These authors contributed equally to this work.
Lamstatin – a novel inhibitor of lymphangiogenesis derived from collagen IV
Article first published online: 13 DEC 2012
© 2012 The Authors Journal of Cellular and Molecular Medicine © 2012 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd
Journal of Cellular and Molecular Medicine
Volume 16, Issue 12, pages 3062–3073, December 2012
How to Cite
Weckmann, M., Moir, L. M., Heckman, C. A., Black, J. L., Oliver, B. G. and Burgess, J. K. (2012), Lamstatin – a novel inhibitor of lymphangiogenesis derived from collagen IV. Journal of Cellular and Molecular Medicine, 16: 3062–3073. doi: 10.1111/j.1582-4934.2012.01648.x
- Issue published online: 13 DEC 2012
- Article first published online: 13 DEC 2012
- Accepted manuscript online: 21 SEP 2012 08:57AM EST
- Manuscript Accepted: 12 SEP 2012
- Manuscript Received: 29 MAR 2012
- type IV collagen alpha5 chain
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.