title: Distinct roles of vascular endothelial growth factor-D in lymphangiogenesis and metastasis.
abstract: In many human carcinomas, expression of the lymphangiogenic factor vascular endothelial growth factor-D (VEGF-D) correlates with up-regulated lymphangiogenesis and regional lymph node metastasis. Here, we have used the Rip1Tag2 transgenic mouse model of pancreatic beta-cell carcinogenesis to investigate the functional role of VEGF-D in the induction of lymphangiogenesis and tumor progression. Expression of VEGF-D in beta cells of single-transgenic Rip1VEGF-D mice resulted in the formation of peri-insular lymphatic lacunae, often containing leukocyte accumulations and blood hemorrhages. When these mice were crossed to Rip1Tag2 mice, VEGF-D-expressing tumors also exhibited peritumoral lymphangiogenesis with lymphocyte accumulations and hemorrhages, and they frequently developed lymph node and lung metastases. Notably, tumor outgrowth and blood microvessel density were significantly reduced in VEGF-D-expressing tumors. Our results demonstrate that VEGF-D induces lymphangiogenesis, promotes metastasis to lymph nodes and lungs, and yet represses hemangiogenesis and tumor outgrowth. Because a comparable transgenic expression of vascular endothelial growth factor-C (VEGF-C) in Rip1Tag2 has been shown previously to provoke lymphangiogenesis and lymph node metastasis in the absence of any distant metastasis, leukocyte infiltration, or angiogenesis-suppressing effects, these results reveal further functional differences between VEGF-D and VEGF-C.
authors: Institute of Biochemistry and Genetics, Department of Clinical-Biological Sciences, University of Basel, Center of Biomedicine, Mattenstrasse 28, CH-4058 Basel, Switzerland.
authors: Lucie
authors: L
authors: Kopfstein
authors: Tanja
authors: T
authors: Veikkola
authors: Valentin G
authors: VG
authors: Djonov
authors: Vanessa
authors: V
authors: Baeriswyl
authors: Tibor
authors: T
authors: Schomber
authors: Karin
authors: K
authors: Strittmatter
authors: Steven A
authors: SA
authors: Stacker
authors: Marc G
authors: MG
authors: Achen
authors: Kari
authors: K
authors: Alitalo
authors: Gerhard
authors: G
authors: Christofori
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D005260:Female; D005838:Genotype; D006801:Humans; D015151:Immunoblotting; D007962:Leukocytes / Q000378:metabolism / Q000473:pathology; D008175:Lung Neoplasms / Q000235:genetics / Q000503:physiopathology / Q000556:secondary; D008198:Lymph Nodes / Q000378:metabolism / Q000473:pathology; D042583:Lymphangiogenesis / Q000235:genetics / Q000502:physiology*; D042601:Lymphatic Vessels / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008855:Microscopy, Electron, Scanning; D046529:Microscopy, Electron, Transmission; D009362:Neoplasm Metastasis / Q000235:genetics / Q000503:physiopathology*; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000503:physiopathology; D010190:Pancreatic Neoplasms / Q000098:blood supply / Q000473:pathology / Q000648:ultrastructure; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D042643:Vascular Endothelial Growth Factor D / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: D011993:Recombinant Fusion Proteins; D042643:Vascular Endothelial Growth Factor D