The ADAMTS
proteinases are a family of secreted, matrix-associated
enzymes that have diverse roles in the regulation of tissue organization and vascular homeostasis. Several of the 19 human family members have been identified as having either
tumor promoting or suppressing roles. We previously demonstrated that decreased ADAMTS15 expression correlated with a worse clinical outcome in mammary
carcinoma (e.g., Porter et al., Int J
Cancer 2006;118:1241-7). We have explored the effects of A
Disintegrin and
Metalloproteinase with
Thrombospondin motifs-15 (ADAMTS-15) on the behavior of MDA-MB-231 and MCF-7
breast cancer cells by stable expression of either a wild-type (wt) or
metalloproteinase-inactive (E362A)
protein. No effects on
mammary cancer cell proliferation or apoptosis were observed for either form of ADAMTS-15. However, both forms reduced cell migration on
fibronectin or
laminin matrices, though motility on a
Type I collagen matrix was unimpaired. Knockdown of
syndecan-4 attenuated the inhibitory effects of ADAMTS-15 on cell migration. In contrast to its effects on cell migration, wt ADAMTS-15 but not the E362A inactive mutant inhibited endothelial tubulogenesis in 3D
collagen gels and angiogenesis in the aortic ring assay. In experimental
metastasis assays in nude mice, MDA-MB-231 cells expressing either form of ADAMTS-15 showed reduced spread to the liver, though lung colonization was enhanced for cells expressing wt ADAMTS-15. These studies indicate that extracellular ADAMTS-15 has multiple actions on
tumor pathophysiology. Via modulation of cell-ECM interactions, which likely involve
syndecan-4, it attenuates
mammary cancer cell migration independent of its
metalloproteinase activity; however, its antiangiogenic action requires catalytic functionality, and its effects on
metastasis in vivo are tissue niche-dependent.