Open AccessLamstatin – a novel inhibitor of lymphangiogenesis derived from collagen IV
Author(s) -
Weckmann Markus,
Moir Lyn Margaret,
Heckman Caroline Akemi,
Black Judith Lee,
Oliver Brian Gregory,
Burgess Janette Kay
Publication year - 2012
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/j.1582-4934.2012.01648.x
Subject(s) - lymphangioleiomyomatosis , lymphangiogenesis , lymphatic system , pathology , lymphatic endothelium , in vivo , cancer research , immunohistochemistry , metastasis , medicine , biology , tuberous sclerosis , cancer , microbiology and biotechnology
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 ( CP 17) and tested their effects in vitro and in vivo . Recombinant lamstatin and CP 17 inhibited proliferation, migration and cord formation of human microvascular lung lymphatic endothelial cells, in vitro . Furthermore, lamstatin and CP 17 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.