Authors:
Mandriota, S.J.;
Jussila, L.;
Jeltsch, M.;
Compagni, A.;
Baetens, D.;
Prevo, R.;
Banerji, S.;
Huarte, J.;
Montesano, R.;
Jackson, D.G.;
Orci, L.;
Alitalo, K.;
Christofori, G.;
Pepper, M.S.Source:
EMBO J, Volume 20, Issue 4, Department of Morphology, University Medical Centre, 1 rue Michel Servet, 1211 Geneva 4, Switzerland, p.672-82 (2001)
URL:
http://emboj.org/emboj/journal/v20/n4/full/7593573a.html
Abstract:
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