Kari Alitalo
University of Helsinki,
Helsinki, Finland

Angiogenesis, Lymphangiogenesis and Metastasis

Angiogenesis and permeability of blood vessels are regulated by vascular endothelial growth factor (VEGF) via its two known receptors VEGFR-1 and VEGFR-2. The VEGFR-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 targeted mice die 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. 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 (Achen et al., 1998). Thus, VEGF-C and VEGF-D appear to be both angiogenic and lymphangiogenic growth factors. When overexpressed as a transgene in the RIP-Tag model of pancreatic ß-cell tumors, VEGF-C induced the growth of peritumoral lymphatic vessels and was associated with lymphatic metastasis. VEGF-C overexpression also led to lymphangiogenesis, intralymphatic tumor growth and lymph node metastasis in an orthotopic model of human breast carcinoma in immunoincompetent mice. Furthermore, soluble VEGFR-3, which blocks embryonic lymphangiogenesis, blocked these changes. However, VEGFR-3 is also induced in blood vessels of various types of human cancer. Ongoing experiments address the role of the VEGFR-3 signaling pathway in embryonic and tumor angiogenesis and the mechanisms of lymphatic metastasis as well as the effects of blocking the VEGFR-3 signal transduction pathway by various means.

References:

Veikkola et al., Cancer Res. 60: 203-212, 2000
Karkkainen et al., Nature Genetics 25: 153-159, 2000
Iljin et al., FASEB J. 2001 15:1028-1036
Enholm et al., Circ Res. 2001 88:623-9.
Karpanen et al., Cancer Res. 2001 61:1786-90
Veikkola et al., EMBO J. 2001 20:1223-31
Mandriota et al., EMBO J. 2001 20:672-82
Makinen et al., Nat Med. 2001 7:199-205