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VEGF-D promotes the metastatic spread of tumor cells via the lymphatics

Abstract

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.

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Figure 1: Expression analyses of VEGF, VEGF-C and VEGF-D in 293EBNA cells.
Figure 2: Expression of VEGF family members enhances tumor growth and angiogenesis.
Figure 3: Immunohistochemical staining of tumors with vascular markers.
Figure 4: Immunohistochemical analysis of tumors for LYVE-1 and PECAM-1.
Figure 5: Metastatic spread of VEGF-D-293 cells in SCID/NOD mice.

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Acknowledgements

We thank T. Helman and the staff of the animal house at the Ludwig Institute for Cancer Research for assistance with the SCID mice; A. Scott and C. Hall for advice on animal tumor models; B. Mann for discussions on dye injection; M. Smyth for discussions on mouse models; S. Squinto for supplying the pAPEX vector; and A. Burgess and M. Hibbs for critical reading of this manuscript. This work was funded in part by project grants from the National Health and Medical Research Council of Australia and the Anti-Cancer Council of Victoria. D. J. is supported by the UK Medical Research Council and by a project grant (00-311) from the Association for International Cancer Research.

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Correspondence to Steven A. Stacker.

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Stacker, S., Caesar, C., Baldwin, M. et al. VEGF-D promotes the metastatic spread of tumor cells via the lymphatics. Nat Med 7, 186–191 (2001). https://doi.org/10.1038/84635

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