• Open Access

Lamstatin – a novel inhibitor of lymphangiogenesis derived from collagen IV

Authors

  • Markus Weckmann,

    1. Woolcock Institute of Medical Research, Glebe, NSW, Australia
    2. Cooperative Research Centre for Asthma and Airways, Glebe, NSW, Australia
    3. Discipline of Pharmacology, University of Sydney, NSW, Australia
    4. Bosch Institute, Sydney, NSW, Australia
    Current affiliation:
    1. Pediatric Pneumology & Allergology, Department of Pediatric Medicine, University Medical Center Schleswig-Holstein, Campus Centrum Lübeck, Airway Research Center North (ARCN), Member of the German Center for Lung Research, Lübeck, Germany
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  • Lyn Margaret Moir,

    1. Woolcock Institute of Medical Research, Glebe, NSW, Australia
    2. Cooperative Research Centre for Asthma and Airways, Glebe, NSW, Australia
    3. Discipline of Pharmacology, University of Sydney, NSW, Australia
    4. Bosch Institute, Sydney, NSW, Australia
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  • Caroline Akemi Heckman,

    1. FIMM - Institute for Molecular Medicine Finland, University of Helsinki, Finland
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  • Judith Lee Black,

    1. Woolcock Institute of Medical Research, Glebe, NSW, Australia
    2. Cooperative Research Centre for Asthma and Airways, Glebe, NSW, Australia
    3. Discipline of Pharmacology, University of Sydney, NSW, Australia
    4. Bosch Institute, Sydney, NSW, Australia
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  • Brian Gregory Oliver,

    1. Woolcock Institute of Medical Research, Glebe, NSW, Australia
    2. Cooperative Research Centre for Asthma and Airways, Glebe, NSW, Australia
    3. Discipline of Pharmacology, University of Sydney, NSW, Australia
    4. Bosch Institute, Sydney, NSW, Australia
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    • These authors contributed equally to this work.
  • Janette Kay Burgess

    Corresponding author
    1. Cooperative Research Centre for Asthma and Airways, Glebe, NSW, Australia
    2. Discipline of Pharmacology, University of Sydney, NSW, Australia
    3. Bosch Institute, Sydney, NSW, Australia
    • Woolcock Institute of Medical Research, Glebe, NSW, Australia
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    • These authors contributed equally to this work.

Correspondence to: Assoc Prof Janette BURGESS, Cell Biology Group, Woolcock Institute of Medical Research, University of Sydney, PO Box M77, Missenden Road, Camperdown, NSW 2050, Australia.

Tel.: +61-2-9114-0368

Fax: +61-2-9114-0399

E-mail: janette.burgess@sydney.edu.au

Abstract

The lymphatic system is essential for the maintenance of tissue homeostasis and immunity. Its dysfunction in disease (such as lymphangioleiomyomatosis) can lead to chylous effusions, oedema or dissemination of malignant cells. Collagen IV has six α chains, of which some of the non-collagenous-1 domains have endogenous anti-angiogenic properties, however, little is known about specific endogenous anti-lymphangiogenic characteristics. In this study we sought to investigate the expression levels of collagen IV non-collagenous-1 domains in lung tissue of patients with and without lymphangioleiomyomatosis to explore the hypothesis that a member of the collagen IV family, specifically the non-collagenous domain-1 of α5, which we named lamstatin, has anti-lymphangiogenic properties. Levels of lamstatin detected by immunohistochemistry were decreased in lungs of lymphangioleiomyomatosis patients. We produced recombinant lamstatin in an E.coli expression system and synthesized a 17-amino acid peptide from a theoretically identified, active region (CP17) and tested their effects in vitro and in vivo. Recombinant lamstatin and CP17 inhibited proliferation, migration and cord formation of human microvascular lung lymphatic endothelial cells, in vitro. Furthermore, lamstatin and CP17 decreased complexity and dysplasia of the tumour-associated lymphatic network in a lung adenocarcinoma xenograft mouse model. In this study we identified a novel, direct inhibitor of lymphangiogenesis, derived from collagen IV. This may prove useful for exploring new avenues of treatment for lymphangioleiomyomatosis and metastasis via the lymphatic system in general.

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