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Inhibition of VEGFR-3 activation in tumor-draining lymph nodes suppresses the outgrowth of lymph node metastases in the MT-450 syngeneic rat breast cancer model

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Abstract

For many types of human cancer, the expression of vascular endothelial growth factor-C (VEGF-C) correlates with enhanced tumor-associated lymphatic vessel density, metastasis formation and poor prognosis. In experimental animals, VEGF-C produced by primary tumors can induce lymphangiogenesis within and/or at the periphery of the tumor, and promotes metastasis formation. Tumor-induced lymphangiogenesis is therefore thought to expedite entry of tumor cells into the lymphatic vasculature and their trafficking to regional lymph nodes, thereby fostering metastatic dissemination. Tumour-produced VEGF-C can also drain to the regional lymph nodes and induce lymphangiogenesis there. Whether this activity promotes metastasis formation remains unclear. To address this issue we manipulated VEGF-C activity and VEGFR-3 activation in the lymph nodes draining syngeneic rat breast cancers using intra-dermal delivery of either recombinant VEGF-C or VEGFR-3 blocking antibodies to induce or suppress lymph node lymphangiogenesis, respectively. Recombinant VEGF-C induced lymph node lymphangiogenesis, but was not sufficient to promote metastasis formation by poorly metastatic NM-081 breast tumours. Conversely, inhibition of lymph node lymphangiogeneis induced by highly metastatic MT-450 breast tumours suppressed the outgrowth of lymph node metastases, but not the initial colonization of the lymph nodes. Lung metastasis was also not affected. We conclude that tumor-derived VEGF-C draining to regional lymph nodes promotes the outgrowth of lymph node metastases. VEGF-C may induce lung metastasis independently of its effects on lymph node metastasis.

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Acknowledgments

We gratefully acknowledge the expert technical assistance of Gitta Flaig, Diana Plaumann, Annette Gruber, Sabine Müller and Selma Huber. Melanie Rothley provided excellent support with VEGF-C ∆N∆C and VEGF-C ∆N∆C Cys production, and Anna Poletti critically read the manuscript. This work was supported by grants to JPS from the European Union (FP7 Collaborative Project TuMIC, Contract No. HEALTH-F2-2008-201662), and from the Deutsche Forschungsgemeinschaft under the auspices of Schwerpunktprogramm 1190 (Tumor-vessel interface). LQ gratefully acknowledges receipt of a Heidelberg University Dissertation Grant. JPS is the “Franz-Volhard-Stipftungsprofessur für Mikrovaskuläre Biologie und Pathobiologie” funded by the Klinikum Mannheim gGmbH.

Conflict of interest

BP is employed by ImClone Systems, and AH and RP are employed by Becton–Dickinson, whose products were used in this study. JPS has performed contract research for Eli Lilly. LQ, NC and WT and have no conflict of interest to declare.

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Authors and Affiliations

  1. Centre for Biomedicine and Medical Technology Mannheim (CBTM), Medizinische Fakultät Mannheim, Universitätsmedizin Mannheim, Universität Heidelberg, TRIDOMUS-Gebäude Haus C, Ludolf-Krehl-Str. 13-17, 68167, Mannheim, Germany

    Luca Quagliata, Natascha Cremers, Wilko Thiele & Jonathan P. Sleeman

  2. Institut für Toxikologie und Genetik, KIT, Campus Nord, Postfach 3640, 76021, Karlsruhe, Germany

    Sandra Klusmeier, Wilko Thiele & Jonathan P. Sleeman

  3. ImClone Systems, Eli Lilly and Company, 450 East 29th Street, New York, NY, 10016, USA

    Bronislaw Pytowski

  4. BD Technologies, PO Box 12016, 21 Davis Dr, Research Triangle Park, Durham, NC, 27709, USA

    Alfred Harvey & Ronald J. Pettis

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  1. Luca Quagliata
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  2. Sandra Klusmeier
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Correspondence to Jonathan P. Sleeman.

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Quagliata, L., Klusmeier, S., Cremers, N. et al. Inhibition of VEGFR-3 activation in tumor-draining lymph nodes suppresses the outgrowth of lymph node metastases in the MT-450 syngeneic rat breast cancer model. Clin Exp Metastasis 31, 351–365 (2014). https://doi.org/10.1007/s10585-013-9633-2

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  • DOI: https://doi.org/10.1007/s10585-013-9633-2

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