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

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]

MMP generated matrikines

“…Matrikines are involved in the process of extracellular matrix renewal and cellular proliferation. Currently, intact proteins including elastin 1 , extracellular matrix collagen 2 , osteopontin 3 , tenascin, laminin, decorin, thrombospondin, integrin, versican 4 , type XIX collagen 5 , biotinylated peptide 6 , mactinin 7 , tetrastatin 8 , and lumican 9 have been identified as the sources of matrikines.…”

“…Inhibition of matrikine signaling has been implicated in halting tumor growth 5 . Matrikine activity is dictated via differing regulatory mechanisms.…”

Collagen-derived matricryptins promote inhibitory nerve terminal formation in the developing neocortex

“…a bioactive molecule that exhibits functions distinct from those of the full-length matrix molecule from which it was released (Ramont et al, 2007). Outside of the nervous system, matricryptins influence many aspects of cell behavior (Kalluri, 2003).…”

Inhibition of Elastin Peptide-Mediated Angiogenic Signaling Mechanism(s) in Choroidal Endothelial Cells by the α6(IV)NC1 Collagen Fragment

“…A similar effect of decrease in MT1-MMP expression levels was reported previously in human microvascular endothelial cells-1 (HMEC-1) subjected to NC1 domain derived from collagen XIX. 37 Regulation of angiogenic responses in ECs by NC1 domains of type IV collagen and EDPs are facilitated through the binding of these angiogenic regulators to the cell surface receptors. 17,21,28,[38][39][40] Such binding leads to integrin receptor activation and downstream kinase activation promoting EC migration.…”