TY - JOUR T1 - Adenoviral expression of vascular endothelial growth factor-C induces lymphangiogenesis in the skin JF - Circ Res Y1 - 2001 A1 - Enholm, B A1 - Karpanen, T A1 - Jeltsch, M A1 - Kubo, H A1 - Stenback, F A1 - Prevo, R A1 - Jackson, D G A1 - Yla-Herttuala, S A1 - Alitalo, K AB - The growth of blood and lymphatic vasculature is mediated in part by secreted polypeptides of the vascular endothelial growth factor (VEGF) family. The prototype VEGF binds VEGF receptor (VEGFR)-1 and VEGFR-2 and is angiogenic, whereas VEGF-C, which binds to VEGFR-2 and VEGFR-3, is either angiogenic or lymphangiogenic in different assays. We used an adenoviral gene transfer approach to compare the effects of these growth factors in adult mice. Recombinant adenoviruses encoding human VEGF-C or VEGF were injected subcutaneously into C57Bl6 mice or into the ears of nude mice. Immunohistochemical analysis showed that VEGF-C upregulated VEGFR-2 and VEGFR-3 expression and VEGF upregulated VEGFR-2 expression at 4 days after injection. After 2 weeks, histochemical and immunohistochemical analysis, including staining for the lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1), the vascular endothelial marker platelet-endothelial cell adhesion molecule-1 (PECAM-1), and the proliferating cell nuclear antigen (PCNA) revealed that VEGF-C induced mainly lymphangiogenesis in contrast to VEGF, which induced only angiogenesis. These results have significant implications in the planning of gene therapy using these growth factors. VL - 88 UR - http://view.ncbi.nlm.nih.gov/pubmed/11282897 IS - 6 JO - Circulation Research ER - TY - JOUR T1 - Vascular endothelial growth factor-C-mediated lymphangiogenesis promotes tumour metastasis JF - EMBO J Y1 - 2001 A1 - Mandriota, S J A1 - Jussila, L A1 - Jeltsch, M A1 - Compagni, A A1 - Baetens, D A1 - Prevo, R A1 - Banerji, S A1 - Huarte, J A1 - Montesano, R A1 - Jackson, D G A1 - Orci, L A1 - Alitalo, K A1 - Christofori, G A1 - Pepper, M S AB - Metastasis is a frequent and lethal complication of cancer. Vascular endothelial growth factor-C (VEGF-C) is a recently described lymphangiogenic factor. Increased expression of VEGF-C in primary tumours correlates with dissemination of tumour cells to regional lymph nodes. However, a direct role for VEGF-C in tumour lymphangiogenesis and subsequent metastasis has yet to be demonstrated. Here we report the establishment of transgenic mice in which VEGF-C expression, driven by the rat insulin promoter (Rip), is targeted to beta-cells of the endocrine pancreas. In contrast to wild-type mice, which lack peri-insular lymphatics, RipVEGF-C transgenics develop an extensive network of lymphatics around the islets of Langerhans. These mice were crossed with Rip1Tag2 mice, which develop pancreatic beta-cell tumours that are neither lymphangiogenic nor metastatic. Double-transgenic mice formed tumours surrounded by well developed lymphatics, which frequently contained tumour cell masses of beta-cell origin. These mice frequently developed pancreatic lymph node metastases. Our findings demonstrate that VEGF-C-induced lymphangiogenesis mediates tumour cell dissemination and the formation of lymph node metastases. VL - 20 UR - http://view.ncbi.nlm.nih.gov/pubmed/11179212 IS - 4 JO - The EMBO Journal ER -