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Research Articles: Therapeutics, Targets, and Development

The NC1 domain of type XIX collagen inhibits in vivo melanoma growth

¹ Laboratoire de Biochimie Médicale et Biologie Moléculaire Centre National de la Recherche Scientifique Unite Mixte de Recherche 6198 ² Laboratoire d'Anatomie Pathologie, Faculté de Medecine; and ³ Centre National de la Recherche Scientifique; Formation de Recherche en Evolution (FRE) 2715: Isolation, Structure, Transformation et Synthèse de Substance Naturelles, Institut Fédératif de Recherche 53 Biomolécules, Université de Reims Champagne-Ardenne, Reims, France

Requests for reprints: Laurent Ramont, Laboratoire de Biochimie Médicale et Biologie Moléculaire, Faculté de Medecine, Centre National de la Recherche Scientifique Unité Mixte de Recherche 6198, Institut Fédératif de Recherche 53 Biomolecules, Université de Reims Champagne-Ardenne, 51 rue Cognacq Jay, F-51095 Reims Cedex, France. Phone: 33-3-26-78-31-81; Fax: 33-3-26-78-85-39. E-mail: lramont{at}chu-reims.fr

Abstract

Type XIX collagen is a minor collagen that localizes to basement membrane zones, together with types IV, XV, and XVIII collagens. Because several NC1 COOH-terminal domains of other chains from basement membrane collagens were reported to exhibit antitumor activity, we decided to study the effects of the NC1(XIX) collagen domain on tumor progression using an experimental in vivo model of mouse melanoma. We observed a 70% reduction in tumor volume in NC1(XIX)-treated mice compared with the corresponding controls. Histologic examination of the tumors showed a strong decrease in tumor vascularization in treated mice. In vitro, NC1(XIX) inhibited the migrating capacity of tumor cells and their capacity to invade Matrigel. It also inhibited the capacity of human microvascular endothelial cells to form pseudotubes in Matrigel. This effect was accompanied by a strong inhibition of membrane type-1 matrix metalloproteinase (matrix metalloproteinase-14) and vascular endothelial growth factor expression. Collectively, our data indicate that the NC1 domain of type XIX collagen exerts antitumor activity. This effect is mediated by a strong inhibition of the invasive capacities of tumor cells and antiangiogenic effects. NC1(XIX) should now be considered as a new member of the basement membrane collagen-derived matrikine family with antitumor and antiangiogenic activity. [Mol Cancer Ther 2007;6(2):506–14]

Grant support: Université de Reims-Champagne-Ardenne, the Centre National de la Recherche Scientifique, the Ligue Nationale contre le Cancer (Comité de la Haute Marne), the Association pour la Recherche sur le Cancer, and the Canceropole Grand Est.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 4/14/06; revised 11/14/06; accepted 12/21/06.