Abstract
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.
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Acknowledgements
The authors acknowledge F Olivier, G Roland and L Volders for their excellent technical assistance. This work was supported by grants from Ministerio de Ciencia e Innovación, Fundación M. Botin (Spain), the FP7-HEALTH-2007-A—Project No. 201279 ‘MICROENVIMET’, the Fonds de la Recherche Scientifique-FNRS (FRS-FNRS, Belgium), the Foundation against Cancer (foundation of public interest, Belgium), the DGTRE from the SPW (Région Wallonne, Belgium), the Interuniversity Attraction Poles Programme—Belgian Science Policy (Brussels, Belgium). MEH, AM, JD, LH and FE are recipients of grants from the Fonds de la Recherche Scientifique (FRS-FNRS, Belgium).
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El Hour, M., Moncada-Pazos, A., Blacher, S. et al. Higher sensitivity of Adamts12-deficient mice to tumor growth and angiogenesis. Oncogene 29, 3025–3032 (2010). https://doi.org/10.1038/onc.2010.49
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DOI: https://doi.org/10.1038/onc.2010.49
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