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AOP: 298
Title
Increase in reactive oxygen species (ROS) leading to human treatment-resistant gastric cancer via chronic ROS
Short name
Graphical Representation
Point of Contact
Contributors
- Shihori Tanabe
Coaches
- Edward Perkins
OECD Information Table
OECD Project # | OECD Status | Reviewer's Reports | Journal-format Article | OECD iLibrary Published Version |
---|---|---|---|---|
1.58 | Under Review |
This AOP was last modified on June 12, 2025 02:06
Revision dates for related pages
Page | Revision Date/Time |
---|---|
Treatment-resistant gastric cancer | June 12, 2025 01:33 |
Chronic reactive oxygen species | June 12, 2025 02:03 |
Increase, porcupine-induced Wnt secretion and Wnt signaling activation | June 04, 2025 02:36 |
beta-catenin activation | November 25, 2022 01:14 |
Epithelial Mesenchymal Transition | April 24, 2024 00:44 |
Increase, Reactive oxygen species | June 12, 2025 01:27 |
Increase, ROS leads to Increase, porcupine-induced Wnt secretion and Wnt signaling activation | March 14, 2025 16:54 |
Chronic ROS leads to Increase, porcupine-induced Wnt secretion and Wnt signaling activation | June 12, 2025 02:09 |
Increase, porcupine-induced Wnt secretion and Wnt signaling activation leads to beta-catenin activation | November 09, 2021 01:23 |
beta-catenin activation leads to EMT | April 23, 2024 17:35 |
EMT leads to Resistant gastric cancer | April 23, 2024 17:37 |
Wnt | May 29, 2019 03:59 |
WNT2 | May 29, 2019 03:59 |
Porcupine | January 19, 2020 21:19 |
Wntless | January 19, 2020 21:20 |
Ionizing Radiation | May 07, 2019 12:12 |
ferric nitrilotriacetate | May 27, 2020 02:40 |
Abstract
This AOP entitled “Increase in reactive oxygen species (ROS) leading to human treatment-resistant gastric cancer via chronic ROS” consists of MIE as KE1115 “Increase, ROS” followed by KE1 as KE1753 “Chronic ROS,” KE2 as KE1754 “porcupine-induced Wnt secretion and Wnt signaling activation,” KE3 as KE1755 “beta-catenin activation,” KE4 as KE1457 “epithelial-mesenchymal transition (EMT),” and AO as KE1651 “human treatment-resistant gastric cancer.” ROS has multiple roles in disease, such as the development and progression of cancer or apoptotic induction, causing anti-tumor effects. In this AOP, we focus on sustained levels of chronic reactive oxygen species (ROS) in inducing therapy resistance in human gastric cancer. Epithelial-mesenchymal transition (EMT), a cellular phenotypic change from epithelial to mesenchymal-like features, demonstrates cancer stem cell-like characteristics in human gastric cancer. EMT is induced by Wnt/beta-catenin signaling, providing the rationale to have Wnt secretion and beta-catenin activation as KE1 and KE2 on the AOP, respectively. The AOP might be useful for the development of anti-cancer drugs or the prediction of adverse effects of therapeutics, which are possible regulatory relevance.
AOP Development Strategy
Context
Strategy
The references related to reactive oxygen species and human treatment-resistant gastric cancer were serched in PubMed.
Gene expression analysis was performed in diffuse- and intestinal-type gastric cancer to elucidate mechanisms of epithelial-mesenchymal transition in human treatment-resistant gastric cancer.
Summary of the AOP
Events:
Molecular Initiating Events (MIE)
Key Events (KE)
Adverse Outcomes (AO)
Type | Event ID | Title | Short name |
---|
MIE | 1115 | Increase, Reactive oxygen species | Increase, ROS |
MIE | 1753 | Chronic reactive oxygen species | Chronic ROS |
KE | 1754 | Increase, porcupine-induced Wnt secretion and Wnt signaling activation | Increase, porcupine-induced Wnt secretion and Wnt signaling activation |
KE | 1755 | beta-catenin activation | beta-catenin activation |
KE | 1457 | Epithelial Mesenchymal Transition | EMT |
AO | 1651 | Treatment-resistant gastric cancer | Resistant gastric cancer |
Relationships Between Two Key Events (Including MIEs and AOs)
Title | Adjacency | Evidence | Quantitative Understanding |
---|
Increase, ROS leads to Increase, porcupine-induced Wnt secretion and Wnt signaling activation | adjacent | Moderate | Moderate |
Chronic ROS leads to Increase, porcupine-induced Wnt secretion and Wnt signaling activation | adjacent | Moderate | Moderate |
Increase, porcupine-induced Wnt secretion and Wnt signaling activation leads to beta-catenin activation | adjacent | Moderate | Moderate |
beta-catenin activation leads to EMT | adjacent | Moderate | Moderate |
EMT leads to Resistant gastric cancer | adjacent | Moderate | Moderate |
Network View
Prototypical Stressors
Life Stage Applicability
Life stage | Evidence |
---|---|
All life stages | High |
Taxonomic Applicability
Term | Scientific Term | Evidence | Link |
---|---|---|---|
Homo sapiens | Homo sapiens | High | NCBI |
Sex Applicability
Sex | Evidence |
---|---|
Unspecific | High |
Overall Assessment of the AOP
1. Support for Biological Plausibility of KERs |
|
MIE1 => KE1: Increase, ROS lead to porcupine-induced Wnt secretion and Wnt signaling activation |
Biological Plausibility of the MIE1 => KE1 is moderate. Rationale: Increase in ROS caused by/causes DNA damage, which will alter several signaling pathways, including Wnt signaling. ROS stimulate inflammatory factor production and Wnt/beta-catenin signaling (Vallée & Lecarpentier, 2018). |
MIE2 => KE1: Chronic ROS leads to porcupine-induced Wnt secretion and Wnt signaling activation |
Biological Plausibility of the MIE2 => KE1 is moderate. Rationale: Sustained ROS increase caused by/causes DNA damage, which will alter several signaling pathways, including Wnt signaling. Macrophages accumulate into injured tissue to recover the tissue damage, which may be followed by porcupine-induced Wnt secretion. ROS stimulate inflammatory factor production and Wnt/beta-catenin signaling (Vallée & Lecarpentier, 2018). |
KE1 => KE2: Porcupine-induced Wnt secretion and Wnt signaling activation leads to beta-catenin activation |
Biological Plausibility of the KE1 => KE2 is moderate. Rationale: Secreted Wnt ligand stimulates Wnt/beta-catenin signaling, in which beta-catenin is activated. Wnt ligand binds to the Frizzled receptor, which leads to GSK3beta inactivation. GSK3beta inactivation leads to beta-catenin dephosphorylation, which avoids the ubiquitination of the b-catenin and stabilizes the beta-catenin (Clevers & Nusse, 2012). |
KE2 => KE3: beta-catenin activation leads to Epithelial-mesenchymal transition (EMT) |
Biological Plausibility of the KE2 => KE3 is moderate. Rationale: beta-catenin activation, whose mechanism includes the stabilization of the dephosphorylated beta-catenin and translocation of b-catenin into the nucleus, induces the formation of beta-catenin-TCF complex and transcription of transcription factors such as Snail, Zeb and Twist (Clevers & Nusse, 2012) (Ahmad et al., 2012; Pearlman et al., 2017; Sohn et al., 2019; Yang W et al., 2019). EMT-related transcription factors, including Snail, ZEB, and Twist, are up-regulated in cancer cells (Diaz et al., 2014). The transcription factors such as Snail, ZEB, and Twist bind to the E-cadherin (CDH1) promoter and inhibit the CDH1 transcription via the consensus E-boxes (5’-CACCTG-3’ or 5’-CAGGTG-3’), which leads to EMT (Diaz et al., 2014). |
KE3 => AO: Epithelial-mesenchymal transition (EMT) leads to treatment-resistant gastric cancer |
Biological Plausibility of the KE3 => AO is moderate. Rationale: Some populations of the cells exhibiting EMT demonstrate the feature of cancer stem cells (CSCs), which are related to cancer malignancy (Shibue & Weinberg, 2017; Tanabe, 2015a, 2015b; Tanabe et al., 2015). The EMT phenomenon is related to cancer metastasis and cancer therapy resistance (Smith & Bhowmick, 2016; Tanabe, 2013). In EMT, increased expression of enzymes that degrade the extracellular matrix components and a decrease in adhesion to the basement membrane induce cell escape from the basement membrane and metastasis (Smith & Bhowmick, 2016). Morphological changes observed during EMT are associated with therapy resistance (Smith & Bhowmick, 2016). |
2. Support for essentiality of KEs |
|
KE1: Porcupine-induced Wnt secretion and Wnt signaling activation |
Essentiality of the KE1 is moderate. Rationale for Essentiality of KEs in the AOP: The Wnt signaling activation is essential for the subsequent beta-catenin activation and cancer resistance. |
KE2: beta-catenin activation |
Essentiality of the KE2 is moderate. Rationale for Essentiality of KEs in the AOP: beta-catenin activation is essential for Wnt-induced cancer resistance. |
KE3: Epithelial-mesenchymal transition (EMT) |
Essentiality of the KE3 is moderate. Rationale for the Essentiality of KEs in the AOP: EMT is essential for promoting Wnt-induced cancer and acquiring resistance to anti-cancer drugs. |
3. Empirical support for KERs |
|
MIE1 => KE1: Increase, ROS lead to porcupine-induced Wnt secretion and Wnt signaling activation |
Empirical Support of the MIE1 => KE1 is moderate. Rationale: The production of ROS by DNA double-strand break causes tissue damage (Gao et al., 2019). ROS-related signaling induces Wnt/beta-catenin pathway activation (Pérez et al., 2017). |
MIE2 => KE1: Chronic ROS leads to porcupine-induced Wnt secretion and Wnt signaling activation |
Empirical Support of the MIE2 => KE1 is moderate. Rationale: The production of ROS and DNA double-strand break causes tissue damage (Gao et al., 2019). ROS signaling induces Wnt/beta-catenin signaling (Pérez et al., 2017). |
KE1 => KE2: Porcupine-induced Wnt secretion and Wnt signaling activation leads to beta-catenin activation |
Empirical Support of the KE1 => KE2 is moderate. Rationale: Dishevelled (DVL), a positive regulator of Wnt signaling, forms the complex with FZD and leads to trigger the Wnt signaling together with Wnt coreceptor low-density lipoprotein (LDL) receptor-related protein 6 (LRP6) (Clevers & Nusse, 2012; Jiang et al., 2015). Wnt binds to FZD and activates the Wnt signaling (Clevers & Nusse, 2012; Janda et al., 2012; Nile et al., 2017). Wnt binding towards FZD induces the formation of the protein complex with LRP5/6 and DVL, leading to the downstream signaling activation including beta-catenin (Clevers & Nusse, 2012). |
KE2 => KE3: beta-catenin activation leads to Epithelial-mesenchymal transition (EMT) |
Empirical Support of the KE2 => KE3 is moderate. Rationale: The inhibition of c-MET, which is overexpressed in diffuse-type gastric cancer, induced an increase in phosphorylated beta-catenin and a decrease in beta-catenin and Snail (Sohn et al., 2019). The garcinol, which has an anti-cancer effect, increases phosphorylated beta-catenin, decreases beta-catenin and ZEB1/ZEB2, and inhibits EMT (Ahmad et al., 2012). The inhibition of sortilin by AF38469 (a sortilin inhibitor) or small interference RNA (siRNA) results in a decrease in beta-catenin and Twist expression in human glioblastoma cells (Yang W. et al., 2019). Histone deacetylase inhibitors affect EMT-related transcription factors, including ZEB, Twist, and Snail (Wawruszak et al., 2019). Snail and Zeb induce EMT and suppress E-cadherin (CDH1) (Batlle et al., 2000; Diaz et al., 2014; Peinado et al., 2007). |
KE3 => AO: Epithelial-mesenchymal transition (EMT) leads to Treatment-resistant gastric cancer |
Empirical Support of the KE3 => AO is moderate. Rationale: EMT activation induces the expression of multiple members of the ATP-binding cassette (ABC) transporter family, which results in doxorubicin resistance (Saxena et al., 2011; Shibue & Weinberg, 2017). TGFbeta-1-induced EMT results in acquiring cancer stem cell (CSC)-like properties (Pirozzi et al., 2011; Shibue & Weinberg, 2017). Snail-induced EMT induces cancer metastasis and resistance to dendritic cell-mediated immunotherapy (Kudo-Saito et al., 2009). Zinc finger E-box-binding homeobox (ZEB1)-induced EMT results in relief of miR-200-mediated repression of programmed cell death 1 ligand (PD-L1) expression, a major inhibitory ligand for the programmed cell death protein (PD-1) immune-checkpoint protein on CD8+ cytotoxic T lymphocyte (CTL), subsequently the CD8+ T cell immunosuppression and metastasis (Chen et al., 2014). |
Domain of Applicability
The AOP298 applies to Homo sapiens (human), all life stages, and both male and female.
Essentiality of the Key Events
Sustained ROS contributes to the initiation and development of human gastric cancer (Gu H. 2018).
Wnt signaling is involved in cancer malignancy (Tanabe, 2018).
Upon stimulation with Wnt ligand to the Frizzled receptor, Wnt/beta-catenin signaling is activated. Wnt/beta-catenin consists of GSK3 beta inactivation, beta-catenin activation, and up-regulation of transcription factors such as Zeb, Twist, and Snail. The transcription factors Zeb, Twist and Snail relate to the activation of EMT-related genes. EMT is regulated with various gene networks (Tanabe, 2015c).
Evidence Assessment
The Wnt signaling promotes EMT and cancer malignancy in colorectal cancer (Lazarova & Bordonaro, 2017). Although the potential pathways other than Wnt signaling exist in EMT induction and the mechanism underlaid cancer malignancy, Wnt signaling is one of the main pathways to induce EMT and cancer malignancy (Polakis, 2012).
Known Modulating Factors
Modulating Factor (MF) | Influence or Outcome | KER(s) involved |
---|---|---|
Quantitative Understanding
Wnt signaling activates the CSCs to promote cancer malignancy (Reya & Clevers, 2005). The responses in KEs related to Wnt signaling, Frizzled activation, GSK3beta inactivation, beta-catenin activation, Snail, Zeb, and Twist activation are dose-dependently related. The quantification of EMT and cancer malignancy would require further investigation.
Considerations for Potential Applications of the AOP (optional)
AOP entitled “Increase in reactive oxygen species (ROS) and chronic ROS leading to human treatment-resistant gastric cancer” might be utilized for the development and risk assessment of anti-cancer drugs. EMT is involved in the acquisition of drug resistance, which is one of the critical features of cancer malignancy. The assessment of the activity of the EMT network would serve as a prediction of the adverse effects of or responsiveness to anti-cancer drugs (Tanabe et al., 2023). The detection methods for increases in ROS in this AOP have future regulatory potentials to assess the human health effects of radiation or ROS-related diseases. The detection methods for human treatment-resistant gastric cancer have future regulatory potentials to diagnose the diseases.
References
Kudo-Saito, C., Shirako, H., Takeuchi, T., & Kawakami, Y. (2009). Cancer Metastasis Is Accelerated through Immunosuppression during Snail-Induced EMT of Cancer Cells. Cancer Cell, 15(3), 195-206. doi: 10.1016/j.ccr.2009.01.023
Nile, A. H., Mukund, S., Stanger, K., Wang, W., & Hannoush, R. N. (2017). Unsaturated fatty acyl recognition by Frizzled receptors mediates dimerization upon Wnt ligand binding. Proc Natl Acad Sci U S A, 114(16), 4147-4152. doi:10.1073/pnas.1618293114
Tanabe S, Quader S, Ono R, Cabral H, Aoyagi K, Hirose A, Perkins EJ, Yokozaki H, Sasaki H. (2023). Regulation of Epithelial–Mesenchymal Transition Pathway and Artificial Intelligence-Based Modeling for Pathway Activity Prediction. Onco, 3(1):13-25. doi: 10.3390/onco3010002