Full-length ADAMTS-1 and the ADAMTS-1 fragments display pro- and antimetastatic activity, respectively

Abstract

The exact role of a disintegrin and metalloproteinase with thrombospondin motifs-1 (ADAMTS-1) and the underlying mechanism of its involvement in tumor metastasis have not been established. We have now demonstrated that overexpression of ADAMTS-1 promotes pulmonary metastasis of TA3 mammary carcinoma and Lewis lung carcinoma cells and that a proteinase-dead mutant of ADAMTS-1 (ADAMTS-1E/Q) inhibits their metastasis, indicating that the prometastatic activity of ADAMTS-1 requires its metalloproteinase activity. Overexpression of ADAMTS-1 in these cells promoted tumor angiogenesis and invasion, shedding of the transmembrane precursors of heparin-binding epidermal growth factor (EGF) and amphiregulin (AR), and activation of the EGF receptor and ErbB-2, while overexpression of ADAMTS-1E/Q inhibited these events. Furthermore, we found that ADAMTS-1 undergoes auto-proteolytic cleavage to generate the NH 2 -and COOH-terminal cleavage fragments containing at least one thrombospondin-type-I-like motif and that overexpression of the NH 2 -terminal ADAMTS-1 fragment and the COOH-terminal ADAMTS-1 fragment can inhibit pulmonary tumor metastasis. These fragments also inhibited Erk1/2 kinase activation induced by soluble heparin-binding EGF and AR. Taken together, our results suggest that the proteolytic status of ADAMTS-1 determines its effect on tumor metastasis, and that the ADAMTS-1E/Q and the ADAMTS-1 fragments likely inhibit tumor metastasis by negatively regulating the availability and activity of soluble heparin-binding EGF and AR.

The ADAMTS1 Protease Gene Is Required for Mammary Tumor Growth and Metastasis

“…19 This activity was dependent on protease activity of ADAMTS1, which also mediated activation of the cell surface EGF-like ligands amphiregulin and heparin binding-EGF. A similar mechanism was demonstrated by overexpression of both MMP1 and ADAMTS1 proteases in weakly metastatic MDA-MB231 breast cancer sublines, resulting in augmented paracrine release of EGF-like ligands and enhanced bone metastasis.…”

“…17 Overexpression of full-length ADAMTS1 in Chinese hamster ovary (CHO) cells enhanced growth of tumor xenografts in nude mice, 18 and overexpression of active ADAMTS1 promoted pulmonary metastasis of murine mammary carcinoma (TA3) and Lewis lung carcinoma cells, but catalytically inactive mutant ADAMTS1 prevented metastasis. 19 Thus, the protease action of ADAMTS1 is predicted to participate in the ECM remodeling that promotes metastasis.…”

Emerging roles of ADAM and ADAMTS metalloproteinases in cancer

“…Dysregulation of ADAM and ADAMTS expression has been reported in different types of cancer by RT-PCR profiling and microarray analysis [64][65][66][67]. The picture is rendered complex by the existence of different isoforms resulting from alternative splicing described in ADAM-8, -9, -10, -11, -12, -15, -19, -22, -28, -29, -30 and -33 or ADAMTS-4 and TS-6 genes [36,50,51,[68][69][70][71][72][73][74][75][76][77] or from putative post-translational modulations [23] resulting from a processing of the molecule by the metalloproteinase domain itself [78] or by other MMPs [79].…”

“…Among those, it is worth noting that ADAMTS-1 comprises TSP-1 repeats which may contribute to the antiangiogenic activity by trapping vascular endothelial growth factor (VEGF) 165 [100,102]. Taking these data together, ADAMTS-1 C-terminal domain should be considered as an anti-tumour and anti-metastatic region [78,103]. The ADAMTS-1 story will probably mature in the next few years since some authors have also shown that overexpression of full-length ADAMTS-1 in CHO cells enhances tumour growth [103] and promotes pulmonary metastasis of TA3 mammary carcinoma or Lewis lung cells [78].…”

“…Taking these data together, ADAMTS-1 C-terminal domain should be considered as an anti-tumour and anti-metastatic region [78,103]. The ADAMTS-1 story will probably mature in the next few years since some authors have also shown that overexpression of full-length ADAMTS-1 in CHO cells enhances tumour growth [103] and promotes pulmonary metastasis of TA3 mammary carcinoma or Lewis lung cells [78]. One possible approach to rationalize the apparently contradictory information on ADAMTS-1 is to consider that this molecule undergoes auto-proteolytic cleavage that can account for pro-or anti-metastatic effects depending on the cleavage site [78].…”