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 clinsci.org Clin. 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 Hematopoiesis Blood cells VEGF-A VEGFR-1 VEGFR-2 Angioblast Primary vascular plexus Vasculogenesis VEGF-A VEGFR-1 Angiogenesis VEGFR-2 VEGFR-3 Enlarged embryonic vasculature (arteries & veins) Lymphangioblast VEGF-C VEGF-D VEGFR-3 EG-VEGF Endothelial differentiation Lymphangiogenesis VEGF-C VEGF-D VEGFR-3 prox-1 permeable blood vessels in steroidogenic glands tight blood vessels e.g. brain Lymphatic vessels Alitalo 2001, Stacker 1999
VEGFs and their Receptors Clinical Science www.clinsci clinsci.org Clin. Sci.. (2005) 109, 227-241 Chick CAM Assay Chorio-Allantoic-Membrane +/- VEGF-A VEGF-Knock-out heterozygous lethal!
Hypoxia-induction of VEGF-A gene expression Harris, 2001 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 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 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 LN MET 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.