Abstract
Epithelial-mesenchymal transition (EMT) and cancer stem cells (CSCs) are involved in drug resistance in cancer, and share some molecular characteristics. EMT, which is cellular phenotypic change from epithelial to mesenchymal-like feature, demonstrates CSC-like characteristics in human gastric cancer (GC). To reveal the molecular networks responsible for cancer malignancy and responsiveness to therapeutics, gene expression and molecular networks in diffuse-type GC, which is resistant to anti-cancer drugs, and in intestinal-type GC were analyzed with Ingenuity Pathway Analysis (IPA). The injury or sustained reactive oxygen species (ROS) causes resistance in human GC. ROS has multiple roles such as development and progression of cancer, or apoptotic induction causing anti-tumor effects. Adverse Outcome Pathway (AOP) 298 “Increases in cellular ROS and chronic ROS leading to human treatment-resistant GC” has been developed in OECD AOP project. This AOP298 consists of Molecular Initiating Event (MIE) as KE1940 “Increases in cellular ROS” and KE1753 “Chronic ROS”, followed by Key Event (KE) 1 as KE1754 “porcupine-induced Wnt secretion and Wnt signaling activation”, KE2 as KE1755 “beta-catenin activation”, KE3 as KE1650 “EMT”, and Adverse Outcome (AO) as KE1651 “human treatment-resistant GC”. AOP298 includes Wnt secretion and beta-catenin activation as KE1 and KE2, respectively, since EMT is induced by Wnt/beta-catenin signaling. We focus on the role of chronic ROS with sustained level to induce the therapy-resistance in human GC in the AOP.
