VEGF-C, VEGF-D and VEGFR-3 in Tumor Angiogenesis, Lymphangiogenesis and Metastasis
Karl Alitalo and collaborators Molecular/Cancer Biology Laboratory. Haartman Institute, 00014 University of Helsinki, FINLAND
Angiogenesis and permeability of blood vessels are regulated by vascular enothelial growth factor (VEGF) via its two known receptors VEGFR-1 and VEGFR-2. Recently, additional VEGF genes have been cloned and new insight has been obtained of the molecular mechanisms regulating the function of endothelial cells of lymphatic vessels. VEGF-D and VEGF-D have been shown to stimulate lymphangiogenesis and their receptor VEGFR-3 has been linked to human hereditary lymphoedema, although there is evidence that also other genes are involved. Such molecules may allow the regulation of angiogenesis and lymphangiogenesis as well as tissue edema involved in many diseases.
The VEGVR-3 receptor tyrosine kinase is related to the VEGF receptors, but does not bind VEGF and its expression becomes restricted mainly to lymphatic endothelia during development. We have found that homozygous VEGFR-3 knock-outs die after around day 10 of embryonic development due to failure of cardiovascular development and that heterozygous missense mutations of VEGFR-3 inactivating the tyrosine kinase activity are associated with human hereditary lymphedema. We have also purified and cloned the VEGFR-3 ligand VEGF-C, which is made as a precursor protein having an extended N-terminus and a C-terminal half containing extra cysteine-rich motifs characteristic of a protein component of silk. Transgenic mice expressing VEGF-C developed a hyperplastic lymphatic vessel network and show evidence of lymphangiogenesis. However, proteolytically processed VEGF-C was also capable of stimulating VEGFR-2 and was weakly angiogenic VEGF-C induced vascular permeability, but its point mutant, which retained lymphangiogenic properties and activated only VEGFR-3 did not. 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 angiogenic and lymphangiogenic growth factors. When overexpressed as a transgene in the RIP-Tag model of pancreatic � cell tumors, VEGF-C induced the growth of peritumoral lymphatic vessels and was associated with lymphatic metastasis. However, its receptor VEGFR-3 is induced in tumor vessels of various types of human cancer and upon tumor cell transfection and implantation into mice, VEGF-C was also angiogenic. Ongoing experiments address the role of the VEGFR-3 signaling pathway in embryonic and tumor angiogenesis and the mechanisms of lymphatic metastasis.
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