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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.

Original publication

DOI

10.1038/84635

Type

Journal article

Journal

Nat Med

Publication Date

02/2001

Volume

7

Pages

186 - 191

Keywords

Animals, Cell Line, Transformed, Endothelial Growth Factors, Female, Humans, Lymphatic Metastasis, Mice, Mice, Inbred NOD, Mice, SCID, Neoplasms, Neovascularization, Pathologic, Vascular Endothelial Growth Factor D