Morphofunctional Aspects of Tumor Microcirculation

121 Pages·2012·2.458 MB·English

by  Domenico Ribatti (auth.)

Morphofunctional Aspects of Tumor
Microcirculation
Domenico Ribatti
Morphofunctional Aspects
of Tumor Microcirculation
2123
Prof.Dr.DomenicoRibatti
Policlinico,DepartmentofBasicMedicalSciences
SectionofHumanAnatomyandHistology
UniversityofBariMedicalSchool
Bari
Italy
ISBN978-94-007-4935-1 ISBN978-94-007-4936-8(eBook)
DOI10.1007/978-94-007-4936-8
SpringerDordrechtHeidelbergLondonNewYork
LibraryofCongressControlNumber:2012949567
© SpringerScience+BusinessMediaDordrecht2012
Nopartofthisworkmaybereproduced,storedinaretrievalsystem,ortransmittedinanyformorby
anymeans,electronic,mechanical,photocopying,microfilming,recordingorotherwise,withoutwritten
permissionfromthePublisher,withtheexceptionofanymaterialsuppliedspecificallyforthepurposeof
beingenteredandexecutedonacomputersystem,forexclusiveusebythepurchaserofthework.
Printedonacid-freepaper
SpringerispartofSpringerScience+BusinessMedia(www.springer.com)
Acknowledgments
TheresearchleadingtotheseresultshasreceivedfundingfromtheEuropeanUnion
SeventhFrameworkProgramme(FP7/2007–2013)undergrantagreementn◦278570
v
Contents
1 Introduction................................................... 1
2 MorphologicalAspectsofTumorVasculature...................... 5
2.1 TumorEndothelialCellFeatures .............................. 5
2.2 TumorPericytes............................................ 10
2.3 TumorLymphaticVessels.................................... 15
3 MechanismsofControlofAngiogenesisinTumorVasculature....... 21
3.1 TumorAngiogenesis ........................................ 21
3.2 TheRoleofInflammatoryCellsinTumorAngiogenesis .......... 25
3.2.1 Neutrophils ......................................... 26
3.2.2 Basophils........................................... 28
3.2.3 Eosinophils ......................................... 29
3.2.4 Monocytes-macrophages .............................. 30
3.2.5 Lymphocytes........................................ 34
3.2.6 DendriticCells ...................................... 35
3.2.7 MastCells .......................................... 35
3.2.8 Platelets ............................................ 38
3.3 AlternativeModeofTumorVascularGrowth.................... 39
3.4 TheRoleofBoneMarrowStemCellsinTumorAngiogenesis ..... 44
3.4.1 EndothelialPrecursorCells ............................ 45
3.4.2 CirculatingEndothelialCells .......................... 49
3.4.3 MultipotentAdultProgenitorCells...................... 50
3.4.4 Myeloid-derivedSuppressorCells ...................... 50
3.4.5 MesenchymalProgenitorCells ......................... 51
4 Anti-AngiogenesisandVascularTargetinginTumorVasculature .... 53
4.1 Anti-AngiogenicTherapy .................................... 53
4.1.1 Interferons .......................................... 53
4.1.2 CartilageandProtamine............................... 55
4.1.3 VascularDisruptingAgents ............................ 55
4.1.4 AngiostaticSteroids .................................. 56
4.1.5 Fumagillin .......................................... 56
vii
viii Contents
4.1.6 Thrombospondins.................................... 57
4.1.7 Angiostatin ......................................... 57
4.1.8 ThalidomideandImmunomodulatoryDrugs.............. 59
4.1.9 Bevacizumab........................................ 59
4.1.10 TyrosineKinaseInhibitors............................. 62
4.2 MetronomicChemotherapy .................................. 66
4.3 CombinatorialApproach..................................... 67
4.4 VascularTargetingtotheTumorVasculature .................... 69
4.5 TumorVascularNormalization................................ 75
4.6 DrawbacksofAnti-angiogenesisTherapies ..................... 77
References........................................................ 83
Index ............................................................ 115
List of abbreviations
AE Adverseeffects
Ang Angiopoietin
AP Aminopeptidase
APC Antigenpresentingcell
ATP Adenosinetriphosphate
BLI Bioluminescenceimaging
CAM Chorioallantoicmembrane
CI Confidenceinterval
COX Cycloxygenase
CSF Colonystimulatingfactor
DC Dendritccell
DXR Doxorubicin
EDGF-1 Endothelialdifferentiationgene-1
EGFR Epidermalgrowthfactorreceptor
eNOS Endothelialnitricoxidesynthase
EPC Endothelialprecursorcell
EPH Ephrin
FDA FoodandDrugAdministration
FGF-2 Fibroblastgrowthfactor-2
G-CSF Granulocyte-colonystimulatingfactor
GFP Greenfluorescentprotein
GIST Gastrointestinalstromaltumors
GM-CSF Granulocytemacrophage-colonystimulatingfactor
GRO Growthrelatedoncogene
HGF Hepatocytegrowthfactor
HIF Hypoxiainduciblefactor
HPV Humanpapillomavirus
HSC Hematopoieticstemcells
IFL Irinotecan5-fluorouracilandleucovirin
IFN Interferon
IL Interleukin
IMG Intussusceptivemicrovasculargrowth
ix
x Listofabbreviations
LDL Lowdensitylipoprotein
MAPC Multipotentadultprogenitorcells
MBP Majorbasicprotein
MCP Monocytechemoattractantprotein
MDSC Myeloid-derivedsuppressorcells
MHC Majorhistocompatibilitycomplex
MIP Macrophageinflammatoryprotein
MMP Matrixmetalloproteinase
MRD Minimalresidualdisease
MRI Magneticresonanceimaging
NECA (N-ethylcarboxámido)adenosine
NGF Nervegrowthfactor
NK Naturalkiller
NRP Neuropilin
NSCLC Nonsmallcelllungcancer
OS Overallsurvival
PA Plasminogenactivator
PAR Proteinaseactivatedreceptor
PDGF Plateletderivedgrowthfactor
PDGF-R Plateletderivedgrowthfactor-receptor
PF4 Plateletfactor4
PFS Progression-freesurvival
PG Prostaglandin
PlGF Placentalgrowthfactor
PR Partialresponse
PSMA Prostate-specificmembranedomain
PyMT Polyomamiddle-T
RIP1-TAG2 Ratinsulinpromoter-1T-antigen-transgene2
RTK Receptortyrosinekinase
SAGE Serialanalysisofgeneexpression
SCID Severecombinedimmunodeficiency
SD Stabledisease
SDF Stromal-cellderivedfactor
SKITL SolubleKITligand
SR Stableresponse
STAT3 Signaltransducerandactivatoroftranscription3
TAM Tumorassociatedmacrophage
TDI Toluenediisocyanate
TEM Tie-2expressingmonocytes
TGF-β Transforminggrowthfactor-β
TKI Tyrosinekinaseinhibitors
TIMP Tissueinhibitorofmatrixmetalloproteinase
TNF-α Tumornecrosisfactorα
TSP Thrombospondin
TSP Thrombospondinrepeat
Listofabbreviations xi
VDA Vasculardisruptingagents
VE-cadherin Vascularendothelialcadherin
VEGF Vascularendothelialgrowthfactor
VEGFR Vascularendothelialgrowthfactorreceptor
VTA Vasculartargetingagents
VVO Vesciculo-vacuolarorganelles
vWF vonWillbrandfactor
ZO Zonulaoccludens
Chapter 1
Introduction
Thehumanvascularsystemiscomposedofanetworkofvesselslinedbyendothelial
cells.Inadditiontoitscriticalroleingasexchange,bloodcomponentsaredistributed
totissuesviathisroute,includingnutrients,hormones,growthfactors,inflammatory
mediators,andinflammatorycells.
Thenormalmicrovesselsconsistofarterioles,capillaries,andvenules,andform
awell-organized,regulatedandfunctionalarchitectureandarecharacterizedbydi-
chotomous branching. Arteries and veins of different size share many similarities
ofarchitectureandfunctionalorganization.Veinsaremorenumerousandgenerally
havelargercaliberandthinnerwallswithlessmuscleandelasticitythattheirarterial
counterparts, because they carry more volume at lower pressure. Each vessel usu-
allyhasanintimawithluminalendothelialcellscharacterizedbypeculiarproperties
(Table 1.1) and subendothelial fibroelastic connective tissue, a media formed of
smooth muscle cells, elastic fibers and collagen, and the adventitia formed of
connectivetissue,nervesandcapillaries(vasavasorum).
Capillariesarethebloodvesselswiththesmallestdiameter,buttheyhaveagreat
surfacearea.Theirbasicstructureconsistsofanendothelialcellslayer,abasement
membrane,andsupportingcellstermedpericytes.Therearethreetypesofcapillaries:
continuous, fenestrated, and sinusoidal. Fenestrations are approximately circular,
50–100nmindiameter,andattheiredgetheluminalandabluminalmembranesof
theendothelialcellscomeincontactwitheachother.Fenestratedcapillariesoccurin
renalglomeruliandinendocrineglands.Sinusoidsareexpandedcapillariesandare
largeandirregularinshape.Theyhavetruediscontinuitiesintheirwalls,allowing
intimatecontactbetweenbloodandparenchyma.Sinusoidsoccurinliver,spleenand
bonemarrow.Continuouscapillariesoccurinthebrain,striatedandsmoothmuscles.
Innormalcondition, thegrossvascularanatomyofthevascularsystemischar-
acterizedbyareproduciblebranchingpattern.Controlofbranchpatterningincludes
bothattractiveandrepulsiveguidancesignals(Childsetal. 2002)andisregulated
bybothpositiveandnegativeregulators(Leeetal.2001).
Vasculararchitectureintumorisdifferentfromnormaltissues(Table1.2)andis
determinedbymicroheterogeneitiesinthecellularinteractionswiththeextracellular
matrix.Intumors,theorgan-andtissue-specificvasculararchitectureisnotretained.
The highest vessel densities are usually found in the periphery within the invasive
D.Ribatti,MorphofunctionalAspectsofTumorMicrocirculation, 1
DOI10.1007/978-94-007-4936-8_1,©SpringerScience+BusinessMediaDordrecht2012