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BBB seminar: Kari Alitalo

Growth factor pathways for inhibition of angiogenesis, lymphangiogenesis and tumor metastasis

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 showed evidence of lymphangiogenesis and VEGF-C knockout mice had defective lymphatic vessels. VEGF-C could be used to treat lymphedema, even in a genetic mouse model where VEGFR-3 is mutant (Milroy's disease). 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 induced 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. We also recently found a role for VEGFR-3 signaling in settings of physiological and pathological angiogenesis in mice. Antibodies directed against VEGFR-3 showed significant inhibition of tumor growth in several xenograft models. We have localized VEGFR-3 to endothelial sprouts, and saw inhibition of VEGFR-3 signaling suppressed angiogenic sprouting. Blocking the Notch signaling pathway lead to widespread endothelial VEGFR-3 expression and excessive angiogenesis, which was inhibited by blocking VEGFR-3. Our results thus suggest that VEGFR-3 could also provide a target to complement current anti-angiogenic therapies.

Selected publications:

Alitalo K et al. , Lymphangiogenesis in development and human disease. Nature  438: 946-53, 2005.

Karpanen T, Alitalo K, Molecular biology and pathology of lymphangiogenesis. Annu Rev Pathol  3: 367-397, 2008.


Host: Helge Wiig <helge.wiig@biomed.uib.no>, Department of Biomedicine