title: Vascular endothelial growth factor-C-mediated lymphangiogenesis promotes tumour metastasis.
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.
authors.affiliation: Department of Morphology, University Medical Centre, 1 rue Michel Servet, 1211 Geneva 4, Switzerland.
authors.forename: S J
authors.initials: SJ
authors.lastname: Mandriota
authors.forename: L
authors.initials: L
authors.lastname: Jussila
authors.forename: M
authors.initials: M
authors.lastname: Jeltsch
authors.forename: A
authors.initials: A
authors.lastname: Compagni
authors.forename: D
authors.initials: D
authors.lastname: Baetens
authors.forename: R
authors.initials: R
authors.lastname: Prevo
authors.forename: S
authors.initials: S
authors.lastname: Banerji
authors.forename: J
authors.initials: J
authors.lastname: Huarte
authors.forename: R
authors.initials: R
authors.lastname: Montesano
authors.forename: D G
authors.initials: DG
authors.lastname: Jackson
authors.forename: L
authors.initials: L
authors.lastname: Orci
authors.forename: K
authors.initials: K
authors.lastname: Alitalo
authors.forename: G
authors.initials: G
authors.lastname: Christofori
authors.forename: M S
authors.initials: MS
authors.lastname: Pepper
mesh_terms: D000818:Animals; D018076:DNA, Complementary; D016228:Endothelial Growth Factors / Q000235:genetics / Q000502:physiology*; D006801:Humans; D007150:Immunohistochemistry; D008208:Lymphatic System / Q000254:growth & development*; D051379:Mice; D008822:Mice, Transgenic; D009362:Neoplasm Metastasis; D010179:Pancreas / Q000648:ultrastructure; D042582:Vascular Endothelial Growth Factor C
chemical_list: D018076:DNA, Complementary; D016228:Endothelial Growth Factors; D042582:Vascular Endothelial Growth Factor C