Tissue-Specific Vascular Endothelial Signals and Vector Targeting, Part B

160 Pages·2010·5.58 MB·2-157\160

by  Renata Pasqualini (Eds.)

Advances
in
Genetics, Volume 69
Serial Editors
Theodore Friedmann
University of California at San Diego, School of Medicine, USA
Jay C. Dunlap
Dartmouth Medical School, Hanover, NH, USA
Stephen F. Goodwin
University of Oxford, Oxford, UK
AcademicPressisanimprintofElsevier
525BStreet,Suite1900,SanDiego,CA92101-4495,USA
30CorporateDrive,Suite400,Burlington,MA01803,USA
32JamestownRoad,London,NW17BY,UK
Radarweg29,POBox211,1000AEAmsterdam,TheNetherlands
Firstedition2010
Copyright(cid:1)2010ElsevierInc.Allrightsreserved.
Nopartofthispublicationmaybereproduced,storedinaretrievalsystem
ortransmittedinanyformorbyanymeanselectronic,mechanical,photocopying,
recordingorotherwisewithoutthepriorwrittenpermissionofthepublisher
PermissionsmaybesoughtdirectlyfromElsevier’sScience&TechnologyRights
DepartmentinOxford,UK:phone[phone];fax[phone];
email:[e-mail]tyourrequestonlineby
visitingtheElsevierwebsiteathttp://www.elsevier.com/locate/permissions,andselecting
ObtainingpermissiontouseElseviermaterial.
Notice
Noresponsibilityisassumedbythepublisherforanyinjuryand/ordamagetopersonsor
propertyasamatterofproductsliability,negligenceorotherwise,orfromanyuseoroperation
ofanymethods,products,instructionsorideascontainedinthematerialherein.Becauseof
rapidadvancesinthemedicalsciences,inparticular,independentverificationofdiagnosesand
drugdosagesshouldbemade.
ISBN:978-0-12-375022-8
ISSN:0065-2660
ForinformationonallAcademicPresspublications
visitourwebsiteatelsevierdirect.com
PrintedandboundinUSA
10 11 12 10 9 8 7 6 5 4 3 2 1
Contributors
Numbersinparenthesesindicatethepagesonwhichtheauthors’contributionsbegin.
Wadih Arap (31, 97, 115) DavidH.KochCenter,TheUniversityofTexasM.D.
Anderson Cancer Center, Houston, Texas, USA, and Department of
Experimental Diagnostic Imaging, The University of Texas M.D.
Anderson Cancer Center, Houston, Texas, USA, and Department of
Genitourinary Medical Oncology, The University of Texas M.D.
AndersonCancerCenter,Houston,Texas,USA;DepartmentofCancer
Biology, The University of Texas M.D. Anderson Cancer Center,
Houston,Texas,USA
Zaver M. Bhujwalla (1) JHU ICMIC Program, Russell H. Morgan Department
ofRadiologyandRadiologicalScience,TheJohnsHopkinsUniversity
School of Medicine, Baltimore, Maryland, USA, and The Sidney
Kimmel Comprehensive Cancer Center, The Johns Hopkins
UniversitySchool ofMedicine, Baltimore, Maryland, USA
LawrenceF.Bronk(115) DavidH.KochCenter,TheUniversityofTexasM.D.
AndersonCancer Center,Houston, Texas, USA
Paolo Decuzzi (31, 115) Department of Nanomedicine and Biomedical
Engineering, The University of Texas Health Science Center
Houston, Houston, Texas, USA, and Center of Bio-/Nanotechnology
andEngineeringforMedicine,UniversityofMagnaGraecia,Catanzaro,
Italy
Wouter H. P. Driessen (31, 115) David H. Koch Center, The University of
Texas M.D. Anderson Cancer Center, Houston, Texas, USA, and
Department of Genitourinary Medical Oncology, The University of
Texas M.D. Anderson Cancer Center, Houston, Texas, USA;
Department of Cancer Biology, The University of Texas M.D.
AndersonCancer Center,Houston, Texas, USA
Julianna K. Edwards (115) David H. Koch Center, The University of Texas
M.D.Anderson CancerCenter, Houston, Texas,USA
MauroFerrari(31) DepartmentofNanomedicineandBiomedicalEngineering,
The University of Texas Health Science Center, Houston, Texas,
USA, and Department of Experimental Therapeutic, The University
of Texas M.D. Anderson Cancer Center, Houston, Texas, USA;
ix
x Contributors
Department of Biomedical Engineering, Rice University, Houston,
Texas,USA
Biana Godin (31) Department of Nanomedicine and Biomedical Engineering,
TheUniversityofTexasHealthScienceCenter,Houston,Texas,USA
AminHajitou(65) DepartmentofGeneTherapy,Section/DivisionofInfectious
Diseases, Faculty of Medicine, Imperial College London, Wright-
Fleming Institute, St Mary’s Campus, Norfolk Place, London, United
Kingdom
Sei-YoungLee(31) DepartmentofNanomedicineandBiomedicalEngineering,
The University of Texas Health Science Center, Houston, Texas,
USA, and Department of Mechanical Engineering, The University of
TexasatAustin, Austin,Texas, USA
StevenK.Libutti(135) MontefioreMedicalCenter,AlbertEinsteinCollegeof
Medicine, Bronx,New York,USA
Xiaoli Lu (83) Department of Microbiology and Molecular Genetics,
427 Bridgeside Point II, 450 Technology Drive, University of
Pittsburgh SchoolofMedicine, Pittsburgh, Pennsylvania, USA
Zhibao Mi (83) Department of Microbiology and Molecular Genetics,
427 Bridgeside Point II, 450 Technology Drive, University of
Pittsburgh SchoolofMedicine, Pittsburgh, Pennsylvania, USA
RenataPasqualini(31,97,115) DavidH.KochCenter,TheUniversityofTexas
M.D.AndersonCancerCenter,Houston,Texas,USA,andDepartment
of Experimental Diagnostic Imaging, The University of Texas M.D.
Anderson Cancer Center, Houston, Texas, USA, and Department of
Genitourinary Medical Oncology, The University of Texas M.D.
AndersonCancerCenter,Houston,Texas,USA;DepartmentofCancer
Biology, The University of Texas M.D. Anderson Cancer Center,
Houston,Texas,USA
ArvindP.Pathak (1) JHUICMIC Program,Russell H.Morgan Departmentof
Radiology and Radiological Science, The Johns Hopkins University
School of Medicine, Baltimore, Maryland, USA, and The Sidney
Kimmel Comprehensive Cancer Center, The Johns Hopkins
University SchoolofMedicine, Baltimore, Maryland, USA
Marie-FrancePenet(1) JHUICMICProgram,RussellH.MorganDepartment
ofRadiologyandRadiologicalScience,TheJohnsHopkinsUniversity
SchoolofMedicine, Baltimore, Maryland, USA
Bettina Proneth (31, 115) David H. Koch Center, The University of Texas
M.D. Anderson Cancer Center, Houston, Texas, USA, and
Department of Genitourinary Medical Oncology, The University of
Texas M.D. Anderson Cancer Center, Houston, Texas, USA;
Department of Cancer Biology, The University of Texas M.D.
AndersonCancer Center, Houston,Texas, USA
Contributors xi
Paul D. Robbins (83) Department of Microbiology and Molecular Genetics,
427 Bridgeside Point II, 450 Technology Drive, University of
PittsburghSchool ofMedicine, Pittsburgh, Pennsylvania, USA
RolandoRumbaut(31) Children’sNutritionResearchCenter,BaylorCollegeof
Medicine, Houston,Texas, USA
Masanori Sato (97) David H. Koch Center, The University of Texas M.D.
AndersonCancer Center,Houston, Texas, USA
Glauco R. Souza (115) David H. Koch Center, The University of Texas M.D.
AndersonCancer Center,Houston, Texas, USA
Prashanth Sreeramoju (135) Montefiore Medical Center, Albert Einstein
CollegeofMedicine, Bronx,NewYork,USA
Srimeenakshi Srinivasan (31) Department of Nanomedicine and Biomedical
Engineering, The University of Texas Health Science Center,
Houston,Texas, USA
Virginia J. Yao (97) David H. Koch Center, The University of Texas M.D.
AndersonCancer Center,Houston, Texas, USA
Maliha Zahid (83) Department of Microbiology and Molecular Genetics,
427 Bridgeside Point II, 450 Technology Drive, University of
PittsburghSchool ofMedicine, Pittsburgh, Pennsylvania, USA
1
MR Molecular Imaging of
Tumor Vasculature and
Vascular Targets
Arvind P. Pathak,*,† Marie-France Penet,* and
Zaver M. Bhujwalla*,†
*JHU ICMIC Program, Russell H. Morgan Department of Radiology and
Radiological Science, The Johns Hopkins University School of Medicine,
Baltimore,Maryland,USA
†The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins
UniversitySchoolofMedicine,Baltimore,Maryland,USA
I. Introduction
II. Structural,Functional,andMolecularCharacteristics
ofTumorVasculature
III. BasisofContrastinMRImages
A. Endogenouscontrast
B. Exogenouscontrast
C. Lowmolecularweightcontrastagents
D. Highmolecularweightcontrastagents
IV. ImagingReceptorExpression
V. ImagingVascularTargeting
VI. MultimodalMolecular-FunctionalImagingof
TumorVasculature
VII. Conclusion
Acknowledgments
References
AdvancesinGenetics,Vol.69 0065-2660/10$35.00
Copyright2010,ElsevierInc.Allrightsreserved. DOI:10.1016/S0065-2660(10)69010-4
2 Pathak et al.
ABSTRACT
Tumor angiogenesis and the ability of cancer cells to induce neovasculature
continue to be a fascinating area of research. As the delivery network that
provides substrates and nutrients, aswell as chemotherapeutic agents tocancer
cells, but allows cancer cells to disseminate, the tumor vasculature is richly
primed with targets and mechanisms that can be exploited for cancer cure or
control. The spatial and temporal heterogeneity of tumor vasculature, and the
heterogeneity of response to targeting, make noninvasive imaging essential for
understanding the mechanisms of tumor angiogenesis, tracking vascular target-
ing,anddetectingtheefficacyofantiangiogenictherapies.Withitsnoninvasive
characteristics, exquisite spatial resolution and range of applications, magnetic
resonanceimaging(MRI)techniqueshaveprovidedawealthoffunctionaland
molecular information on tumor vasculature in applications spanning from
“benchtobedside”.Theintegrationofmolecularbiologyandchemistrytodesign
novelimagingprobesensuresthecontinuedevolutionofthemolecularcapabil-
itiesofMRI.Inthisreview,wehavefocusedondevelopmentsinthecharacteri-
zationoftumorvasculaturewithfunctionalandmolecularMRI. (cid:1)2010,ElsevierInc.
I. INTRODUCTION
The two major mechanisms resulting in the formation of blood vessels are
vasculogenesis and angiogenesis. Vasculogenesis describes the establishment of
the vasculature during embryogenesis and development. Angiogenesis, a term
coinedbyDr.JohnHunterin1794todescribetheformationofnewbloodvessels
from extant vasculature (Hunter, 1794), is a process that occurs in both the
embryo and the adult (Carmeliet, 2005). In 1865, Rudolf Virchow made the
observationthattumorshavedistinctcapillarynetworks(Virchow,1863),which
wasfollowedbythefirstsystematicstudiesofthetumorvasculaturebyGoldman
in1907(Goldman,1907)andbyLewisin1927whodeterminedthatthetumor
environment has a profound effect on the architecture of angiogenic vessels
(Lewis, 1927). (See Ribatti’s (2009) comprehensive treatise on the history of
tumorangiogenesisresearch.)Acenturylater,theobservationthatadultangio-
genesiswasahallmarkofpathologiesrangingfromcancertodiabeticretinopa-
thy(JainandCarmeliet,2001)ledFolkman(1971)topositinhisseminalpaper
thatsolidtumorgrowthwas“angiogenesis-dependent”.Init,healsointroduced
the concept of “antiangiogenic” therapy or the idea that solid tumor growth
couldbearrestedbypreventingtherecruitmentandformationofdenovoblood
vessels. In the decades since, a comprehensive understanding of the molecular
1.MolecularMRIofTumorVasculature 3
mechanismsregulatingtumorangiogenesishasemerged,resultingintheidenti-
fication of a slew of angiogenesis inhibitors, many of which are currently in
clinicaltrials(Folkman,2007).
Inacarefulstudyofcarcinomaofthebronchus,ThomlinsonandGray
observedthattheonsetofnecrosisoccurredatapproximately160(cid:1)mfromthe
nearestvessel,adistancecalculatedtobethediffusionlimitofoxygen.Basedon
thesedata,theypredictedthepresenceofhypoxiaintumorsthatwouldleadto
radioresistance(ThomlinsonandGray,1955).Almostfourdecadeslater,withthe
discovery of the hypoxia inducible factor-1 (HIF-1), and its role as a transcrip-
tionalregulatorofanever-increasinglistofgenes(Semenza,2010),tumorhypoxia
resultingfromthechaotictumorvasculaturehasbeenimplicatedinmetabolism,
angiogenesis,invasion,metastasis,anddrugresistance(Bertoutetal.,2008).
SinceClarketal.(1931)createdsomeoftheearliestimagesofneovas-
cularizationintransparentrabbitearchambersinthe1930s,advancesinphysics
(e.g., new imaging methods), chemistry (e.g., the synthesis of novel imaging
probes),andbiology(e.g.,developmentofinnovativegenereportersystemsand
theidentificationofnoveltargets)haveusheredinanewerainthecharacteri-
zationofangiogenesisandantiangiogenictherapyusingimaging(McDonaldand
Choyke, 2003; Pathak et al., 2008a). Even a century ago, the importance of
“individualizingcancertreatment”and“penetratingintothedarknessofphysio-
logical conditions existing in tumor growths” was recognized in the prescient
remarksmadebyE.Goldmanin1907(Goldman,1907).
Theimportanceoftumorvasculatureinseveralphenotypiccharacteristics
ofcancer,aswellasindrugdeliveryandmetastasis,hasbecomeveryevident,and
angiogenicorvasculartargetingismeetingwithsomesuccessasapotentialtreat-
mentforcancer(Folkman,2007;NeriandBicknell,2005).Thesedevelopments
havenotonlynecessitatedthegenomicandfunctionalcharacterizationofindivid-
ualtumorstoidentifyspecificmoleculartargets,butalsotheabilitytononinvasively
detectthespatialandtemporalresponsetothesenewtargetedtherapies.Noninva-
sive imaging techniques, the availability of “smart probes” as well as molecular
strategiessuchastheuseofsmallinterferingRNAtodownregulatespecifictargets
areplayinganincreasinglyimportantroleinthiseraoftargetedmolecularmedicine.
ThepurposeofthisreviewistodescriberecentadvancesinMRIasappliedtotumor
vasculaturecharacterizationandtargeting.
II. STRUCTURAL, FUNCTIONAL, AND MOLECULAR
CHARACTERISTICS OF TUMOR VASCULATURE
Studiesoftumorvascularmorphologyhaveidentifiedavarietyofstructuraland
functional differences between tumor and normal vasculature (see Konerding
et al., 2000 for a comprehensive review). Tumor-induced blood vessels are
4 Pathak et al.
typicallysinusoidal,exhibitdiscontinuousbasementmembranes,andlacktight
endothelial cell junctions making them highly permeable to macromolecules.
Other characteristics of the tumor vasculature include (i) spatial heterogeneity
and loss of branching hierarchy, (ii) arteriovenous shunts, (iii) acutely and
transiently collapsing vessels, (iv) poor differentiation and a lack of smooth
musclecelllining,and(v)aninabilitytomatchtheelevatedmetabolicdemand
ofcancercells,resultinginareasofhypoxiaandnecrosis.
Pioneering work by Jain, Vaupel, and others has demonstrated that
structural anomalies of the tumor vasculature result in altered hemodynamics,
bloodrheology,andtumorbloodflow(Jain,1988;Vaupeletal.,1989).Figure1.1
summarizesthebidirectionalrelationshipsbetweentheanomalousaspectsofthe
tumorvasculatureandtheresultingpathophysiologicalandmolecularperturba-
tionsinthetumormicroenvironment.
In addition to angiogenesis-dependent pathways, nonangiogenic path-
waysfortumorgrowthhavealsobeenobserved.Ofthese,vascularcooptionand
vasculogenic mimicry are the most well known. In a landmark study, Holash
Abnormal tumor
vessel architecture
Abnormal hemodynamics Abnormal rheology Abnormal interstitial space
Abnormal oxygenation, pH,
nutrient supply, drainage,
and metabolism
Gene expression
Clonal heterogeneity
(e.g. VEGF, HIF-1 etc.)
Metastatic and
Cell cycle effects
invasive potential
Sensitivity to radiotherapy Anticancer drug delivery
Figure 1.1. Schematic to illustrate how abnormal tumor vessel architecture results in altered
hemodynamics (blood flow), blood rheology, and elevated interstitial fluid pressure.
Thesealterationsinturnprofoundlyaffectsthetumormicroenvironment(i.e.,oxyge-
nation, pH, etc.), which in turn modulates multiple phenomena ranging from gene
expressiontosensitivitytoradiotherapy.AdaptedfromMollsandVaupel(2000).
1.MolecularMRIofTumorVasculature 5
et al., (1999) demonstrated that in contrast to the prevailing view that most
tumorsbeginasavascularmasses,asubsetoftumorsinitiallygrewby“coopting”
existing host blood vessels. This coopted host vasculature did not immediately
undergoangiogenesisbutinitiallyregressed,leadingtoanavasculartumorwith
massivetumorcellloss.Eventually,theremainingtumorwasrescued byrobust
angiogenesisatthetumorrim.Maniotisetal.(1999)describedanothermodeof
vascularchannelformationwhichwasdubbed“vasculogenicmimicry”tohigh-
light the fact that parts of the microcirculation of aggressive uveal melanomas
consist of channels lined by a layer of extracellular matrix and the tumor cells
themselves.Changetal.(2000)havedescribedtheformationof“mosaicvessels”
inacoloncarcinomamodel,whereinbothtumorandendothelialcellscontrib-
utedtovasculartubeformation.
Theheterogeneity of tumorvasculature canpose a formidable clinical
challenge. The structural and functional deficiencies of the tumor vasculature
profoundly impact drug delivery, radiosensitivity, proliferation rate, invasion,
metastases, andthemetabolic micromilieu (pO2, pH,energy status;Konerding
etal.,2000)ofthetumor.However,asdiscussedsubsequently,thisheterogeneity
of the tumor vasculature also presents an opportunity for the identification of
noveldrugtargetsthatcanbeexploitedtodeveloptumorvasculature-selective
therapeuticstrategies(NeriandBicknell,2005).
As summarized in several excellent reviews (Baluk et al., 2005;
McDonald and Choyke, 2003; Munn, 2003), the physiology and organization
of the tumor vasculature at the spatial scale of the endothelial cell is also
abnormal. Such abnormalities include gaps in interendothelial tight junctions
resultinginlossofbarrierfunction,looseornoassociationwithpericytes,anda
compromised or incomplete basement membrane (Kalluri, 2003). This micro-
scopicpictureisfurthercomplicatedbythephenomenaofvasculogenicmimicry
and mosaic vessels described earlier. However, at this scale, the diversity of
surface proteins selectively expressed by angiogenic tumor vessels has been
exploitedastargetsfornovelcontrastagentsusingarangeofimagingmodalities
(McDonaldandChoyke,2003).Someoftheseepitopesonangiogenicendothe-
lial cells andbasement membrane components have alsobeen tested fortumor
vessel selective drug-targeting strategies as summarized in Table 1.1 (Molema,
2005). The review by Langenkamp and Molema (2009) lists endothelial cell-
specificgenesusedtoidentifytissuemicrovasculature,whilealandmarkpaperby
Croix et al. (2000) demonstrates the diversity of the genes expressed in human
tumorendothelium.Bothimagingreceptorexpressionandvasculartargetingare
discussedindetailinensuingsections.
Conventionalimage contrastinradiologic images providesdifferences
in the level of brightness or intensity of parts of the image corresponding to
anatomically or physiologically different locations. While traditionally such
contrast has aided in the differentiation of normal from pathologic tissue, such