title: Tetrastatin, the NC1 domain of the α4(IV) collagen chain: a novel potent anti-tumor matrikine.
abstract: BACKGROUND
  NC1 domains from α1, α2, α3 and α6(IV) collagen chains were shown to exert anti-tumor or anti-angiogenic activities, whereas the NC1 domain of the α4(IV) chain did not show such activities so far.
  
  
  RESULTS
  We demonstrate in the present paper that the NC1 α4(IV) domain exerts a potent anti-tumor activity both in vitro and in an experimental human melanoma model in vivo. The overexpression of NC1 α4(IV) in human UACC-903 melanoma cells strongly inhibited their in vitro proliferative (-38%) and invasive (-52%) properties. MT1-MMP activation was largely decreased and its cellular distribution was modified, resulting in a loss of expression at the migration front associated with a loss of migratory phenotype. In an in vivo xenograft model in athymic nude mice, the subcutaneous injection of NC1 α4(IV)-overexpressing melanoma cells induced significantly smaller tumors (-80% tumor volume) than the Mock cells, due to a strong inhibition of tumor growth. Exogenously added recombinant human NC1 α4(IV) reproduced the inhibitory effects of NC1 α4(IV) overexpression in UACC-903 cells but not in dermal fibroblasts. An anti-αvβ3 integrin blocking antibody inhibited cell adhesion on recombinant human NC1 α4(IV) substratum. The involvement of αvβ3 integrin in mediating NC1 α4(IV) effect was confirmed by surface plasmon resonance (SPR) binding assays showing that recombinant human NC1 α4(IV) binds to αvβ3 integrin (K(D) = 148 ± 9.54 nM).
  
  
  CONCLUSIONS
  Collectively, our results demonstrate that the NC1 α4(IV) domain, named tetrastatin, is a new endogenous anti-tumor matrikine.
authors.affiliation: CNRS UMR 6237, Université de Reims Champagne-Ardenne, Reims, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Brassart-Pasco
authors.forename: Karine
authors.initials: K
authors.lastname: Sénéchal
authors.forename: Jessica
authors.initials: J
authors.lastname: Thevenard
authors.forename: Laurent
authors.initials: L
authors.lastname: Ramont
authors.forename: Jérome
authors.initials: J
authors.lastname: Devy
authors.forename: Ludivine
authors.initials: L
authors.lastname: Di Stefano
authors.forename: Aurélie
authors.initials: A
authors.lastname: Dupont-Deshorgue
authors.forename: Stéphane
authors.initials: S
authors.lastname: Brézillon
authors.forename: Jezabel
authors.initials: J
authors.lastname: Feru
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Jazeron
authors.forename: Marie-Danièle
authors.initials: MD
authors.lastname: Diebold
authors.forename: Sylvie
authors.initials: S
authors.lastname: Ricard-Blum
authors.forename: François-Xavier
authors.initials: FX
authors.lastname: Maquart
authors.forename: Jean Claude
authors.initials: JC
authors.lastname: Monboisse
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D024141:Collagen Type IV / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000276:immunology / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000378:metabolism; D008546:Melanoma, Experimental / Q000188:drug therapy*; D051379:Mice; D008819:Mice, Nude; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D020349:Surface Plasmon Resonance; D014183:Transplantation, Heterologous
chemical_list: D000906:Antibodies; D000970:Antineoplastic Agents; D024141:Collagen Type IV; D039302:Integrin alphaVbeta3; D011994:Recombinant Proteins; D020782:Matrix Metalloproteinases