K201	Lymphangiogenesis.
K.Alitalo and collaborators
Molecular/Cancer Biology Laboratory and Ludwig Institute for Cancer Research, Haartman Institute and Biomedicum, Helsinki, FI.

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 the 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. Lymphangiogenic signals may also be intimately coupled to various inflammatory processes. 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 2004 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. Tammela T, Saaristo A, Lohela M, Morisada T, Tornberg J, Norrmén C, Oike Y, Pajusola K, Thurston G, Suda T, Yla-Herttuala S, Alitalo K. Angiopoietin-1 promotes lymphatic sprouting and hyperplasia. Blood, March 3; [Epub ahead of print], 2005. Saharinen P, Tammela T, Karkkainen MJ, Alitalo K. Lymphatic vasculature: development, molecular regulation and role in tumor metastasis and inflammation. Trends Immunol. 25:387-95, 2004.

Copyright © 2005 S. Karger AG, Basel. Any further use of this abstract requires written permission from the publisher.