title: Contribution of ADAMTS1 as a tumor suppressor gene in human breast carcinoma. Linking its tumor inhibitory properties to its proteolytic activity on nidogen-1 and nidogen-2.
abstract: The extracellular protease ADAMTS1 (A disintegrin and metalloprotease with thrombospondin repeats 1) has been described as an anti-angiogenic molecule and its role as a putative tumor protective molecule has also been suggested. Here, we have used a tumor xenograft model to determine the role of ADAMTS1 in tumor growth and angiogenesis. Increasing levels of the protease led to the complete inhibition of tumor growth. In an attempt to elucidate the mechanism of action of this protease, we focused our attention on its proteolytic activity on nidogens, one of the main components of the vascular basement membrane. The increased expression of ADAMTS1 was accompanied by increased proteolysis of nidogen-1 and -2 and their almost complete removal from vascular structures, together with major morphological alterations of tumor blood vessels and a decreased vessel density. The clinical relevance of this work is supported by our observations that ADAMTS1 expression is decreased in breast tumor specimens when compared with healthy tissue. Our studies also reveal that the cleavage of nidogen-1 and -2 is partially inhibited in human tumor samples. Moreover, the deposition of both nidogens surrounding vascular structures is drastically altered, implying a possible reduction in the maintenance of vessel integrity. Our studies reflect the requirement to explore the functional interactions between proteases and specific substrates in cancer biology.
authors.affiliation: GENYO, Centre for Genomics and Oncological Research: Pfizer/Universidad de Granada/Junta de Andalucía, Granada, Spain.
authors.forename: Estefanía
authors.initials: E
authors.lastname: Martino-Echarri
authors.forename: Rubén
authors.initials: R
authors.lastname: Fernández-Rodríguez
authors.forename: Francisco Javier
authors.initials: FJ
authors.lastname: Rodríguez-Baena
authors.forename: Antonio
authors.initials: A
authors.lastname: Barrientos-Durán
authors.forename: Antoni X
authors.initials: AX
authors.lastname: Torres-Collado
authors.forename: María del Carmen
authors.initials: Mdel C
authors.lastname: Plaza-Calonge
authors.forename: Suyapa
authors.initials: S
authors.lastname: Amador-Cubero
authors.forename: Javier
authors.initials: J
authors.lastname: Cortés
authors.forename: Louise E
authors.initials: LE
authors.lastname: Reynolds
authors.forename: Kairbaan M
authors.initials: KM
authors.lastname: Hodivala-Dilke
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Rodríguez-Manzaneque
mesh_terms: D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism*; D000071097:ADAMTS1 Protein; D000818:Animals; D001485:Basement Membrane / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000098:blood supply / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002135:Calcium-Binding Proteins; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D015536:Down-Regulation; D016147:Genes, Tumor Suppressor; D006025:Glycosaminoglycans / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D057809:HEK293 Cells; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010447:Peptide Hydrolases / Q000378:metabolism*; D059748:Proteolysis; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D002135:Calcium-Binding Proteins; D015815:Cell Adhesion Molecules; D006025:Glycosaminoglycans; D008562:Membrane Glycoproteins; C114729:NID2 protein, human; D025521:Tumor Suppressor Proteins; C029967:nidogen; C007858:glucuronyl glucosamine glycan sulfate; D010447:Peptide Hydrolases; D051722:ADAM Proteins; D000071097:ADAMTS1 Protein; C103859:ADAMTS1 protein, human
keywords: ADAMTS; breast carcinoma; extracellular proteolysis; nidogens; vascular basement membrane