# Adverse Outcome Pathway 298: Increase in Reactive Oxygen Species Leading to Human Treatment-Resistant Gastric Cancer

## TL;DR

This paper describes a biological pathway showing how increased reactive oxygen species can lead to treatment-resistant gastric cancer through specific signaling events.

## Contribution

The paper introduces AOP 298, a novel adverse outcome pathway linking ROS to treatment-resistant gastric cancer via Wnt/beta-catenin and EMT.

## Key findings

- Sustained ROS levels trigger Wnt/beta-catenin signaling and EMT in gastric cancer.
- EMT induced by Wnt signaling leads to treatment-resistant cancer with stem cell-like traits.
- AOP 298 outlines four key event relationships connecting ROS to therapy resistance.

## Abstract

This research aims to elucidate a pathway starting with increases in reactive oxygen species (ROS) and leading to human treatment-resistant gastric cancer through Wnt/beta-catenin signaling and epithelial–mesenchymal transition (EMT). The main topic in this article is Adverse Outcome Pathway (AOP) 298, entitled “increase in reactive oxygen species (ROS) leading to human treatment-resistant gastric cancer.” It consists of a molecular initiating event (MIE), “increase in ROS”; three key events (KEs), namely “porcupine-induced Wnt secretion and Wnt signaling activation,” “beta-catenin activation,” and “epithelial–mesenchymal transition (EMT)”; and an adverse outcome (AO), “treatment-resistant gastric cancer,” illustrating a mechanism of human treatment-resistant gastric cancer induced by drugs, therapy, or radiation.

Injury causes resistance in human gastric cancer. Adverse Outcome Pathway (AOP) 298, entitled “increase in reactive oxygen species (ROS) leading to human treatment-resistant gastric cancer,” consists of “increase in ROS” as a molecular initiating event (MIE), followed by a series of key events (KEs), namely “porcupine-induced Wnt secretion and Wnt signaling activation,” “beta-catenin activation,” and “epithelial–mesenchymal transition (EMT),” and the adverse outcome (AO) of “treatment-resistant gastric cancer” in the sequence. AOP 298 includes four KE relationships (KERs): “increase in ROS leads to porcupine-induced Wnt secretion and Wnt signaling activation,” “porcupine-induced Wnt secretion and Wnt signaling activation leads to beta-catenin activation,” “beta-catenin activation leads to EMT,” and “EMT leads to treatment-resistant gastric cancer.” ROS has multiple roles in disease, such as in the development and progression of cancer, or apoptotic induction, causing anti-tumor effects. Regarding AOP 298, we focus on the role of sustained chronic ROS levels in inducing therapy resistance in human gastric cancer. EMT, induced by Wnt/beta-catenin signaling, demonstrates cancer stem cell-like characteristics in human gastric cancer.