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(American Journal of Pathology. 2007;170:1348-1361.)
© 2007 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2007.060835

Distinct Roles of Vascular Endothelial Growth Factor-D in Lymphangiogenesis and Metastasis

Lucie Kopfstein^*, Tanja Veikkola, Valentin G. Djonov, Vanessa Baeriswyl^*, Tibor Schomber^*, Karin Strittmatter^*, Steven A. Stacker, Marc G. Achen, Kari Alitalo and Gerhard Christofori^*

From the Department of Clinical-Biological Sciences,^* Institute of Biochemistry and Genetics, University of Basel, Basel, Switzerland; the Institute of Anatomy, University of Berne, Berne, Switzerland; the Molecular/Cancer Biology Laboratory and Ludwig Institute for Cancer Research, Biomedicum, University of Helsinki, Helsinki, Finland; and the Ludwig Institute for Cancer Research, Royal Melbourne Hospital, Victoria, Australia

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 ß-cell carcinogenesis to investigate the functional role of VEGF-D in the induction of lymphangiogenesis and tumor progression. Expression of VEGF-D in ß 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.

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