Cleavage Of Extracellular Matrix Molecules: A Role For Adam8 In Tumour Cell Invasion

Processing of extracellular matrix (ECM) components is attributed mainly to zinc‐dependent proteases such as MMPs, as they are associated with invasive behavior of tumor cells. Interestingly, ADAM8, a member of the membrane‐bound zinc‐dependent family of ADAM proteases, seems to adapt an invasive phenotype when overexpressed and has been described in highly invasive cancer pathologies. It is also involved in conditions such as allergy, asthma and neurodegeneration. We postulate that cellular processing of ADAM8 eventually leads to ‘MMP‐like’ activity which could modulate the tumor microenvironment. We investigate the mechanism by which ADAM8 contributes to cancer cell invasion. We identified a soluble form of murine ADAM8 released from transfected cells by proteolytic processing, which cleaves CD23 fluorescence peptide suggesting proteolytic activity. In vitro assay shows that recombinant soluble human ADAM8 cleave fibronectin, collagen IV and collagen type I. Furthermore, in both matrigel invasion and FITC‐labeled fibronectin assays, we have seen migration and cleavage of COS‐7 cells transfected with wildtype ADAM8 compared to an inactive mutant. Cancer cell lines with upregulated ADAM8 expression, such as human osteosarcoma (HOS), degrade collagen type I. We conclude that ADAM8 degrades ECM molecules, both in vitro and in vivo , enabling cancer cell invasion. Thus, ADAM8 may be a potential target for therapeutic intervention in metastatic cancer.