The ADAMTS12 metalloproteinase exhibits anti-tumorigenic properties through modulation of the Ras-dependent ERK signalling pathway

Citations Over TimeTop 10% of 2007 papers

Abstract

Members of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) family of proteolytic enzymes are implicated in a variety of physiological processes, such as collagen maturation, organogenesis, angiogenesis, reproduction and inflammation. Moreover, deficiency or overexpression of certain ADAMTS proteins is directly involved in serious human diseases, including cancer. However, the functional roles of other family members, such as ADAMTS12, remain unknown. Here, by using different in vitro and in vivo approaches, we have evaluated the possible role of ADAMTS12 in the development and progression of cancer. First, we show that expression of ADAMTS12 in Madin-Darby canine kidney (MDCK) cells prevents the tumorigenic effects of hepatocyte growth factor (HGF) by blocking the activation of the Ras-MAPK signalling pathway and that this regulation involves the thrombospondin domains of the metalloproteinase. We also show that addition of recombinant human ADAMTS12 to bovine aortic endothelial cells (BAE-1 cells) abolishes their ability to form tubules upon stimulation with vascular endothelial growth factor (VEGF). Additionally, tumours induced in immunodeficient SCID mice injected with A549 cells overexpressing ADAMTS12 show a remarkable growth deficiency in comparison with tumours formed in animals injected with parental A549 cells. Overall, our data suggest that ADAMTS12 confers tumour-protective functions upon cells that produce this proteolytic enzyme.

Related Papers

• → Emerging roles of ADAM and ADAMTS metalloproteinases in cancer(2007)264 cited
• → Advances in Matrix Metalloproteinases (MMPs), Membrane-Type MMPs, and a Disintegrin and Metalloproteinase and Their Roles in Cellular Interaction and Migration(2003)1 cited
• ADAMTS-2, a metalloproteinase containing a disintegrin domain and thrombospondin type I repeats, a new regulator of angiogenesis(2005)
• FRS-078 ADAMTS-1, A Disintegrin And Metalloprotease with ThromboSpondin motifs-1, Is a Novel Hypoxic Immediate Gene Expressed by Endothelial Cells(NO and Cardiovascular System (H) : FRS10)(Featured Research Session (English))(2004)
• Effect of ADAMTS-2, a metalloproteinase containing a disintegrin domain and thrombospondin type I repeats, during angiogenesis in vitro and in vivo(2004)