Anti-ADAM9 (C-terminal) polyclonal antibody

Tumor cell migration is mediated by cell-autonomous signaling mechanisms as well as paracrine and autocrine factors secreted by activated stromal cells in the tumor microenvironment. Like other members of the ADAM (a disintegrin and metalloproteinase) family, the integrin-binding metalloproteinase ADAM9 modulates cell-cell and cell-matrix interactions as well as ectodomain shedding of cell surface receptors and ligands, thereby modifying intracellular and extracellular signaling. ADAM9 transcripts are alternatively spliced to express a transmembrane protein (ADAM9-L) and a secreted variant (ADAM9-S). In this study, we show that ADAM9-S promotes breast cancer cell migration in a manner requiring its metalloproteinase activity, whereas ADAM9-L suppresses cell migration independent of its metalloproteinase activity. Suppression of migration by ADAM9-L requires a functional disintegrin domain and integrin binding. Expression analysis revealed that both ADAM9 isoforms are expressed in breast cancer cell lines and tissues. Therefore, relative levels of membrane-tethered and secreted variants of ADAM9 are a key determinant in manifestation of aggressive migratory phenotypes associated with breast cancer progression. Cancer Res; 70(20); 8187-98. (C) 2010 AACR.

Epithelial-to-mesenchymal transition (EMT) is associated with tumor metastasis and tumorigenesis in lung cancer stem-like cells (CSCs). However, the exact mechanism underlying this is not clear. We used microarray analysis to identify candidate genes responsible for EMT in spheroid and monolayer cultures of lung cancer cells. We found increased expression of a variety of adhesion molecules in CSCs. One of these molecules, Collagen XVII (Col XVII), was demonstrated to be required for maintenance of EMT phenotypes and metastasis ability in lung CSCs. We showed that Col XVII stabilized laminin-5 to activate the FAK/AKT/GSK3 ss pathway, thereby suppressing Snail ubiquitination-degradation. The function of Col XVII was mainly dependent on shedding by ADAM9 and ADAM10. Patients who underwent surgical resection for lung cancer, and displayed overexpression of both Col XVII and laminin-5, had the worst prognosis of all expression types. Moreover, blockage of the Col XVII/laminin-5 pathway reduced the EMT phenotypes of lung CSCs in vitro and decreased the potential of lung metastasis in vivo. Our findings suggested that targeting Col XVII and laminin-5 could be novel therapeutic strategies for treating lung cancer patients, and warrant further investigation.