title: Lamstatin--a novel inhibitor of lymphangiogenesis derived from collagen IV.
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.
authors.affiliation: Woolcock Institute of Medical Research, Glebe, NSW, Australia.
authors.forename: Markus
authors.initials: M
authors.lastname: Weckmann
authors.forename: Lyn Margaret
authors.initials: LM
authors.lastname: Moir
authors.forename: Caroline Akemi
authors.initials: CA
authors.lastname: Heckman
authors.forename: Judith Lee
authors.initials: JL
authors.lastname: Black
authors.forename: Brian Gregory
authors.initials: BG
authors.lastname: Oliver
authors.forename: Janette Kay
authors.initials: JK
authors.lastname: Burgess
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D024141:Collagen Type IV / Q000737:chemistry* / Q000494:pharmacology; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D042583:Lymphangiogenesis / Q000187:drug effects*; D018192:Lymphangioleiomyomatosis / Q000188:drug therapy* / Q000378:metabolism; D042601:Lymphatic Vessels; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology*; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D024141:Collagen Type IV; D010446:Peptide Fragments; D011994:Recombinant Proteins; C586238:lamstatin