ADAMTS-2 functions as anti-angiogenic and anti-tumoral molecule independently of its catalytic activity

Abstract

ADAMTS-2 is a metalloproteinase that plays a key role in the processing of fibrillar procollagen precursors into mature collagen molecules by excising the amino-propeptide. We demonstrate that recombinant ADAMTS-2 is also able to reduce proliferation of endothelial cells, and to induce their retraction and detachment from the substrate resulting in apoptosis. Dephosphorylation of Erk1/2 and MLC largely precedes the ADAMTS-2 induced morphological alterations. In 3-D culture models, ADAMTS-2 strongly reduced branching of capillarylike structures formed by endothelial cells and their long-term maintenance and inhibited vessels formation in embryoid bodies (EB). Growth and vascularization of tumors formed in nude mice by HEK 293-EBNA cells expressing ADAMTS-2 were drastically reduced. A similar anti-tumoral activity was observed when using cells expressing recombinant deleted forms of ADAMTS-2, including catalytically inactive enzyme. Nucleolin, a nuclear protein also found to be associated with the cell membrane, was identified as a potential receptor mediating the antiangiogenic properties of ADAMTS-2.

New and Paradoxical Roles of Matrix Metalloproteinases in the Tumor Microenvironment

“…The related ADAMTS family contains 19 human metalloproteinases with a variable number of type-1 thrombospondin (TSP-1) domains in their C-terminal region. ADAMTSs are now viewed as key regulators of collagen maturation (ADAMTS-2, -3, and -14; Colige et al, 2005; Dubail et al, 2010), cartilage degradation (ADAMTS-1, -4, -5, -8, and -9), microfibril biogenesis (Hubmacher and Apte, 2011), von Willebrand factor maturation (ADAMTS-13), reproduction (ADAMTS-9, -20; Llamazares et al, 2007), and cancer progression (Handsley and Edwards, 2005; Rocks et al, 2008). …”

“…The N-terminal non-collagenous domain of these fibrillar collagens is proteolytically removed by ADAMTS-2 (Dubail et al, 2010). Interstitial collagenases are the only known mammalian enzymes able to degrade triple-helical fibrillar collagens through specific cleavage of all three α-chains at a single locus three-quarters from the N-terminus.…”

The Role of Stromal Myofibroblast and Extracellular Matrix in Tumor Angiogenesis

“…45 So far, only 6 ADAMTSs (ADAMTS-1, -2, -8, -9, -12, -15) are known to affect angiogenesis, and all of them appear to exert anti-angiogenic effects. [46][47][48][49] This is attributed, in part, to their TSP domains, which may directly interact with Tumor angiogenesis is also regulated by the ECM architecture. ECM stiffness, density, and patterning have been implicated in modulating endothelial cell survival, sprouting, and migration.…”

Modelling Lymphatic and Blood Capillary Patterning

“…BECs or LECs derived from human or mouse ES cells can be cultured in a matrix as 3D-structures called embryoid bodies 12,37,38,80 . These spheroids are useful to study cell migration, proliferation and lumen formation.…”