BBB seminar: Kari Alitalo
Lymphangiogenesis in development and human disease
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Kari Alitalo
Molecular/Cancer Biology Laboratory and Ludwig Institute for Cancer Research, Haartman Institute and Biomedicum Helsinki, University of Helsinki, Finland
Angiogenesis and permeability of blood vessels are regulated by vascular endothelial growth factor (VEGF) via its two receptors VEGFR-1 and VEGFR-2. The VEGFR-3 receptor does not bind VEGF and its expression becomes restricted mainly to lymphatic endothelia during development. We have found that homozygous VEGFR-3 targeted mice die around midgestation due to failure of cardiovascular development. We have also purified and cloned the VEGFR-3 ligand, VEGF-C. Transgenic mice expressing VEGF-C show evidence of lymphangiogenesis and VEGF-C knockout mice have defective lymphatic vessels. The proteolytically processed form of VEGF-C binds also to VEGFR-2 and is angiogenic. VEGF-D is closely related to VEGF-C, similarly processed and binds to the same receptors. Thus VEGF-C and VEGF-D appear to be both angiogenic and lymphangiogenic growth factors. VEGF-C overexpression led to lymphangiogenesis and growth of draining lymphatic vessels, intralymphatic tumor growth and lymph node metastasis in several tumor models. Furthermore, soluble VEGFR-3, which blocked embryonic lymphangiogenesis, also blocked lymphatic metastasis in breast and lung cancer models. These results together with recent clinical cancer studies suggest that paracrine signal transduction between tumor cells and the lymphatic endothelium may be involved in lymphatic metastasis of human cancers.
Selected references:
Tammela T, Petrova TV, Alitalo K. Molecular lymphangiogenesis: new players. Trends Cell Biol. 15: 434-41, 2005.
He Y, Rajantie I, Pajusola K, Jeltsch M, Holopainen T, Yla-Herttuala S, Harding T, Jooss K, Takahashi T, Alitalo K. Vascular endothelial cell growth factor receptor 3-mediated activation of lymphatic endothelium is crucial for tumor cell entry and spread via lymphatic vessels. Cancer Res. 65: 4739-46, 2005.
Tammela T, Saaristo A, Lohela M, Morisada T, Tornberg J, Norrmen C, Oike Y, Pajusola K, Thurston G, Suda T, Yla-Herttuala S, Alitalo K. Angiopoietin-1 promotes lymphatic sprouting and hyperplasia. Blood 105: 4642-8, 2005.
Karkkainen MJ, Haiko P, Sainio K, Partanen J, Taipale J, Petrova TV, Jeltsch M, Jackson DG, Talikka M, Rauvala H, Betsholtz C, Alitalo K. Vascular endothelial growth factor C is required for sprouting of the first lymphatic vessels from embryonic veins. Nature Immunology 5: 74-80, 2004.
Petrova TV, Karpanen T, Norrmen C, Mellor R, Tamakoshi T, Finegold D, Ferrell R, Kerjaschki D, Mortimer P, Yla-Herttuala S, Miura N, Alitalo K. Defective valves and abnormal mural cell recruitment underlie lymphatic vascular failure in lymphedema distichiasis. Nature Medicine 10: 974-981, 2004.
He Y, Rajantie I, Ilmonen M, Makinen T, Karkkainen MJ, Haiko P, Salven P, Alitalo K. Preexisting lymphatic endothelium but not endothelial progenitor cells are essential for tumor lymphangiogenesis and lymphatic metastasis. Cancer Res. 64: 3737-40, 2004.
Lin J, Lalani AS, Harding TC, Gonzalez M, Wu WW, Luan B, Tu GH, Koprivnikar K, VanRoey MJ, He Y, Alitalo K, Jooss K. Inhibition of lymphogenous metastasis using adeno-associated virus-mediated gene transfer of a soluble VEGFR-3 decoy receptor. Cancer Res. 65: 6901-9, 2005.
Host: Rolf Bjerkvig, Department of Biomedicine
Academy Professor Kari Alitalo serves as Director of the University of Helsinki's Molecular Cancer Biology Programme at the Biomedicum Helsinki, University of Helsinki. He also directs one of the Centres of Excellence at the Academy of Finland. The main aim of his research is to understand the mechanisms involved in the development of blood vessels in a process called angiogenesis and to learn about the analogous mechanisms of lymphangiogenesis. His group has described a number of fundamental mechanisms related to the formation of blood and lymphatic vessels where the focus has been on growth factor-receptor signalling, and growth factor-mediated endothelial cell reprogramming. In particular, the group has discovered novel mechanisms involved in the regulation of angiogenesis and identified a number of new vascular endothelial growth factors (VEGFs) and their receptors, which include the endothelial Tie receptor tyrosine kinase. Kari Alitalo has received numerous international prizes for his ground-breaking research on angiogenesis. |