Abstract
Advanced gastric cancer is one of the most aggressive gastrointestinal malignancies, and ADAM (A disintegrin and metalloproteinase)-9 is a cell-surface membrane glycoprotein with oncogenic properties that is overexpressed in several cancers. Herein, we investigated the biologic mechanism of ADAM9 in the progression, proliferation, and invasion of gastric cancer. First, we detected ADAM's expression, processing, and protease activity in gastric cancer cells. Protease activity was moderately correlated with ADAM9 protein expression, but was better related to a processed smaller molecular weight (84 kDa) form of ADAM9. Knockdown of ADAM9 or specifically targeted monoclonal antibody (RAV-18) suppressed cancer cell proliferation and invasion in high ADAM9-expressing cells, not in low ADAM9-expressing cells. RAV-18 showed in vivo antitumor activity in a gastric cancer xenograft model. Hypoxia (1% oxygen) induced ADAM9 expression and functional activity in low ADAM9-expressing gastric cancer cells that was inhibited by siRNA knockdown or RAV-18 antibody to levels in normoxic cells. Overall, our studies show that ADAM9 plays an important role in gastric cancer proliferation and invasion, and that while expressed in some gastric cancer cells at high levels that are responsive to functional inhibition and antitumor activity of a catalytic site-directed antibody, other gastric cancer cells have low levels of expression and only when exposed to hypoxia do ADAM9 levels increase and the cells become responsive to ADAM9 antibody inhibition. Therefore, our findings suggest that ADAM9 could be an effective therapeutic target for advanced gastric cancer.