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AOP: 298
Title
Increases in cellular reactive oxygen species and chronic reactive oxygen species leading to human treatment-resistant gastric cancer
Short name
Graphical Representation
Point of Contact
Contributors
- Shihori Tanabe
- Agnes Aggy
Coaches
Status
Handbook Version | OECD status | OECD project |
---|---|---|
v2.0 | EAGMST Under Review | 1.58 |
This AOP was last modified on April 29, 2023 13:02
Revision dates for related pages
Page | Revision Date/Time |
---|---|
Epithelial-mesenchymal transition | November 25, 2022 01:18 |
Treatment-resistant gastric cancer | October 13, 2022 02:18 |
Chronic reactive oxygen species | November 09, 2021 00:35 |
Porcupine-induced Wnt secretion and Wnt signaling activation | November 25, 2022 01:11 |
beta-catenin activation | November 25, 2022 01:14 |
Increases in cellular reactive oxygen species | May 10, 2022 21:44 |
Increases in cellular ROS leads to Porcupine-induced Wnt secretion and Wnt signaling activation | April 27, 2022 01:24 |
Chronic ROS leads to Porcupine-induced Wnt secretion and Wnt signaling activation | May 13, 2021 02:22 |
Porcupine-induced Wnt secretion and Wnt signaling activation leads to beta-catenin activation | November 09, 2021 01:23 |
beta-catenin activation leads to Epithelial-mesenchymal transition | November 09, 2021 01:58 |
Epithelial-mesenchymal transition leads to Resistant gastric cancer | May 13, 2021 03:08 |
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
The injury causes resistance in human gastric cancer. This AOP entitled “Increases in cellular reactive oxygen species (ROS) and chronic ROS leading to human treatment-resistant gastric cancer” consists of MIE as KE1940 “Increases in cellular ROS” and KE1753 “Chronic ROS”, followed by KE1 as KE1754 “porcupine-induced Wnt secretion and Wnt signaling activation”, KE2 as KE1755 “beta-catenin activation”, KE3 as KE1650 “EMT”, and AO as KE1651 “human treatment-resistant GC”. ROS has multiple roles in disease such as development and progression of cancer, or apoptotic induction causing anti-tumor effects. In this AOP, we focus on the role of sustained levels of chronic ROS to induce the therapy-resistance in human gastric cancer. EMT, which is 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.
AOP Development Strategy
Context
Strategy
Summary of the AOP
Events:
Molecular Initiating Events (MIE)
Key Events (KE)
Adverse Outcomes (AO)
Type | Event ID | Title | Short name |
---|
MIE | 1940 | Increases in cellular reactive oxygen species | Increases in cellular ROS |
MIE | 1753 | Chronic reactive oxygen species | Chronic ROS |
KE | 1754 | Porcupine-induced Wnt secretion and Wnt signaling activation | Porcupine-induced Wnt secretion and Wnt signaling activation |
KE | 1755 | beta-catenin activation | beta-catenin activation |
KE | 1650 | Epithelial-mesenchymal transition | Epithelial-mesenchymal transition |
AO | 1651 | Treatment-resistant gastric cancer | Resistant gastric cancer |
Relationships Between Two Key Events (Including MIEs and AOs)
Title | Adjacency | Evidence | Quantitative Understanding |
---|
Increases in cellular ROS leads to Porcupine-induced Wnt secretion and Wnt signaling activation | adjacent | Moderate | Moderate |
Chronic ROS leads to Porcupine-induced Wnt secretion and Wnt signaling activation | adjacent | Moderate | Moderate |
Porcupine-induced Wnt secretion and Wnt signaling activation leads to beta-catenin activation | adjacent | Moderate | Moderate |
beta-catenin activation leads to Epithelial-mesenchymal transition | adjacent | Moderate | Moderate |
Epithelial-mesenchymal transition 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: Increases in cellular ROS leads to porcupine-induced Wnt secretion and Wnt signaling activation |
Biological Plausibility of the MIE1 => KE1 is moderate. Rationale: Increases in cellular ROS caused by/causes DNA damage, which will alter several signaling pathways including Wnt signaling. ROS stimulate inflammatory factor production and Wnt/b-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/b-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/b-catenin signaling, in which b-catenin is activated. Wnt ligand binds to Frizzled receptor, which leads to GSK3b inactivation. GSK3b inactivation leads to b-catenin dephosphorylation, which avoids the ubiquitination of the b-catenin and stabilize the b-catenin (Clevers & Nusse, 2012). |
KE2 => KE3: beta-catenin activation leads to Epithelial-mesenchymal transition (EMT) |
Biological Plausibility of the KE2 => KE3 is moderate. Rationale: b-catenin activation, of which mechanism include the stabilization of the dephosphorylated b -catenin and translocation of b-catenin into the nucleus, induce the formation of b-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 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 population of the cells exhibiting EMT demonstrates the feature of cancer stem cells (CSCs), which are related to cancer malignancy (Shibue & Weinberg, 2017; Tanabe, 2015a, 2015b; Tanabe et al., 2015). EMT phenomenon is related to cancer metastasis and cancer therapy resistance (Smith & Bhowmick, 2016; Tanabe, 2013). Increase expression of enzymes that degrade the extracellular matrix components and the decrease in adhesion to the basement membrane in EMT induce the cell escape from the basement membrane and metastasis (Smith & Bhowmick, 2016). Morphological changes observed during EMT is 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 b-catenin activation and cancer resistance. |
KE2: beta-catenin activation |
Essentiality of the KE2 is moderate. Rationale for Essentiality of KEs in the AOP: b-catenin activation is essential for the Wnt-induced cancer resistance. |
KE3: Epithelial-mesenchymal transition (EMT) |
Essentiality of the KE3 is moderate. Rationale for Essentiality of KEs in the AOP: EMT is essential for the Wnt-induced cancer promotion and acquisition of resistance to anti-cancer drug. |
3. Empirical support for KERs |
|
MIE1 => KE1: Increases in cellular ROS leads to porcupine-induced Wnt secretion and Wnt signaling activation |
Empirical Support of the MIE1 => KE1 is moderate. Rationale: Production of ROS by DNA double-strand break causes the tissue damages (Gao et al., 2019). ROS signaling induces Wnt/b-catenin signaling (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: Production of ROS by DNA double-strand break causes the tissue damages (Gao et al., 2019). ROS signaling induces Wnt/b-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, form the complex with FZD and lead 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 activate the Wnt signaling (Clevers & Nusse, 2012; Janda et al., 2012; Nile et al., 2017). Wnt binding towards FZD induce the formation of the protein complex with LRP5/6 and DVL, leading to the down-stream 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 increase in phosphorylated b-catenin, decrease in b-catenin and Snail (Sohn et al., 2019). The garcinol, that has anti-cancer effect, increases phosphorylated beta-catenin, decreases b-catenin and ZEB1/ZEB2, and inhibit EMT (Ahmad et al., 2012). The inhibition of sortilin by AF38469 (a sortilin inhibitor) or small interference RNA (siRNA) results in decrease in b-catenin and Twist expression in human glioblastoma cells (Yang W. et al., 2019). Histone deacetylase inhibitors effect on EMT-related transcription factors including ZEB, Twist and Snail (Wawruszak et al., 2019). Snail and Zeb induces 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). TGFb-1 induced EMT results in the acquisition of cancer stem cell (CSC) like properties (Pirozzi et al., 2011; Shibue & Weinberg, 2017). Snail-induced EMT induces the 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
Homo sapiens
Essentiality of the Key Events
Sustained ROS contributes into 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 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, Twist activation are dose-dependently related. The quantification of EMT and cancer malignancy would require the further investigation.
Considerations for Potential Applications of the AOP (optional)
AOP entitled “Chronic reactive oxygen species 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 on activity of EMT network would serve as prediction of the adverse effects of, or responsiveness to anti-cancer drugs (Tanabe et al., 2023).
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:https://doi.org/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. https://doi.org/10.3390/onco3010002