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Induction of tumor lymphangiogenesis by VEGF-C promotes breast cancer metastasis

Abstract

Metastasis of breast cancer occurs primarily through the lymphatic system, and the extent of lymph node involvement is a key prognostic factor for the disease. Whereas the significance of angiogenesis for tumor progression has been well documented, the ability of tumor cells to induce the growth of lymphatic vessels (lymphangiogenesis) and the presence of intratumoral lymphatic vessels have been controversial. Using a novel marker for lymphatic endothelium, LYVE-1, we demonstrate here the occurrence of intratumoral lymphangiogenesis within human breast cancers after orthotopic transplantation onto nude mice. Vascular endothelial growth factor (VEGF)-C overexpression in breast cancer cells potently increased intratumoral lymphangiogenesis, resulting in significantly enhanced metastasis to regional lymph nodes and to lungs. The degree of tumor lymphangiogenesis was highly correlated with the extent of lymph node and lung metastases. These results establish the occurrence and biological significance of intratumoral lymphangiogenesis in breast cancer and identify VEGF-C as a molecular link between tumor lymphangiogenesis and metastasis.

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Figure 1: Overexpression of VEGF-C in MDA-MB-435/GFP cells.
Figure 2: Intratumoral lymphangiogenesis in control and VEGF-C–overexpressing MDA-MB-435/GFP tumors.
Figure 3: Specific expression of LYVE-1 in lymphatic vessels of normal mouse skin (upper panel) and tumors (lower panel).
Figure 4: VEGF-C overexpression induces intratumoral lymphangiogenesis.
Figure 5: VEGF-C increases the incidence of lymph node metastases.
Figure 6: Overexpression of VEGF-C in breast cancer cells resulted in increased lung metastases.

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Acknowledgements

We thank R. Timpl for the anti-collagen XVIII antibody; M. Swartz and V. Joukov for helpful discussions; and H. Oura for technical assistance. This work was supported by the Human Frontier Science Program (to M.S.), Deutsche Forschungsgemeinschaft (to T.H.), by NIH/NCI grants CA69184 and CA86410 (to M.D.) and by the Cutaneous Biology Research Center through the Massachusetts General Hospital/Shiseido Co. Ltd. Agreement (to M.D.). 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 Michael Detmar.

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Skobe, M., Hawighorst, T., Jackson, D. et al. Induction of tumor lymphangiogenesis by VEGF-C promotes breast cancer metastasis. Nat Med 7, 192–198 (2001). https://doi.org/10.1038/84643

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