In vivo effects and therapeutic potential of VEGF-C

................................................................................................................................... 7 REVIEW OF THE LITERATURE ............................................................................................ 8 The formation of blood and lymphatic vessel networks during embryonic development .................... 8 Vasculogenesis and angiogenesis................................................................................................................ 8 Endothelial cell differentiation.................................................................................................................... 8 Lymphangiogenesis ................................................................................................................................... 10 Characteristics of lymphatic vessels ......................................................................................................... 11 Molecular regulation of the blood and lymphatic vessel growth ............................................................ 14 VEGF and its receptors.............................................................................................................................. 14 VEGF-B and PlGF..................................................................................................................................... 16 VEGF-C, VEGF–D and their receptors .................................................................................................... 18 Angiopoietins and their Tie-receptors....................................................................................................... 19 Ephrins........................................................................................................................................................ 20 Lymphatic vessel markers ......................................................................................................................... 20 Diseases associated with lymphatic vessel function .................................................................................. 23 Lymphedema.............................................................................................................................................. 23 Tumorigenesis and metastasis ................................................................................................................... 26 AIMS OF THE STUDY.............................................................................................................. 30 MATERIALS AND METHODS ............................................................................................... 31 RESULTS AND DISCUSSION ................................................................................................. 34 I Expression of VEGF-C and its receptor VEGFR-3 in nasal mucosa and in nasopharyngeal tumors 34 II Expression of VEGF-C, VEGF-D and VEGFR-3 in normal human tissues..................................... 34 III In vivo effect of VEGF-C on blood and lymphatic vessels .............................................................. 35 IV Characterization of the VEGFR-3 specific mutant form of VEGF-C (VEGF-C156S) as a lymphangiogenic factor ............................................................................................................................ 38 CONCLUSIONS.......................................................................................................................... 42 ACKNOWLEDGEMENTS........................................................................................................ 44 REFERENCES ............................................................................................................................ 45