We propose that ADAM9 coordinates plasminogen activator-based network for ESCC progression through two major functions of ADAM9: protease activity for increasing tPA expression/activity and nuclear translocation of ADAM9 for suppressing PAI-1 and PGK1 expression (PAI-1 for reducing plasmin and PGK1 for increasing angiostatin), two inhibitory factors involved in plasminogen activator-mediated angiogenesis. Here, SERPINE1 is linked to esophageal squamous cell carcinoma.