Open AccessHigher sensitivity of Adamts12-deficient mice to tumor growth and angiogenesis
Author(s) -
Mehdi El Hour,
Ángela Moncada-Pazos,
Silvia Blacher,
Anne Masset,
Santiago Cal,
Sarah Berndt,
Johann Detilleux,
Lorin Host,
Álvaro J. Obaya,
Catherine Maillard,
Jean–Michel Foidart,
Fabien Ectors,
Agnès Noël,
Carlos LópezOtín
Publication year - 2010
Publication title -
oncogene
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.395
H-Index - 342
eISSN - 1476-5594
pISSN - 0950-9232
DOI - 10.1038/onc.2010.49
Subject(s) - adamts , angiogenesis , biology , thrombospondin , neovascularization , matrix metalloproteinase , matrigel , metalloproteinase , disintegrin , cancer research , nude mouse , microbiology and biotechnology , in vivo , biochemistry , genetics
ADAMTS (a disintegrin and metalloproteinase domain with thrombospondin motifs) constitute a family of endopeptidases related to matrix metalloproteinases. These proteases have been largely implicated in tissue remodeling and angiogenesis associated with physiological and pathological processes. To elucidate the in vivo functions of ADAMTS-12, we have generated a knockout mouse strain (Adamts12(-/-)) in which Adamts12 gene was deleted. The mutant mice had normal gestations and no apparent defects in growth, life span and fertility. By applying three different in vivo models of angiogenesis (malignant keratinocyte transplantation, Matrigel plug and aortic ring assays) to Adamts12(-/-) mice, we provide evidence for a protective effect of this host enzyme toward angiogenesis and cancer progression. In the absence of Adamts-12, both the angiogenic response and tumor invasion into host tissue were increased. Complementing results were obtained by using medium conditioned by cells overexpressing human ADAMTS-12, which inhibited vessel outgrowth in the aortic ring assay. This angioinhibitory effect of ADAMTS-12 was independent of its enzymatic activity as a mutated inactive form of the enzyme was similarly efficient in inhibiting endothelial cell sprouting in the aortic ring assay than the wild-type form. Altogether, our results show that ADAMTS-12 displays antiangiogenic properties and protect the host toward tumor progression.