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Chemokine-mediated migration of melanoma cells towards lymphatics – a mechanism contributing to metastasis

Oncogene volume 26, pages 2997–3005 (2007)Cite this article

Abstract

The mechanisms that cause tumors such as melanomas to metastasize into peripheral lymphatic capillaries are poorly defined. Non-mutually-exclusive mechanisms are lymphatic endothelial cell (LEC) chemotaxis and proliferation in response to tumor cells (chemotaxis-lymphangiogenesis hypothesis) or LECs may secrete chemotactic agents that attract cancer cells (chemotactic metastasis hypothesis). Using migration assays, we found evidence supporting both hypotheses. Conditioned medium (CM) from metastatic malignant melanoma (MMM) cell lines attracted LEC migration, consistent with the lymphangiogenesis hypothesis. Conversely, CM from mixed endothelial cells or LECs, but not blood endothelial cells, attracted MMM cells but not non-metastatic melanoma cells, consistent with the chemotactic metastasis hypothesis. MMM cell lines expressed CCR7 receptors for the lymphatic chemokine CCL21 and CCL21 neutralizing antibodies prevented MMM chemotaxis in vitro. To test for chemotactic metastasis in vivo tumor cells were xenotransplanted into nude mice ∼1 cm from an injected LEC depot. Two different MMM grew directionally towards the LECs, whereas non-metastatic melanomas did not. These observations support the hypothesis that MMM cells grow towards regions of high LEC density owing to chemotactic LEC secretions, including CCL21. This chemotactic metastasis may contribute to the close association between metastasizing tumor cells and peri-tumor lymphatic density and promote lymphatic invasion.

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Acknowledgements

We acknowledge the kind gift of VEGF-C from Kari Alitalo, the LYVE-1 antibody from David Jackson, A375P cells from IJ Fidler, some LEC cells from Carolyn Yong and Melody Swartz and the technical help of Mr Sam Baldwin. This research was supported by the Wellcome Trust (66011 and 62951), the British Heart Foundation (BB2000003), the Skin Cancer Research Fund (ScaRF), the Luff Fund and the Healing Foundation.

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Author notes

  1. J D Shields, M S Emmett and D B A Dunn: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Physiology, Microvascular Research Laboratories, University of Bristol, Bristol, UK

    J D Shields, M S Emmett, D B A Dunn, K D Joory, L M Sage & D O Bates

  2. Department of Pathology, Frenchay Hospital, Bristol, UK

    H Rigby

  3. Department of Cardiac and Vascular Sciences, Dermatology Unit, St George's Hospital Medical School, London, UK

    P S Mortimer

  4. Department of Plastic Surgery, Frenchay Hospital, Bristol, UK

    A Orlando

  5. Department of Physiology, St George's Hospital Medical School, London, UK

    J R Levick

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  1. J D Shields
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  2. M S Emmett
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  4. K D Joory
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  5. L M Sage
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  7. P S Mortimer
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  8. A Orlando
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  9. J R Levick
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  10. D O Bates
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Correspondence to D O Bates.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Shields, J., Emmett, M., Dunn, D. et al. Chemokine-mediated migration of melanoma cells towards lymphatics – a mechanism contributing to metastasis. Oncogene 26, 2997–3005 (2007). https://doi.org/10.1038/sj.onc.1210114

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