuroblastomaandgliomatumorstem/initiatingcellsleadstoreduced
levels of VEGF and poorly vascularized, highly necrotic tumors. As high HIF-2a
expression further correlates with disseminated disease as demonstrated in neuro-
blastoma, glioma, and breast carcinoma, we propose that targeting HIF-2a and/or
the pseudo-hypoxic phenotype induced by HIF-2 under normoxic conditions has
greatclinicalpotential.
1 Introduction
Mammalian cells, including tumor cells, require oxygen for maintenance of an
efficient energy supply and lack of oxygen eventually leads to cell death due to
impaired energy requiring processes. Cells can withstand fluctuations in oxygen
levelsbyadaptingtoadecreaseinoxygeninvolvingreductionofenergyconsump-
tionandincreaseinanaerobicmetabolism.Duringtheadaptationprocess,thereisa
dramaticshiftintheexpressionofgenesregulatinganumberofcellularfunctions
includingglucose transportandmetabolism,angiogenesis,andcellsurvival.Cen-
tral to this phenotypic shift are the hypoxia inducible factors (HIFs), HIF-1, and
HIF-2.Thesefactorsareheterodimerictranscriptionfactorscomposedofaunique
alphasubunitandabetasubunit(ARNT/HIF-1b)sharedbyallthreeHIFs.Classi-
cally,HIFsareregulatedbydegradationofthealphasubunitathighoxygenlevels
and by stabilization at hypoxia (reviewed in Kaelin and Ratcliffe 2008). In the
dimeric,activestate,HIF-1andHIF-2bindtohypoxiaresponsiveelements(HREs)
locatedingenesregulatedbyhypoxiaandHIFs.AlthoughHIF-1andHIF-2seemto
activate hypoxia-responsive genes by similar means (Tian et al. 1997; Wiesener
et al. 1998), the HIF-a subunits work in a nonredundant manner and several
differences in gene regulation have been proposed, many ofwhich emphasize the
predominant role of HIF-1 in regulating the transcriptional response to hypoxia
(Iyer et al. 1998; Ryan et al. 1998; Hu et al. 2003; Park et al. 2003; Sowter et al.
2003). As detailed below, HIF-2 is also crucial for the hypoxic response, and as
opposedtoHIF-1itisactiveatprolongedhypoxiaaswell(Holmquist-Mengelbier
etal.2006).ThelessstudiedHIF-3ispresentinseveralsplicevariantslackingthe
C-terminaltransactivationdomainandisthoughttonegativelyregulateHIF-1and
HIF-2bysequesteringtheHIF-1andHIF-2alphasubunits,therebyblockingtheir
binding to HREs (Makino et al. 2001; Maynard et al. 2007). Although the main
modeofHIFactivationisviastabilizationofthealphasubunits,HIF-2,aswellas
HIF-1, can be stable and transcriptionally active at physiological or even higher
oxygen tensions, as will be the central theme in this review. We propose that this
phenomenon, at least regarding HIF-2, is largely linked to its role and regulation
duringnormaldevelopment.
ThephenotypesobtainedbyeliminationofeitherHif1aorEpas1/Hif2aclearlyshow
that both genes are needed for proper development and that they are nonredundant.