Get access

Lymphatic endothelium-specific hyaluronan receptor LYVE-1 is expressed by stabilin-1+, F4/80+, CD11b+ macrophages in malignant tumours and wound healing tissue in vivo and in bone marrow cultures in vitro: implications for the assessment of lymphangiogenesis

Authors

  • K Schledzewski,

    Corresponding author
    1. Department of Dermatology, Venerology, and Allergy, University Medical Centre Mannheim, Ruprecht-Karls University Heidelberg, Germany
    • Department of Dermatology, University Medical Centre Mannheim, University of Heidelberg, Theodor-Kutzer Ufer 1-3, 68167 Mannheim, Germany.
    Search for more papers by this author
    • These authors contributed equally to this work.

  • M Falkowski,

    1. Department of Dermatology, Venerology, and Allergy, University Medical Centre Mannheim, Ruprecht-Karls University Heidelberg, Germany
    Search for more papers by this author
    • These authors contributed equally to this work.

  • G Moldenhauer,

    1. Department of Molecular Immunology, Division of Tumour Immunology, German Cancer Research Centre, Heidelberg, Germany
    Search for more papers by this author
  • P Metharom,

    1. Department of Dermatology, Venerology, and Allergy, University Medical Centre Mannheim, Ruprecht-Karls University Heidelberg, Germany
    Search for more papers by this author
  • J Kzhyshkowska,

    1. Department of Dermatology, Venerology, and Allergy, University Medical Centre Mannheim, Ruprecht-Karls University Heidelberg, Germany
    Search for more papers by this author
  • R Ganss,

    1. Department of Molecular Immunology, Division of Tumour Immunology, German Cancer Research Centre, Heidelberg, Germany
    Search for more papers by this author
  • A Demory,

    1. Department of Dermatology, Venerology, and Allergy, University Medical Centre Mannheim, Ruprecht-Karls University Heidelberg, Germany
    Search for more papers by this author
  • B Falkowska-Hansen,

    1. Department of Dermatology, Venerology, and Allergy, University Medical Centre Mannheim, Ruprecht-Karls University Heidelberg, Germany
    Search for more papers by this author
  • H Kurzen,

    1. Department of Dermatology, Venerology, and Allergy, University Medical Centre Mannheim, Ruprecht-Karls University Heidelberg, Germany
    Search for more papers by this author
  • S Ugurel,

    1. Department of Dermatology, Venerology, and Allergy, University Medical Centre Mannheim, Ruprecht-Karls University Heidelberg, Germany
    Search for more papers by this author
  • G Geginat,

    1. Institute for Medical Microbiology and Hygiene, University Medical Centre Mannheim, Ruprecht-Karls University Heidelberg, Germany
    Search for more papers by this author
  • B Arnold,

    1. Department of Molecular Immunology, Division of Tumour Immunology, German Cancer Research Centre, Heidelberg, Germany
    Search for more papers by this author
  • S Goerdt

    1. Department of Dermatology, Venerology, and Allergy, University Medical Centre Mannheim, Ruprecht-Karls University Heidelberg, Germany
    Search for more papers by this author

Abstract

Lymphangiogenesis is a novel prognostic parameter for several cancers that is preferentially quantified by immunohistochemistry of the lymphatic endothelium-specific hyaluronan receptor LYVE-1. Recently, the specificity of LYVE-1 was challenged by serendipitous observations of LYVE-1 expression in rare tissue macrophages. As expression of the hyaluronan receptor-like molecule stabilin-1 is shared by sinusoidal endothelium and macrophages, a thorough analysis of LYVE-1 expression was performed using macrophage-specific markers in vivo and in vitro. In murine tumour models and excisional wound healing, LYVE-1 expression occurred in a subset of CD11b+, F4/80+ tissue macrophages that preferentially co-expressed stabilin-1. Upon comparison of single- and double-labelling immunofluorescence, it became apparent that LYVE-1+ macrophages mimic sprouting and collapsed lymphatic vessels. In vitro, LYVE-1 expression was induced in 25–40% of murine bone marrow-derived macrophages upon exposure to B16F1 melanoma-conditioned medium and IL-4/dexamethasone. By FACS analysis, 11.5% of bone marrow-derived macrophages were LYVE-1+, stabilin-1+ double-positive, while 9.9% were LYVE-1+, stabilin-1 and 33.5% were LYVE-1, stabilin-1+. Northern and western analyses confirmed expression of LYVE-1 mRNA and protein in bone marrow-derived macrophages. In the light of the current debate about true endothelial trans-differentiation versus endothelial mimicry of monocytes/macrophages, LYVE-1+, stabilin-1+ non-continuous endothelial-like macrophages will require further developmental and functional analyses. In conclusion, the findings imply that LYVE-1 staining must be supplemented by double labelling with macrophage markers in order to differentiate clearly between LYVE-1+ lymphatics and LYVE-1+ tumour-infiltrating macrophages. This improved approach will help to clarify the prognostic significance of lymphangiogenesis in malignant tumours. Copyright © 2006 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Ancillary