Aop: 298

AOP Title


Chronic reactive oxygen species leading to human treatment-resistant gastric cancer

Short name:


Chronic ROS leading to human treatment-resistant gastric cancer

Graphical Representation


Click to download graphical representation template




Shihori Tanabe1), Sabina Quader2), Ryuichi Ono3), Horacio Cabral4), Kazuhiko Aoyagi5), Akihiko Hirose1), Hiroshi Yokozaki6), Hiroki Sasaki7)

1Division of Risk Assessment, Center for Biological Safety and Research, National Institute of Health Sciences, Japan

2Innovation Centre of NanoMedicine (iCONM), Kawasaki Institute of Industrial Promotion, Japan

3Division of Cellular and Molecular Toxicology, Center for Biological Safety and Research, National Institute of Health Sciences, Japan

4Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, Japan

5Department of Clinical Genomics, National Cancer Center Research Institute, Japan

6Department of Pathology, Kobe University of Graduate School of Medicine, Japan

7Department of Translational Oncology, National Cancer Center Research Institute, Japan

Point of Contact


Shihori Tanabe   (email point of contact)



  • Shihori Tanabe



Author status OECD status OECD project SAAOP status
Under Development: Contributions and Comments Welcome Under Development 1.58 Included in OECD Work Plan

This AOP was last modified on October 13, 2020 05:35


Revision dates for related pages

Page Revision Date/Time
Epithelial-mesenchymal transition March 23, 2020 04:18
Treatment-resistant gastric cancer May 07, 2020 04:04
Chronic reactive oxygen species September 29, 2020 21:21
Sustained tissue damage / macrophage activation/ porcupine-induced Wnt secretion September 29, 2020 21:20
Proliferation/ beta-catenin activation September 29, 2020 21:25
Chronic ROS leads to Sustained tissue damage / macrophage activation/ porcupine-induced Wnt secretion September 29, 2020 22:05
Sustained tissue damage / macrophage activation/ porcupine-induced Wnt secretion leads to Proliferation/ beta-catenin activation September 29, 2020 21:32
Proliferation/ beta-catenin activation leads to Epithelial-mesenchymal transition September 29, 2020 21:42
Epithelial-mesenchymal transition leads to Resistant gastric cancer September 29, 2020 21:44
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



The injury or sustained reactive oxygen species (ROS) causes resistance in human gastric cancer. This AOP entitled “Chronic reactive oxygen species leading to human treatment-resistant gastric cancer” consists of MIE as sustained ROS, followed by KE1 as sustained tissue damage / macrophage activation / porcupine-induced Wnt secretion, KE2 as proliferation / beta-catenin activation, KE3 as epithelial-mesenchymal transition (EMT), and AO as human treatment-resistant gastric cancer. ROS has multiple roles such as development and progression of cancer, or apoptotic induction causing anti-tumor effects. In this AOP, we focus on the role of chronic ROS with sustained level to induce the therapy-resistance in human gastric cancer. EMT, which is cellular phenotypic change from epithelial to mesenchymal-like feature, demonstrates cancer stem cell-like characteristics in human gastric cancer. EMT is induced by Wnt/beta-catenin signaling, which confers rationale to have Wnt secretion and beta-catenin activation as KE1 and KE2 on the AOP, respectively.

Background (optional)


Summary of the AOP


Events: Molecular Initiating Events (MIE)


Key Events (KE)


Adverse Outcomes (AO)


Sequence Type Event ID Title Short name
1 MIE 1753 Chronic reactive oxygen species Chronic ROS
2 KE 1754 Sustained tissue damage / macrophage activation/ porcupine-induced Wnt secretion Sustained tissue damage / macrophage activation/ porcupine-induced Wnt secretion
3 KE 1755 Proliferation/ beta-catenin activation Proliferation/ beta-catenin activation
4 KE 1650 Epithelial-mesenchymal transition Epithelial-mesenchymal transition
5 AO 1651 Treatment-resistant gastric cancer Resistant gastric cancer

Relationships Between Two Key Events
(Including MIEs and AOs)


Title Adjacency Evidence Quantitative Understanding
Chronic ROS leads to Sustained tissue damage / macrophage activation/ porcupine-induced Wnt secretion adjacent Moderate Moderate
Sustained tissue damage / macrophage activation/ porcupine-induced Wnt secretion leads to Proliferation/ beta-catenin activation adjacent High Moderate
Proliferation/ beta-catenin activation leads to Epithelial-mesenchymal transition adjacent Moderate Moderate
Epithelial-mesenchymal transition leads to Resistant gastric cancer adjacent High Moderate

Network View





Name Evidence Term
Wnt High
WNT2 High
Porcupine Moderate
Wntless Moderate
Ionizing Radiation Moderate
ferric nitrilotriacetate Not Specified

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


Attached file: Aop298 overall assessment 5 8 20

1. Support for Biological Plausibility of KER

MIE => KE1:
Chronic ROS leads to Sustained tissue damage / macrophage activation / porcupine-induced Wnt secretion

Biological Plausibility of the MIE => 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:
Sustained tissue damage / macrophage activation / porcupine-induced Wnt secretion leads to Proliferation / beta-catenin activation

Biological Plausibility of the KE1 => KE2 is high.
Rationale: Secreted Wnt ligand stimulates Wnt/beta-catenin signaling, in which beta-catenin is activated. Wnt ligand binds to Frizzled receptor, which leads to GSK3beta inactivation. GSK3beta inactivation leads to beta-catenin dephosphorylation, which avoids the ubiquitination of the beta-catenin and stabilize the beta-catenin (Clevers & Nusse, 2012).

KE2 => KE3:
Proliferation / beta-catenin activation leads to Epithelial-mesenchymal transition (EMT)

Biological Plausibility of the KE2 => KE3 is moderate.
Rationale: Beta-catenin activation, of which mechanism include the stabilization of the dephosphorylated beta-catenin and translocation of beta-catenin into the nucleus, induce 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, Montes de Oca, Pal, & Afaq, 2017; Sohn et al., 2019; W. Yang et al., 2019).

EMT-related transcription factors including Snail, ZEB and Twist are up-regulated in cancer cells (Diaz, Vinas-Castells, & Garcia de Herreros, 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 human treatment-resistant gastric cancer

Biological Plausibility of the KE3 => AO is high.
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; Shihori Tanabe, 2015a, 2015b; Tanabe, Aoyagi, Yokozaki, & Sasaki, 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: Sustained tissue damage / macrophage activation/ porcupine-induced Wnt secretion

Essentiality of the KE1 is moderate.
Rationale for Essentiality of KEs in the AOP: The sustained tissue damage, macrophage activation and Wnt are essential for the subsequent beta-catenin activation and cancer resistance.

KE2: Proliferation / beta-catenin activation

Essentiality of the KE2 is moderate.
Rationale for Essentiality of KEs in the AOP: Proliferation and beta-catenin activation are 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 resistance to anti-cancer drug.

3. Empirical support for KERs

MIE => KE1:
Chronic ROS leads to Sustained tissue damage / macrophage activation / porcupine-induced Wnt secretion

Empirical Support of the MIE => KE1 is moderate.
Rationale: Production of ROS by DNA double-strand break causes the tissue damages (Gao et al., 2019).

ROS signaling induces Wnt/beta-catenin signaling (Pérez et al., 2017).

KE1 => KE2:
Sustained tissue damage / macrophage activation / porcupine-induced Wnt secretion leads to Proliferation / beta-catenin activation

Empirical Support of the KE1 => KE2 is high.
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, Waghray, Levin, Thomas, & Garcia, 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:
Proliferation / 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 beta-catenin, decrease in beta-catenin and Snail (Sohn et al., 2019).

The garcinol, that has anti-cancer effect, increases phosphorylated beta-catenin, decreases beta-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 beta-catenin and Twist expression in human glioblastoma cells (W. Yang et al., 2019).

Histone deacetylase inhibitors affect 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, Olmeda, & Cano, 2007).

KE3 => AO:
Epithelial-mesenchymal transition (EMT) leads to human 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 the resistant to doxorubicin (Saxena, Stephens, Pathak, & Rangarajan, 2011; Shibue & Weinberg, 2017) 

TGFbeta-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 the 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).

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 of EMT would be the potential prediction of the adverse effects of anti-cancer drugs.



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