PhD program Molecular Signal Tranduction TUMOR ANGIOGENESIS Erhard Hofer Department of Vascular...
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PhD program
Molecular Signal Tranduction
TUMOR ANGIOGENESIS
Erhard Hofer
Department of Vascular Biology and Thrombosis ResearchCenter for Biomolecular Medicine and PharmacologyMedical University of Vienna
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Part I: Overview of vessel formation
1- Angiogenesis and vasculogenesis
2- Important factors and receptors
3- VEGF receptor signaling
4- Tumor angiogenesis
5- Anti-angiogenesis therapies
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Literature:
Books:
B. Alberts et al., Molecular Biology of the Cell,5th Edition, Taylor and Francis Inc., 2007Pg. 1279-1283
R.A. Weinberg, The Biology of Cancer, Garland Science, 2007Pg. 556-585
Tumor Angiogenesis - Basic mechanisms and Cancer Therapy, D. Marme, N. Fusenig, ed.Springer Verlag 2008
Angiogenesis - From basic science to clinical applicationN. Ferrara, ed.CRC Press, Taylor&Francis Group, 2007
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Nature Insight Angiogenesis G.D. Yancopoulos et al. (2000). Vascular-specific growth factors and blood vessel formation. Nature 407, 242-248.
Angiogenesis Focus, Nature Med 9, June 2003Peter Carmeliet, Angiogenesis in Health and DiseaseNapoleone Ferrara et al., The biology of VEGF and its receptorsRakesh K. Jain, Molecular regulation of vessel maturationShanin Rafii and David Lyden, Therapeutic stem and progenitor celltransplantation for organ vascularization and regenerationChristopher W. Pugh and Peter J. Ratcliffe, Regulation of angiogenesis by hypoxia: role of the HIF system
Angiogenesis, Nature Reviews Cancer 3, June 2003 Gabriele Bergers and Laura E. Benjamin, Tumorigenesis and the angiogenic switch
Literature:
Reviews:
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C.J. Schofield and P.J. Ratcliffe. Oxygen sensing by HIF hydroxylases.Nature Rev. Mol. Cell Biol. 5, 343-354 (2004)
Nature Insight Angiogenesis, Vol. 438, pg. 931-974, December 2005Carmeliet, Angiogenesis in life, disease and medicine Coultas, Endothelial cells and VEGF in vascular development Alitalo, Lymphangiogenesis in development and human disease Greenberg, From angiogenesis to neuropathology Gariano, Retinal angiogenesis in development and disease Ferrara, Angiogenesis as a therapeutic target
P. Carmeliet and M. Tessier-Lavigne, Common mechanisms of nerve and blood vessel wiring, Nature 436, 195-200 (2005)
J. Folkman, Angiogenesis: an organizing principle for drug discovery ?Nature Reviews Drug Discovery 6, 273-286 (2007)
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Role of notch:Adams and Alitalo, Molecular regulation of angiogenesis and lymphangiogenesis, Nature Rev Mol Cell Biol 8, 464-478 (2007)Germain et al., Hypoxia-driven angiogenesis, Curr Opinion in Hematol 17 (2010)
Guidance cues:Larrivee et al., Guidance of vascular development: Lessons from the nervous system, Circulation Research 104, 428-441 (2009)Gaur et al., Role of class 3 semaphorins and their receptors in tumor growth and angiogenesis, Clin Cancer Res 15, 6763-70 (2009)
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Unterlagen:
http://mailbox.univie.ac.at/erhard.hoferStudent point, Vorlesungsunterlagen
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Structure of vessels and capillaries
Monocellular layer of endothelial cellsSmall artery:
Capillary: endothelial cell, basal lamina, pericytes
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Angiogenesis:Sprouting of cells from mature endothelial cells of the vessel wall
Mouse cornea:wounding induces angiogenesis,chemotactic response toangiogenic factors
(secretion of proteases, resolution ofBasal lamina, migration towards Chemotactic gradient, proliferation,Tube formation)
VEGF is factor largely specific for endothelial cells,bFGF can also induce, not specific for EC)
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Sprouting towards chemotactic gradient: VEGF
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Hypoxia - HIF - VEGFevery cell must be within 50 to 100 m of a capillary
HIF: hypoxia inducible factorVEGF: vascular endothelial growth factor
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VEGF-gene:Regulated by HIF,HIF is continously produced,ubiquitinylated, degraded in proteasome,therefore low concentration;
Ubiquitinylation dependent onHippel-Lindau tumor suppressor(part of an E3 ubiquitin-ligase complex)
HIF1is modified by a prolyl hydroxylase,then better interaction with vHL protein, high turnover;Hydroxylase is regulated by O2
Von Hippel-Lindau Tumor Suppressor, HIF and VEGF
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capillaries sprouting in the retina of an embryonic mouse
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capillary lumen opening up
behind the tip cell(red dye injected)
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Vasculogenesis
Formation of vessels by differentiation of cells from angioblasts in the yolk sac of the embryo:
Is differentiation and proliferation of endothelial cells in a non-vascularized tissue
Leads to formation of a primitive tubular network
Has to undergo angiogenic remodeling to stable vascular system
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Hemangioblast Angioblast EC
Postnatal vasculogenesis
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Factors and receptors
Endothelium-specific factors:VEGF family: 5 factorsAngiopoietin family : 4 factorsEphrin family : at least 1 factor
Non EC-specific factors :bFGFPDGFTGF-
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VEGF/VEGFR:VEGF-A: initiation of vasculogenesisand sprouting angiogenesis,Immature vessels,Vascular permeability factor,Haploid insufficiency in k.o. mice,
PlGF: remodeling of adult vessels VEGF-B: heart vascularization ?VEGF-C: lymphatic vesselsVEGF-D: lymphatic vessels ?
VEGFR-2: growth and permeabilityVEGFR-1: negative role ?, decoy receptor,
synergism with VEGFR-2 in tumor angiogenesis VEGFR-3: lymphatic vessels
VEGF/VEGFR family
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Figure 13.31 The Biology of Cancer (© Garland Science 2007)
Network of lymphatic vessels (red) and capillaries (green):Lymphatic vessels are larger, not supported by underlying mural cells
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Differential signaling by tyr kinase receptors
gene regulation
proliferationvasculogenesisangiogenesis
Y799
Y820
Y925
Y936
Y951Y994
Y1006
Y1052Y1057
Y1080Y1104
Y1128Y1134
Y1175Y1212Y1221
Y1303Y1307
Y1317
P38, src (vascular leakage?)
TSAd (migration)
PI-3 kinase (survival)
PLC-
EC “specific” factors/receptors:
VEGFR1 VEGF-A, PLGF
VEGFR2 VEGF-AVEGFR3 VEGF-CTIE1 ?TIE2 ANG1,2
VEGFR2
Sakurai et al.PNAS 2005
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82 of the most strongly VEGF-regulated genes (over 5-fold) compared to EGF and IL-1 induction
VEGF + EGF + IL-1 cluster
VEGF + IL-1 cluster
VEGF + EGF cluster
VEGF cluster
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Overlapping and specific gene repertoiresof VEGF, EGF and IL-1
About 60 genes reproducibly induced by VEGF over 3-fold
VEGF-induced genes overlap to a large degreewith IL1-induced genes (50-60 %)
20 % of genes are preferentially induced by VEGF
VEGFEGF
IL-160%20%
20%
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Signaling by receptors of endothelial cells
PPLC-
1175
P
1175
P
Ca++ PKC
Calcineurin RafMEK/ERK
EGR-1NFAT
P951
PI3K
Akt
TsAd
p38
Actincytoskeleton
Grb2
Ras
RafMEK/ERK
EGR-1
MyD88
IKK/IKK/IKK
IBNFB
NFB
gene regulation survivalmigration
inflammation angiogenesis
permeabilityproliferation
IL-1R VEGFR-2 EGFR
Hofer E., Schweighofer B. Signaling transduction induced in endothelial cells by growth factor receptors involved in angiogenesis. Thrombosis ang haemostasis 2007
IL-1 VEGF-A EGF
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Guidance molecules in endothelial tip cell attraction and repulsion
Eichmann A, Curr Opin Neurobiol. 2005
Carmeliet P, Nature. 2005
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Angiopoietins und Tie Receptors:
Ang1: remodeling and maturationQuiescence and stabilityResistance to permeability,Supports interaction with other cells and matrix,Vessel size (VEGF number of vessels),Repair of damaged vessels
Ang2: natural antagonist,Overexpression similar Ang-1 k.o. oder Tie-2 k.o.,Destabilization signal for initiation of vascular remodelingEither regression or increased VEGF sensitivityAng2 is induced in tumors
Ang3: ?Ang4: ?
Tie2: binds Ang1-4
Tie1: ?
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Ephrins und Eph-Receptors:
Largest family of growth factor receptors,Relevant for vascular system:Ephrin B2/ Eph B4 : remodeling and maturation Different for early arterial (Ephrin B2) and venous vessels (EphB4),Hypothesis: role for fusion of arterial/venous vessels
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1-Sprouting
3-incorporation of BM-derived precursors
5-Lymphangiogenesis
Growth of tumor vessels
2-Intussusceptive growth
4-Cooption of existing vessels
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Role of VEGF and Ang2 for tumor angiogenesis,VEGF-blockade is promising for anti-ngiogenesis therapy
Concept 2: many tumors “home in” onto vessels, occupate existing vessels,Vessel produces Ang2, first tumor regression, then VEGF production by tumor
Concept 1: non-vascularized Tumor
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Figure 13.32a The Biology of Cancer (© Garland Science 2007)
Recruitment of capillaries by an implanted tumor
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Figure 13.34a The Biology of Cancer (© Garland Science 2007)
Chaotic organization of tumor-associated vasculature
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Structure and function of tumor vessels:
Chaotic architecture and blood flowTherefore hypoxic and acidic regions in tumorPermeability strongly increased
fenestraeenlarged Junctions
No functional lymphatics inside the tumorenlarged in surrounding,increases metastasis
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Mosaic vessels
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Abnormale endothelium
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Figure 13.33 The Biology of Cancer (© Garland Science 2007)
Tumor vessel is only partially overlaid by pericytes and SMC
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Figure 13.37 The Biology of Cancer (© Garland Science 2007)
The Rip-Tag model of islet tumor cell progressionTransgene: SV40 large and small T transcription driven by insulin promoter
Transcription in b-cells of islets of Langerhans
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Figure 13.38b The Biology of Cancer (© Garland Science 2007)
The angiogenic switch and recruitment of inflammatory cells
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Figure 13.49 The Biology of Cancer (© Garland Science 2007)
Heterotypic interactions as targets for therapeutic intervention
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Inhibition of tumor angiogenesis
1-Bevacizumab 2-VEGF-trap
3-Pegaptinib
(Combination with 5-fluorouracil forcolorectal cancer)
(Macular degeneration)
4
5- SU11248 Bay43-9006
6- downstream Signals ?
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BevacizumabColorectal cancerPhase IIICombination therapy
Hurwitz et al. 2004Mass et al. 2004
IFL: Irinotecan5-fluorouracilLeucovorin
Median survival benefitof two trials (2004):3.7-4.7 months
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Gentherapien:
rAdenovirenrRetroviren
Targeting of viruses to tumors, tumor endothelium
Targeting of liposomes to tumors, tumor endothelium
Oncolytic viruses
BM progenitor cells home to tumor vasculature
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Next meeting in Zürich, June 15-18, 2011organized by Michael Detmar, ETH
Ralf Adams, Max-Planck-Institute, Münster, Germany
Kari Alitalo, University of Helsinki, Finland
Hirofumi Arakawa, National Cancer Center Research Institute, Tokyo, Japan
Hellmut Augustin, German Cancer Research Center, Heidelberg, Germany
Roy Bicknell, University of Birmingham, UK
Georg Breier, Technical University Dresden, Germany
Peter Carmeliet, Catholic University of Leuven, Belgium
Michael Detmar, Swiss Federal Institute of Technology Zurich, Switzerland
Anna Dimberg, Uppsala University, Sweden
Anne Eichmann, INSERM U833, College de France, Paris, France
Britta Engelhardt, University of Bern, Switzerland
Napoleone Ferrara, Genentech Inc., San Francisco, USA
Holger Gerhardt, London Research Institute, Cancer Research UK
Dontscho Kerjaschki, Medical University of Vienna, Austria
Alexander Koch, Genentech Inc., San Francisco, USA
Donald McDonald, University of California, San Francisco, USA
Gera Neufeld, Israel Institute of Technology, Haifa, Israel
Jaques Pouyssegur, Institute of Developmental Biology and Cancer, Nice,
France
Masabumi Shibuya, University of Tokyo, J apan
Dietmar Vestweber, Max-Planck-Institute, Münster, Germany