Contribution of ADAMTS1 as a tumor suppressor gene in human breast carcinoma. Linking its tumor inhibitory properties to its proteolytic activity on nidogen‐1 and nidogen‐2

Abstract

The extracellular protease ADAMTS1 (A disintegrin and metalloprotease with thrombospondin repeats 1) has been described as an anti-angiogenic molecule and its role as a putative tumor protective molecule has also been suggested. Here, we have used a tumor xenograft model to determine the role of ADAMTS1 in tumor growth and angiogenesis. Increasing levels of the protease led to the complete inhibition of tumor growth. In an attempt to elucidate the mechanism of action of this protease, we focused our attention on its proteolytic activity on nidogens, one of the main components of the vascular basement membrane. The increased expression of ADAMTS1 was accompanied by increased proteolysis of nidogen-1 and -2 and their almost complete removal from vascular structures, together with major morphological alterations of tumor blood vessels and a decreased vessel density. The clinical relevance of this work is supported by our observations that ADAMTS1 expression is decreased in breast tumor specimens when compared with healthy tissue. Our studies also reveal that the cleavage of nidogen-1 and -2 is partially inhibited in human tumor samples. Moreover, the deposition of both nidogens surrounding vascular structures is drastically altered, implying a possible reduction in the maintenance of vessel integrity. Our studies reflect the requirement to explore the functional interactions between proteases and specific substrates in cancer biology.

Nidogen-1 is a novel extracellular ligand for the NKp44 activating receptor

“…On the other hand, NID1 may be modified in the ECM by the action of extracellular proteases, such as Cat-S and ADAMTS1 (A Disintegrin and Metalloproteinase with ThromboSpondin motifs). 70 In addition, NID1 can interact with different BM/ECM proteins including laminin, collagen type IV, and perlecan. 57,58 Thus, it is possible that the tissue microenvironment and the molecular context may further influence the functional outcome of the NID1-NKp44 interaction.…”

Stroma-derived but not tumor ADAMTS1 is a main driver of tumor growth and metastasis

“…Importantly, ADAMTS1 was found to be relevant during endothelial cell sprouting in collagen invasion assays [15], and its expression is induced in endothelial cells under hypoxic conditions and VEGF-treatment [16, 17]. The specific influence of stromal ADAMTS1 has been suggested in some studies of breast cancer [4, 18, 19], and the use of the ADAMTS1 knockout mice, in combination with a spontaneous model of mammary carcinogenesis, revealed its participation in tumor growth and metastasis [7]. …”

Downregulation of A disintegrin and metallopeptidase with thrombospondin motif type 1 by DNA hypermethylation in human gastric cancer

“…ADAMTS1 also cleaves large TSP1, and cleaved TSP-1 demonstrates anti-angiogenic activity (26). Several studies have also demonstrated that ADAMTS1 is downregulated in breast cancer, prostate cancer, lung cancer, pancreatic cancer and colorectal cancer (18–20,25,27,28). These findings are in accordance with our previous study, in which the expression of ADAMTS1 was frequently reduced in primary gastric cancer (22).…”

“…ADAMTS1 inhibits angiogenesis through binding to vascular endothelial growth factor (VEGF) 165 and inhibiting VEGF-A165-stimulated phosphorylation of VEGFR-2 (17). In addition, it has decreased expression levels in a number of types of cancer (8,18–20), however, the underlying mechanism remains to be elucidated.…”