Higher sensitivity of Adamts12-deficient mice to tumor growth and angiogenesis

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 À/À 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.

ADAMTS-12 Metalloprotease Is Necessary for Normal Inflammatory Response

“…Furthermore, we know from previous studies that Adamts-12 is also implicated in angiogenesis, apoptosis of tumor cells and modification of the extracellular matrix (7,12,14). Therefore, albeit Adamts-12 is not essential for life, probably due to functional compensation by other ADAMTSs, the contribution of this enzyme to a variety of inflammatory processes highlights its relevance in the context of the large and growing complexity of proteolytic systems operating in life and disease.…”

“…Ϫ/Ϫ mice were generated and genotyped as described previously (14). Briefly, exons 6 and 7 were replaced by a neomycin-phosphoglycerate kinase cassette through homologous recombination, causing introduction of a frameshift.…”

“…Furthermore, ADAMTS12 is hypermethylated in tumors from different origins, and, at least in colorectal cancer, the epigenetic silencing occurring in tumor cells is compensated by its overexpression in myofibroblasts of the surrounding stroma (12,13). To try to elucidate the biological roles of this enzyme, we have recently established a mouse strain lacking Adamts12, which shows no obvious phenotype but exhibits significant differences in cancer susceptibility compared with control mice (14). Thus, Adamts12-deficient mice are more susceptible to cancer development, displaying increased angiogenesis and tumor invasion.…”

Bone marrow-derived mesenchymal cells and MMP13 contribute to experimental choroidal neovascularization

“…For measurement of vessel coverage with pericytes, automatic computer-assisted image analysis was performed in image of lesions obtained after double immunostaining for CD31 and NG2. The ratio between the surface of CD31 staining and NG2 staining was measured by using Aphelio 3.2 software (Asis, France) [34].…”

ADAMTS12 Depletion by Insulin in OUMS-27 Human Chondrosarcoma Cells

“…[7][8][9] ADAMTS12 was shown to be associated with arthritis, 10 intervertebral disc degeneration, 11,12 inflammation, 13,14 tumor invasion, and metastasis. [15][16][17] Also, high levels of ADAMTS12 messenger ribonucleic acid (mRNA) were detected in osteoarthritis and rheumatoid arthritis. 18,19 On the other hand, role of ADAMTS12 in articular cartilage, and regulation and biochemistry of ADAMTS12 at gene level have not been clearly demonstrated.…”