Download Angiogenesis as a therapeutic target

Angiogenesis as a therapeutic target
Lecture
Experimentelle Krebsforschung
SS 07
Prof. Gerhard Christofori
Institute of Biochemistry and Genetics
Department of Clinical-Biological Sciences
University of Basel
Multistage Tumorigenesis
Multistage Colorectal Carcinogenesis
Tumor angiogenesis
Bergers and Benjamin, 2002, Nat. Rev. Cancer
Increased microvessel density in tumors
(for example ductal breast carcinoma)
Vasculogenesis/Angiogenesis
Carmeliet, 2003
Tumor angiogenesis in transplanted tumors
Weinberg, 2006
Genetic manipulation of mice
The Rip1Tag Transgene
Hanahan, Nature, 1985
Rip1Tag2 tumorigenesis
Multistage Tumorigenesis in Rip1Tag2 Transgenic Mice
“The angiogenic switch”
Cellular Events in Tumor Angiogenesis
Key Angiogenic Factors
VEGF Family Members
Clinical Science
www.clinsci
.org
www.clinsci.org
Clin.
Clin. Sci.
Sci. (2005) 109, 227-241
Vascular Endothelial Growth Factors and their Receptors
Cross et al., TIBS, 2003
VEGFs in Vasculogenesis/Angiogenesis
Hemangioblast
VEGFR-2
Hematopoietic precursor
Hematopoietic cells
VEGF-A
VEGFR-1
VEGFR-2
Hematopoiesis
Blood cells
Lymphangioblast
Angioblast
Vasculogenesis
Primary vascular
plexus
VEGF-A
VEGFR-1
Angiogenesis
VEGFR-2
VEGFR-3
Enlarged embryonic vasculature
(arteries & veins)
EG-VEGF
„permeable blood vessels“
in steroidogenic glands
Endothelial
differentiation
„tight blood vessels“
e.g. brain
VEGF-C
VEGF-D
VEGFR-3
Lymphangiogenesis
VEGF-C
VEGF-D
pro
VEGFR-3
x-1
Lymphatic vessels
Alitalo 2001, Stacker 1999
VEGFs and their Receptors
Clinical Science
www.clinsci
.org
www.clinsci.org
Chick CAM Assay
Chorio-Allantoic-Membrane
+/- VEGF-A
VEGF-Knock-out
heterozygous lethal!
Clin.
Clin. Sci.
Sci. (2005) 109, 227-241
Hypoxia-induction of VEGF-A gene expression
Harris, 2001
HIF-1α
HIF-1α regulation
Harris, 2001
Harris, 2001
Vascular Endothelial Growth Factors
and their Receptors
The Angiogenic Switch
VEGF sequestered
by ECM
VEGF released
by MMP activity
(mast cells,
Vascular Endothelial Growth Factor-A
Cross et al., TIBS, 2003
Activation of
Vascular Endothelial Growth Factor-A
Ferrara et al., 2003
MMPs in breast (and other) tumors
Egeblad and Werb, 2002
Angiogenic Factors and the ECM
Sund et al., 2004
A Simplified Picture of Tumor Angiogenesis
VEGFs
FGFs
Angiopoietins
PDGF B
TGFβ
VEGF receptors
FGF receptors
Tie-2 (Tie-1?)
PDGF-β receptor
TGFβ receptors
Angiopoietins
Jones et al., 2001
VEGFs and Angiopoietins
Jones et al., 2001
The Fine Balance of Angiogenesis Regulation
Bergers and Benjamin, 2002, Nat. Rev. Cancer
Angiogenesis Inhibitors
Endogenous
Therapeutic
chemicals
antibodies
peptides/proteins
Folkman, 2004
Angiogenesis Inhibitors
Cilengitide
Endogenous angiogenesis inhibitors
Experimental Therapy in Rip1Tag2 Mice
Interferon α/β
TNP470
Angiostatin
Endostatin
Thrombospondin
MMP inhibitors
Cathepsin inhibitors
Glivec (imatinib
VEFR receptor inhibitors
(PTK787,Sugen 6668, …)
VEGF-Trap, FGF-Trap
VEGF receptor antibodies
Immunoliposomes
Exendin-4 (GLP1R peptide)
AEW471 (IGF1 receptor inhibitor)
PDGF receptor inhibitors
Anti-Angiogenic Therapy in Rip1Tag2 Mice
Bergers et al. Science 1999
Anti-Angiogenic Therapy in Rip1Tag2 Mice
Weinberg, 2006
A selection of anti-angiogenic drugs approved
or in clinical trials
Approved for CRC
first and second line
VEGF-A expression and anti-VEGF-A therapy (Avastin
(Avastin))
Hanrahan et al., 2003
Borgstrom et al., 1999
Avastin in Colorectal Cancer
Hurwitz et al., 2004
Resistance to anti-angiogenic therapy?
Fibroblast Growth Factors and their Receptors
Soluble Receptor Constructs
Compagni et al., Cancer Res. 2000
VEGFs and FGFs are required for Tumor Angiogenesis:
Rip1Tag2 tumorigenesis in vivo
Compagni et al., Cancer Res. 2000
A selection of anti-angiogenic drugs approved
or in clinical trials
A selection of anti-angiogenic drugs approved
or in clinical trials
Maturation of Vessels
Pietras and Hanahan, 2005
Two Vascular Systems!
Jones et al., 2001
The Lymphatic System
Lymphatic vessels
Papoutsi et al. Dev. Dyn. 2001
Lymphatic vessel development
Prox-1 as
master control gene?
Oliver and Detmar, 2002
Prox-1-induced
Prox-1-induced lymphatic differentiation
Petrova et al., 2002
Tumor angiogenesis and lymphangiogenesis
Vasculogenesis = De novo formation of blood vessels
Angiogenesis = Formation of blood vessels from pre-existing blood vessels
Lymphangiogenesis = Formation of lymphatic vessels
Ruoslahti, 2002
Lymphangiogenesis and angiogenesis in tumors
Crnic et al., 2004
VEGF Family Members and their Receptors
ANGIOGENESIS
LYMPHANGIOGENESIS
Forced Lymphangiogenesis in Rip1VEGF-C Mice
wt
Rip1VEGF-C
Mandriota et al., 2001
Forced Lymphangiogenesis in Rip1Tag2 Mice
Rip1Tag2;Rip1VEGF-C
MET
LN
Mandriota et al., 2001
Anti-angiogenic therapy
• ± general mechanism in solid tumors
• no or low resistance
• defined targets
• no angiogenesis in adults, low side effects
• synergism with chemo- and radiotherapy
• anti-metastatic?
• efficacy?
• longterm treatment, side effects?
• resistance afterall?
• lymphangiogenesis - lymph node metastasis
• inflammation!
Reviews:
Carmeliet P. Angiogenesis in health and disease.
Nat Med. 2003 Jun;9(6):653-60.
Alitalo K, Carmeliet P. Molecular mechanisms of lymphangiogenesis in health and disease.
Cancer Cell. 2002 Apr;1(3):219-27.
Stacker SA, Achen MG, Jussila L, Baldwin ME, Alitalo K. Lymphangiogenesis and cancer
metastasis. Nat Rev Cancer. 2002 Aug;2(8):573-83.
Bergers G, Benjamin LE. Tumorigenesis and the angiogenic switch.
Nat Rev Cancer. 2003 Jun;3(6):401-10.
Ferrara N, Gerber HP, LeCouter J.The biology of VEGF and its receptors.
Nat Med. 2003 Jun;9(6):669-76.
Ferrara N. VEGF and the quest for tumour angiogenesis factors. Nat Rev Cancer. 2002
Oct;2(10):795-803.
Folkman J. Angiogenesis: an organizing principle for drug discovery? Nat Rev Drug Discov.
2007 Apr;6(4):273-86.