9510

ADAMTS1

ADAM metallopeptidase with thrombospondin type 1 motif, 1;ADAMTS1;ADAM metallopeptidase with thrombospondin type 1 motif, 1

A disintegrin and metalloproteinase with thrombospondin motifs 1|ADAM-TS 1|ADAM-TS1|ADAMTS-1|METH-1|a disintegrin-like and metalloprotease (reprolysin type) with thrombospondin type 1 motif, 1|human metalloproteinase with thrombospondin type 1 motifs

21q21.2

protein-coding

metastasis is a sequential process that allows cells to move from the primary tumor and grow elsewhere. Because of their ability to cleave a variety of extracellular signaling and adhesion molecules, metalloproteases have been long considered key components of the metastatic program. However, the function of certain metalloproteases, such as ADAMTS1, is not clear and seems to depend on the cellular environment and/or the stage of tumor progression. To characterize the function of ADAMTS1, we performed two alternative proteomic approaches, difference gel electrophoresis and stable isotope labeling by amino acids in cell culture, to identify novel substrates of the metalloprotease. Both techniques showed that overexpression of ADAMTS1 leads to the release of semaphorin 3C from the extracellular matrix. Although semaphorins are well known regulators of axon guidance, accumulating evidence shows that they may also participate in tumor progression. Here, we show that the cleavage of semaphorin 3C induced by ADAMTS1 promotes the migration of breast cancer cells, indicating that the co-expression of these molecules in tumors may contribute to the metastatic program.

BACKGROUND: A disintegrin and metallopeptidase with thrombospondin motif type 1 (ADAMTS1) is a recently discovered metalloproteinase with antiangiogenic activity. The function of ADAMTS1 in gastric cancer remains unknown. Therefore, we were interested in examining ADAMTS1 expression in human gastric cancer, as well as its possible correlation with angiogenesis. METHODS: The mRNA and protein expression of ADAMTS1, thrombospondin type I (TSP1), and vascular endothelial growth factor (VEGF) was evaluated by RT-PCR and immunohistochemistry, respectively, in 56 paired tumor and normal tissue samples, and corresponding metastatic lymph nodes (n = 42). Microvessel density (MVD) was also evaluated by immunohistochemistry. RESULTS: ADAMTS1 mRNA and protein levels were significantly lower in primary tumors than in corresponding normal tissues, and were significantly higher in metastatic lymph nodes compared to their matched primary tumors. High ADAMTS1 mRNA and protein expression was found to be significantly associated with lymph node metastasis in primary tumors. There was a negative correlation between ADAMTS1 and VEGF mRNA and protein expression in primary gastric tumors and normal tissues. A negative correlation was also found between ADAMTS1 protein expression and MVD in primary gastric tumors. In contrast, no correlation was detected between ADAMTS1 and TSP1 mRNA and protein expression in primary gastric tumors, normal tissues, and metastatic lymph nodes. CONCLUSIONS: These findings suggest that ADAMTS1 expression is altered in primary gastric cancer and paired lymph node metastasis. In addition, ADAMTS1 has angioinhibitory effects in primary gastric cancer due to its low expression and negative correlation with VEGF and MVD. However, it appears to lose its anti-angiogenic activity in metastatic lymph nodes in gastric cancer.

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.

Bone metastasis is mediated by complex interactions between tumor cells and resident stromal cells in the bone microenvironment. The functions of metalloproteinases in organ-specific metastasis remain poorly defined despite their well-appreciated role in matrix degradation and tumor invasion. Here, we show a mechanism whereby two distinct metalloproteinases, a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS1) and matrix metalloproteinase-1 (MMP1), orchestrate a paracrine signaling cascade to modulate the bone microenvironment in favor of osteoclastogenesis and bone metastasis. Proteolytic release of membrane-bound epidermal growth factor (EGF)-like growth factors, including Amphiregulin (AREG), heparin-binding EGF (HB-EGF), and transforming growth factor alpha (TGFalpha) from tumor cells suppress the expression of osteoprotegerin (OPG) in osteoblasts and subsequently potentiate osteoclast differentiation. EGF receptor (EGFR) inhibitors block osteolytic bone metastasis by targeting EGFR signaling in bone stromal cells. Furthermore, elevated MMP1 and ADAMTS1 expression is associated with increased risk of bone metastasis in breast cancer patients. This study established MMP1 and ADAMTS1 in tumor cells, as well as EGFR signaling in osteoblasts, as promising therapeutic targets for inhibiting bone metastasis of breast cancer.