VEGF-D promotes the metastatic spread of tumor cells via the lymphatics
Steven A. Stacker1, Carol Caesar1, Megan E. Baldwin1, Gillian E. Thornton1, Richard A. Williams2, Remko Prevo3, David G. Jackson3, Shin-ichi Nishikawa4, Hajime Kubo4, 5
& Marc G. Achen1
1
Ludwig Institute for Cancer Research, Royal Melbourne Hospital, Victoria, Australia
2
Department of Pathology, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, Victoria, Australia
3
University of Oxford, Nuffield Department of Medicine/MRC Human Immunology Unit, Institute of Molecular Medicine, John Radcliffe Hospital, Headington, Oxford, UK
4
Department of Molecular Genetics, Graduate School of Medicine, Kyoto University,Kyoto, Japan
5
Molecular/Cancer Biology Laboratory, Haartman Institute, University of Helsinki, Finland
Metastasis to local lymph nodes via the lymphatic vessels is a common step in the spread of solid tumors. To investigate the molecular mechanisms underlying the spread of cancer by the lymphatics, we examined the ability of vascular endothelial growth factor (VEGF)-D, a ligand for the lymphatic growth factor receptor VEGFR-3/Flt-4, to induce formation of lymphatics in a mouse tumor model. Staining with markers specific for lymphatic endothelium demonstrated that VEGF-D induced the formation of lymphatics within tumors. Moreover, expression of VEGF-D in tumor cells led to spread of the tumor to lymph nodes, whereas expression of VEGF, an angiogenic growth factor which activates VEGFR-2 but not VEGFR-3, did not. VEGF-D also promoted tumor angiogenesis and growth. Lymphatic spread induced by VEGF-D could be blocked with an antibody specific for VEGF-D. This study demonstrates that lymphatics can be established in solid tumors and implicates VEGF family members in determining the route of metastatic spread.
